Each ml of solution contains 50 micrograms palonosetron (as hydrochloride). Each vial of 5 ml of solution contains 250 micrograms palonosetron (as hydrochloride). For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Posology and method of administration

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

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

The safety and efficacy in children have not been established. Currently available data are described in section 5.1 and section 5.2, but no recommendation on posology can be made.

No dose adjustment is necessary for patients with impaired renal function. No data are available for patients with end stage renal disease undergoing haemodialysis.

Contraindications

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

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. Aloxi 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'.

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.

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

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.

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).

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

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

Fertility, pregnancy and lactation

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.

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

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.

Undesirable effects

In clinical studies at a dose of 250 micrograms (total 633 patients) the most frequently observed adverse reactions, at least possibly related to Aloxi, were headache (9 %) and constipation (5 %). In the clinical studies the following adverse reactions (ARs) were observed as possibly or probably related to Aloxi. 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 ARs ( >= 1/100 to<1/10)	Uncommon ARs ( >= 1/1,000 to <1/100)	Very rare ARsdeg (<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

deg From post-marketing experience

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

Overdose

No case of overdose has been reported. Doses of up to 6 mg have been used in 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 Aloxi, 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 Aloxi overdose.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5HT3) antagonists. ATC code: A04AA05 Palonosetron is a selective high-affinity receptor antagonist of the 5HT3 receptor. In two randomised, double-blind studies with a total of 1,132 patients receiving moderately emetogenic chemotherapy that included cisplatin <=50 mg/m2, carboplatin, cyclophosphamide <=1,500 mg/m2 and doxorubicin >25 mg/m2, palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mg (half-life 4 hours) or dolasetron 100 mg (half-life 7.3 hours) administered intravenously on Day 1, without dexamethasone. In a randomised, double-blind study with a total of 667 patients receiving highly emetogenic chemotherapy that included cisplatin >= 60 mg/m2, cyclophosphamide > 1,500 mg/m2 and dacarbazine, palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mg administered intravenously on Day 1. Dexamethasone was administered prophylactically before chemotherapy in 67 % of patients. The pivotal studies were not designed to assess efficacy of palonosetron in delayed onset nausea and vomiting. The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours. Results for the studies on moderately emetogenic chemotherapy and for the study on highly emetogenic chemotherapy are summarised in the following tables. Palonosetron was non-inferior versus the comparators in the acute phase of emesis both in moderately and highly emetogenic setting. Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in controlled clinical studies, 875 patients enrolled in the three phase 3 trials continued in an open label safety study and were treated with palonosetron 750 micrograms for up to 9 additional cycles of chemotherapy. The overall safety was maintained during all cycles.

Table 1: Percentage of patients a responding by treatment group and phase in the Moderately Emetogenic Chemotherapy study versus ondansetron

Table 2: Percentage of patients a responding by treatment group and phase in the Moderately Emetogenic Chemotherapy study versus dolasetron

Table 3: Percentage of patients a responding by treatment group and phase in the Highly Emetogenic Chemotherapy study versus ondansetron

The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in CINV clinical studies. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarisation and to prolong action potential duration. The effect of palonosetron on QTc interval was evaluated in a double blind, randomised, parallel, placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of IV administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in 221 healthy subjects. The study demonstrated no effect on QT/QTc interval duration as well as any other ECG interval at doses up to 2.25 mg. No clinically significant changes were shown on heart rate, atrioventricular (AV) conduction and cardiac repolarisation.

The safety and efficacy of Palonosetron i.v at single doses of 3ug/kg and 10ug/kg was investigated in a clinical study in 72 patients in the following age groups, >28 days to 23 months (12 patients), 2 to 11 years (31 patients), and 12 to 17 years of age (29 patients), receiving highly or moderately emetogenic chemotherapy. No safety concerns were raised at either dose level. The primary efficacy variable was the proportion of patients with a complete response (CR, defined as no emetic episode and no rescue medication) during the first 24 hours after the start of chemotherapy administration. Efficacy after palonosetron 10 ug/kg compared to palonosetron 3ug/kg was 54.1% and 37.1% respectively. Pharmacokinetic information is provided in section 5.2.

