Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
PROFESSIONAL INFORMATION FOR HETNOSET  
SCHEDULING STATUS:  
S4  
1
2
NAME OF THE MEDICINE  
HETNOSET, Solution for Injection.  
QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each ml of solution contains 0,05 mg palonosetron (as hydrochloride).  
Each 5 ml vial contains 0,25 mg palonosetron (as hydrochloride).  
Contains sugar: Each ml contains 41,5 mg mannitol.  
For full list of excipients, see section 6.1.  
3
PHARMACEUTICAL FORM  
Solution for Injection (Injection)  
A clear, colourless solution.  
4
CLINICAL PARTICULARS  
4.1  
Therapeutic indications  
HETNOSET is indicated for the prevention of acute nausea and vomiting associated  
with moderately and highly emetogenic cancer chemotherapy.  
4.2  
Posology and method of administration  
Posology:  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
Adults:  
0,25 mg (5 mL) HETNOSET administered as a single intravenous bolus  
approximately 30 minutes before the start of chemotherapy.  
HETNOSET should be administered over 30 seconds.  
Repeated dosing of HETNOSET within a seven-day interval is not recommended.  
The efficacy of HETNOSET in the prevention of nausea and vomiting induced by  
highly emetogenic chemotherapy may be enhanced by the addition of a corticosteroid  
administered prior to chemotherapy.  
Special populations:  
Elderly patients:  
No dosage adjustment is necessary for elderly patients.  
Renal impairment:  
No dosage adjustment is necessary for patients with renal impairment. No data is  
available for patients with end-stage renal disease undergoing haemodialysis.  
Hepatic impairment:  
No dosage adjustment is necessary for patients with hepatic impairment.  
Paediatric population:  
Use in patients under 18 years of age is not recommended.  
Method of administration:  
For intravenous use.  
Single use only, any unused solution should be discarded.  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
4.3  
Contraindications  
Hypersensitivity to palonosetron or to any of the excipients of HETNOSET. (see  
Section 6.1).  
4.4  
Special warnings and precautions for use  
Constipation:  
HETNOSET may increase large bowel transit time. Patients with a history of  
constipation or signs of sub-acute intestinal obstruction should be monitored after  
administration of HETNOSET. Two cases of constipation with faecal impaction  
requiring hospitalisation have been reported in association with 750 µg of  
palonosetron.  
QT interval:  
HETNOSET does not induce clinically relevant prolongation of the QTc interval.  
Caution is advised with concomitant use of HETNOSET with other medicines that  
increase the QT interval or in patients who have or are likely to develop prolongation  
of the QT interval. These conditions include patients with a personal or family history  
of  
QT  
prolongation,  
and  
electrolyte  
abnormalities,  
congestive  
and in  
heart  
failure,  
taking  
bradydysrhythmias,  
conduction disturbances  
patients  
antidysrhythmic medicines or other medicines that lead to QT prolongation or  
electrolyte abnormalities. Hypokalaemia and hypomagnesemia should be corrected  
prior to 5-HT3-antagonist administration.  
Serotonin syndrome:  
There have been reports of serotonin syndrome with the use of 5-HT3 antagonists,  
either alone or in combination with serotonergic medicines including selective  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors  
(SNRIs) (see Section 4.5). Patients should be observed for serotonin syndrome-like  
symptoms.  
Paediatric population:  
No information available.  
Excipient information  
HETNOSET contains less than 1 mmol sodium (23 mg) per vial, i.e essentially  
“sodium free”.  
4.5  
Interaction with other medicines and other forms of interaction  
Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4  
and CYP1A2 isoenzymes.  
Palonosetron does not inhibit or induce cytochrome P450 isoenzymes at clinically  
relevant concentrations (see Section 5.2, Biotransformation).  
Chemotherapeutic medicines:  
Palonosetron does not inhibit the anti-tumour activity of cisplatin, cyclophosphamide,  
cytarabine, doxorubicin and mitomycin C.  
Metoclopramide:  
There is no significant pharmacokinetic interaction between a single intravenous  
dose of palonosetron and steady state concentration of oral metoclopramide, which  
is a CYP2D6 inhibitor.  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
CYP2D6 inducers and inhibitors:  
Concomitant use of palonosetron and CYP2D6 inducers (dexamethasone and  
rifampicin) and inhibitors (including amiodarone, celecoxib, chlorpromazine,  
cimetidine, doxorubicin, fluoxetine, haloperidol, paroxetine, quinidine, ranitidine,  
ritonavir, sertraline or terbinafine) does not have a significant effect on the clearance  
of palonosetron.  
Corticosteroids:  
Palonosetron as in HETNOSET has been administered safely with corticosteroids.  
Serotonergic medicines:  
Serotonin syndrome can develop with the use of HETNOSET, either alone or in  
combination with serotonergic medicines such as selective serotonin reuptake  
inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs).  
Other medicines:  
HETNOSET has been administered safely with analgesics, anti-emetics, anti-  
nauseants, antispasmodics and anti-cholinergic medicines.  
