4.1. Therapeutic indications

Palonosetron is indicated in adults for:

- the prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy;

- the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

Palonosetron is indicated in paediatric patients 1 month of age and older for:

- the prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy and prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

4.2. Posology and method of administration

Palonosetron should be used only before chemotherapy administration. This medicinal product should be administered by a healthcare professional under appropriate medical supervision.

Posology

Adults

250 micrograms palonosetron administered as a single intravenous bolus approximately 30 minutes before the start of chemotherapy. Palonosetron should be injected over 30 seconds.

The efficacy of Palonosetron 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.

Elderly

No dose adjustment is necessary for the elderly.

Paediatric population

Children and adolescents (aged 1 month to 17 years):

20 micrograms/kg (the maximum total dose should not exceed 1500 micrograms) palonosetron administered as a single 15 minute intravenous infusion beginning approximately 30 minutes before the start of chemotherapy.

The safety and efficacy of palonosetron in children aged less than 1 month have not been established. No data are available. There are limited data on the use of palonosetron in the prevention of nausea and vomiting in children under 2 years of age.

Hepatic impairment

No dose adjustment is necessary for patients with impaired hepatic function.

Renal impairment

No dose adjustment is necessary for patients with impaired renal function.

No data are available for patients with end stage renal disease undergoing haemodialysis.

Method of administration

For intravenous use.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

As palonosetron may increase large bowel transit time, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored following administration. Two cases of constipation with faecal impaction requiring hospitalisation have been reported in association with palonosetron 750 micrograms.

At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QTc interval. A specific thorough QT/QTc study was conducted in healthy volunteers for definitive data demonstrating the effect of palonosetron on QT/QTc (see section 5.1).

However, as for other 5-HT3 antagonists, caution should be exercised in the use of palonosetron 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, electrolyte abnormalities, congestive heart failure, bradyarrhythmias, conduction disturbances and in patients taking anti-arrhythmic agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and hypomagnesemia should be corrected prior to 5-HT3-antagonist administration.

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone or in combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.

Palonosetron should not be used to prevent or treat nausea and vomiting in the days following chemotherapy if not associated with another chemotherapy administration.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2 isoenzymes. Based on in vitro studies, palonosetron does not inhibit or induce cytochrome P450 isoenzyme at clinically relevant concentrations.

Chemotherapeutic agents

In preclinical studies, palonosetron did not inhibit the antitumour activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C).

Metoclopramide

In a clinical study, no significant pharmacokinetic interaction was shown between a single intravenous dose of palonosetron and steady state concentration of oral metoclopramide, which is a CYP2D6 inhibitor.

CYP2D6 inducers and inhibitors

In a population pharmacokinetic analysis, it has been shown that there was no significant effect on palonosetron clearance when co-administered with CYP2D6 inducers (dexamethasone and rifampicin) and inhibitors (including amiodarone, celecoxib, chlorpromazine, cimetidine, doxorubicin, fluoxetine, haloperidol, paroxetine, quinidine, ranitidine, ritonavir, sertraline or terbinafine).

Corticosteroids

Palonosetron has been administered safely with corticosteroids.

Serotonergic drugs (e.g. SSRIs and SNRIs)

There have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and other serotonergic drugs (including SSRIs and SNRIs).

Other medicinal products

Palonosetron has been administered safely with analgesics, antiemetic/antinauseants, antispasmodics and anticholinergic medicinal products.

4.6. Fertility, pregnancy and lactation

Pregnancy

For palonosetron no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Only limited data from animal studies are available regarding the placental transfer (see section 5.3).

There is no experience of palonosetron in human pregnancy. Therefore, palonosetron should not be used in pregnant women unless it is considered essential by the physician.

Breast-feeding

As there are no data concerning palonosetron excretion in breast milk, breast-feeding should be discontinued during therapy.

Fertility

There are no data concerning the effect of palonosetron on fertility.

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.

Since palonosetron may induce dizziness, somnolence or fatigue, patients should be cautioned when driving or operating machines.

4.8. Undesirable effects

In clinical studies in adults at a dose of 250 micrograms (total 633 patients) the most frequently observed adverse reactions, at least possibly related to palonosetron were headache (9 %) and constipation (5 %).

In the clinical studies the following adverse reactions were observed as possibly or probably related to palonosetron.

These were classified as common (≥1/100 to <1/10) or uncommon (≥1/1,000 to <1/100).

Very rare (<1/10,000) adverse reactions were reported post-marketing.

Within each frequency grouping, adverse reactions are presented below in order of decreasing seriousness.

System organ class

Common

(≥ 1/100 to <1/10)

Uncommon

(≥ 1/1,000 to <1/100)

Very rare° (<1/10,000)

Immune system disorders

Hypersensitivity, anaphylaxis, anaphylactic/ anaphylactoid reactions and shock

Metabolism and nutrition disorders

Hyperkalaemia, metabolic disorders, hypocalcaemia, hypokalaemia, anorexia, hyperglycaemia, appetite decreased

Psychiatric disorders

Anxiety, euphoric mood

Nervous system disorders

Headache Dizziness

Somnolence, insomnia, paraesthesia, hypersomnia, peripheral sensory neuropathy

Eye disorders

Eye irritation, amblyopia

Ear and labyrinth disorders

Motion sickness, tinnitus

Cardiac disorders

Tachycardia, bradycardia, extrasystoles, myocardial ischaemia, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles

Vascular disorders

Hypotension, hypertension, vein discolouration, vein distended

Respiratory, thoracic and mediastinal disorders

Hiccups

Gastrointestinal disorders

Constipation

Diarrhoea

Dyspepsia, abdominal pain, abdominal pain upper, dry mouth, flatulence

Hepatobiliary disorders

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Dermatitis allergic, pruritic rash

Musculoskeletal and connective tissue disorders

Arthralgia

Renal and urinary disorders

Urinary retention, glycosuria

General disorders and administration site conditions

Asthenia, pyrexia, fatigue, feeling hot, influenza like illness

Injection site reaction*

Investigations

Elevated transaminases-, electrocardiogram QT prolonged

° From post-marketing experience

* Includes the following: burning, induration, discomfort and pain

Paediatric population

In paediatric clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 402 patients received a single dose of palonosetron (3, 10 or 20 mcg/kg). The following common or uncommon adverse reactions were reported for palonosetron, none were reported at a frequency of >1%.

System organ class

Common

(≥ 1/100 to<1/10)

Uncommon

(≥ 1/1,000 to <1/100)

Nervous system disorders

Headache

Dizziness, dyskinesia

Cardiac disorders

Electrocardiogram QT prolonged conduction disorder, sinus tachycardia

Respiratory, thoracic and mediastinal disorders

Cough, dyspnoea, epistaxis

Skin and subcutaneous tissue disorders

Dermatitis allergic, pruritus, skin disorder, urticaria

General disorders and administration site conditions

Pyrexia, infusion site pain, infusion site reaction, pain

Adverse reactions were evaluated in paediatric patients receiving palonosetron for up to 4 chemotherapy cycles.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.

4.9. Overdose

No case of overdose has been reported.

Doses of up to 6 mg have been used in adult clinical studies. The highest dose group showed a similar incidence of adverse reactions compared to the other dose groups and no dose response effects were observed. In the unlikely event of overdose with Palonosetron, this should be managed with supportive care. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose.

Paediatric population

No case of overdose has been reported in paediatric clinical studies.