Additional information on special populations:  
No information available.  
Paediatric population:  
No information available.  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
4.6  
Fertility, pregnancy, and lactation  
Women of childbearing potential / Contraception in males and females:  
The safety and efficacy of HETNOSET have not been established during pregnancy  
and lactation.  
Pregnancy:  
HETNOSET should not be used during pregnancy.  
Breastfeeding:  
Since there is no data concerning excretion of palonosetron in breast milk,  
HETNOSET should not be used during breastfeeding.  
Fertility:  
No information available.  
4.7  
Effects on ability to drive and use machines  
HETNOSET may cause side effects, such as dizziness and somnolence and can  
affect the ability to drive a vehicle and use machines (see Section 4.8). Caution is  
advised before driving a vehicle or operating machinery until the effects of  
HETNOSET are known.  
4.8  
Undesirable effects  
Summary of the safety profile:  
In clinical studies at a dose of 250 micrograms (total 633 patients) the most frequently  
observed adverse reactions, at least possibly related to palonosetron, were  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
headache and constipation.  
Side effects have been documented below in frequency (i.e. less, more and  
unknown).  
Tabulated summary of adverse reactions:  
Side effects  
Frequent  
Less frequent  
Frequency  
Unknown  
Immune system ---  
---  
Hypersensitivity  
reactions, including  
anaphylaxis.  
---  
disorders  
Metabolism and ---  
nutrition  
Hyperkalaemia,  
metabolic  
disorders,  
disorders  
hypocalcaemia,  
anorexia,  
hyperglycaemia,  
hypokalaemia,  
decreased appetite  
Psychiatric  
disorders  
---  
Anxiety,  
euphoric ---  
mood  
Nervous system Headache,  
Somnolence,  
insomnia,  
paraesthesia,  
hypersomnia,  
peripheral  
---  
disorders  
dizziness  
sensory  
neuropathy, seizures,  
dystonia, dyskinesia,  
oculogyric crisis.  
Eye disorders  
---  
---  
Eye  
irritation, ---  
amblyopia,  
vision,  
blurred  
transient  
blindness  
Motion  
tinnitus  
Ear  
and ---  
sickness, ---  
---  
labyrinth  
disorders  
Cardiac  
disorders  
Tachycardia,  
bradycardia,  
extrasystoles,  
myocardial ischaemia,  
sinus  
sinus  
tachycardia,  
dysrhythmia,  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
supraventricular  
extrasystoles,  
chest  
torsades de  
pain,  
pointes.  
Vascular  
disorders  
---  
Hypotension,  
hypertension,  
discolouration,  
distended vein.  
---  
vein  
Gastrointestinal  
disorders  
Constipation,  
diarrhoea  
Dyspepsia, abdominal ---  
pain, upper abdominal  
pain,  
dry  
mouth,  
flatulence, hiccups.  
Hepato-biliary  
disorders  
---  
Hyper- bilirubinaemia  
---  
Skin  
and ---  
Allergic  
dermatitis, ---  
subcutaneous  
tissue disorders  
pruritic rash, urticaria  
Musculoskeletal, ---  
connective  
Arthralgia  
---  
tissue and bone  
disorders  
Renal  
and ---  
Urinary  
retention, ---  
pyrexia, ---  
urinary  
glycosuria  
disorders  
General  
disorders  
---  
Asthenia,  
fatigue,  
and  
feeling  
hot,  
administration  
site conditions  
Investigations  
influenza-like illness.  
---  
Elevated  
---  
---  
transaminases,  
electrocardiogram QT  
interval prolongation.  
Injury,  
Injection  
site ---  
poisoning,  
procedural  
and reaction  
(burning,  
complications  
induration,  
discomfort,  
and pain).  
Description of selected adverse reactions:  
No information available  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
Paediatric population:  
No information available  
Other special population(s):  
No information available  
Reporting of suspected adverse reactions  
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  
“Adverse drug reaction and quality problem reporting form”, found online under  
SAHPRA’s  
reactions-and-quality-problemreporting-form/ or  
registration through the mail: pvg.cdma@heterogroups.com.  
publications:  
https://www.sahpra.org.za/document/adverse-drug-  
to the Holder of certificate of  
4.9  
Overdose  
No case of overdose has been reported. Doses of up to 6 mg have been used in  
clinical trials. The highest dose group showed a similar incidence of adverse events  
compared to the other dose groups and no dose response effects were observed.  
In the unlikely event of overdose with HETNOSET, the treatment should be  
symptomatic and supportive. Dialysis studies have not been performed, however,  
due to the large volume of distribution, dialysis is unlikely to be effective in the  
treatment of HETNOSET overdose.  
Additional information on special populations:  
No information available  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
Paediatric population:  
No information available  
5
PHARMACOLOGICAL PROPERTIES  
5.1  
Pharmacodynamic properties  
Pharmacological classification: A. 5.10 Serotonin antagonists.  
Pharmacotherapeutic group: Antiemetics and anti-nauseant, serotonin (5-HT3)  
antagonists. ATC code: A04AAOS  
Palonosetron is a potent and selective serotonin subtype 3 (5-HT3) receptor  
antagonist with a strong binding affinity for this receptor – both in vitro and in vivo.  
Palonosetron has little or no affinity for other bioreceptors, including other  
serotonergic receptors (5-HT1, 5-HT2 and 5-HT4). The major human metabolites, M9  
and M4, have only marginal clinically non-relevant activity.  
Paediatric population:  
No information available  
5.2  
Pharmacokinetic properties  
Absorption:  
An initial decline in plasma concentrations is followed by slow elimination from the  
body with a mean terminal elimination half-life of approximately 2 days (40 hours),  
after intravenous administration. Mean maximum plasma concentration (Cmax) and  
area under the concentration-time curve (AUC0-∞) are generally dose-proportional  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
over the dose range of 0,3 – 90 μg/kg in healthy subjects and in cancer patients.  
Distribution:  
Approximately 62 % of palonosetron is bound to plasma proteins. Palonosetron is  
widely distributed in the body with a volume of distribution of approximately 6,9 to 7,9  
L/kg, at the recommended dose.  
Biotransformation:  
Palonosetron is eliminated by dual route; about 40 % eliminated through the kidney  
and with approximately 50 % metabolised to form two primary metabolites, M9 and  
M4, which have less than 1 % of the 5-HT3 receptor antagonist activity of  
palonosetron.  
In vitro, CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes are  
involved in the metabolism of palonosetron. However, clinical pharmacokinetic  
parameters are not significantly different between poor and extensive metabolisers  
of CYP2D6 substrates. Palonosetron does not inhibit or induce cytochrome P450  
isoenzymes at clinically relevant concentrations.  
Elimination:  
After a single intravenous dose of 10 µg/kg [14C]-palonosetron, approximately 80 %  
of the dose was recovered within 144 hours in the urine with palonosetron  
representing approximately 40 % of the administered dose, as unchanged active  
substance.  
After a single intravenous bolus administration in healthy subjects the total body  
clearance of palonosetron was 173 ± 73 mL/min and renal clearance was 53 ± 29  
mL/min. The low total body clearance and large volume of distribution resulted in a  
terminal elimination half-life in plasma of approximately 40 hours. Ten percent of  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
patients have a mean terminal elimination half-life greater than 100 hours.  
Linearity/non-linearity:  
No information available  
Characteristics in specific groups of subjects or patients:  
Elderly patients:  
Age does not affect the pharmacokinetics of palonosetron. No dosage adjustment is  
necessary in elderly patients.  
Gender:  
Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment  
is necessary based on gender.  
Renal impairment:  
Mild to moderate renal impairment does not significantly affect the pharmacokinetics  
of palonosetron. Severe renal impairment reduces renal clearance, however, total  
body clearance in these patients are similar to healthy subjects. No dosage  
adjustment is necessary in patients with renal insufficiency. No pharmacokinetic data  
in haemodialysis patients are available.  
Hepatic impairment:  
Hepatic impairment does not significantly affect total body clearance of palonosetron  
compared to healthy subjects. While the terminal elimination half-life and mean  
systemic exposure of palonosetron is increased in the subjects with severe hepatic  
impairment, this does not justify dose reduction.  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
Paediatric population  
No pharmacokinetic data are available in patients under 18 years of age.  
5.3  
Preclinical safety data  
Environmental Risk Assessment (ERA)  
No information available  
6
PHARMACEUTICAL PARTICULARS  
6.1  
List of excipients  
Citric acid monohydrate,  
Disodium edetate,  
Mannitol,  
Sodium citrate dihydrate,  
Sodium hydroxide,  
Hydrochloric acid,  
Water for injection.  
Contains sugar (each ml contains 41,5 mg mannitol).  
6.2  
Incompatibilities  
No information available.  
6.3  
Shelf life  
24 months  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
6.4  
Special precautions for storage  
Store at or below 25 ºC.  
Keep the vials in the outer carton until required for use.  
KEEP OUT OF REACH OF CHILDREN.  
6.5  
Nature and contents of container  
5 ml clear, tubular glass vial (USP Type I) with a grey bromobutyl rubber stopper with  
2 rings at the centre embossed on the top and a violet colour PP plastic button and  
aluminium flip off seal, packed in an outer carton.  
Pack size: 1 vial, 5 vials, and 10 vials per carton.  
Not all pack sizes may be marketed  
6.6  
Special precautions for disposal <and other handling>  
Discard any unused solution.  
7
HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus,  
Building No. 2, First floor,  
74 Waterfall Drive,  
Midrand,  
2066.  
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Applicant: Hetero Drugs South Africa (Pty) Ltd.  
Proprietary name: HETNOSET  
Module:  
1.3.1.1  
Dosage form and Strength: Injection 0,25 mg/ml  
8
REGISTRATION NUMBER(S)  
54/5.10/0291.289.  
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
04 June 2024.  
10  
DATE OF REVISION OF THE TEXT  
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