The safety and efficacy of Palonosetron i.v at single doses of 1ug/kg and 3ug/kg was compared in a clinical study in 150 patients in the following age groups, >28 days to 23 months (7 patients), 2 to 11 years (96 patients), and 12 to 16 years of age (47 patients) undergoing elective surgery. No safety concerns were raised in either treatment group. The proportion of patients without emesis during 0-72 hours post-operatively was similar after palonosetron 1 ug/kg or 3 ug/kg (88% vs 84%). Please see section 4.2 for information on paediatric use.

Pharmacokinetic properties

Following intravenous administration, an initial decline in plasma concentrations is followed by slow elimination from the body with a mean terminal elimination half-life of approximately 40 hours. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-[?]) are generally dose-proportional over the dose range of 0.3-90 mg/kg in healthy subjects and in cancer patients. Following intravenous administration of palonosetron 0.25 mg once every other day for 3 doses in 11 testicular cancer patients, the mean (+- SD) increase in plasma concentration from Day 1 to Day 5 was 42 +- 34 %. After intravenous administration of palonosetron 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (+- SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110 +- 45 %. Pharmacokinetic simulations indicate that the overall exposure (AUC0-[?]) of 0.25 mg intravenous palonosetron administered once daily for 3 consecutive days was similar to a single intravenous dose of 0.75 mg, although Cmax of the 0.75 mg single dose was higher.

Palonosetron at the recommended dose is widely distributed in the body with a volume of distribution of approximately 6.9 to 7.9 l/kg. Approximately 62 % of palonosetron is bound to plasma proteins.

Palonosetron is eliminated by dual route, about 40 % eliminated through the kidney and with approximately 50 % metabolised to form two primary metabolites, which have less than 1 % of the 5HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have shown that 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.

After a single intravenous dose of 10 micrograms/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 patients have a mean terminal elimination half-life greater than 100 hours.

Age does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary in elderly patients.

Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary based on gender.

Across all age groups, (>28 days to 23 months (11 patients), 2 to 11 years (30 patients), and 12 to 17 years of age (29 patients)) of CINV paediatric patients, exposure to palonosetron was generally dose proportional for the 3mg/kg and 10mg/kg dose levels. Both clearance and volume of distribution appear to increase with increasing age largely due to the expected increase in body weight among the age groups. Mean terminal elimination half-life values ranged from 21-37 hours and did not change with dose or age. There was no effect of gender on clearance, volume of distribution or half-life. Please see section 4.2 for information on paediatric use.

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Severe renal impairment reduces renal clearance, however total body clearance in these patients is similar to healthy subjects. No dosage adjustment is necessary in patients with renal insufficiency. No pharmacokinetic data in haemodialysis patients are available.

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the 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 warrant dose reduction.

Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ion channels involved in ventricular de- and re-polarisation and prolong action potential duration. 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 4.6). Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 30 times the human therapeutic exposure) applied daily for two years caused an increased rate of liver tumours, endocrine neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but not in mice. The underlying mechanisms are not fully understood, but because of the high doses employed and since Aloxi is intended for single application in humans, these findings are not considered relevant for clinical use.

PHARMACEUTICAL PARTICULARS

List of excipients

Mannitol Disodium edetate Sodium citrate Citric acid monohydrate Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for injections

Incompatibilities

Shelf life

5 years. Upon opening of the vial, use immediately and discard any unused solution.

Special precautions for storage

Nature and contents of container

Type I glass vial with chlorobutyl siliconised rubber stopper and aluminium cap. Available in packs of 1 vial containing 5 ml of solution.

Special precautions for disposal

Single use only, any unused solution should be discarded. Any unused product or waste material should be disposed of in accordance with local requirements.

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 March 2005 Date of latest renewal: 23 March 2010

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Aloxi 250 micrograms (n= 189)		Ondansetron 32 milligrams (n= 185)	Delta
	%	%	%
Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b
0 - 24 hours	81.0	68.6	12.4	[1.8 %, 22.8 %]
24 - 120 hours	74.1	55.1	19.0	[7.5 %, 30.3 %]
0 - 120 hours	69.3	50.3	19.0	[7.4 %, 30.7 %]
Complete Control (Complete Response and No More Than Mild Nausea) p-value c
0 - 24 hours	76.2	65.4	10.8	NS
24 - 120 hours	66.7	50.3	16.4	0.001
0 - 120 hours	63.0	44.9	18.1	0.001
No Nausea (Likert Scale) p-value c
0 - 24 hours	60.3	56.8	3.5	NS
24 - 120 hours	51.9	39.5	12.4	NS
0 - 120 hours	45.0	36.2	8.8	NS

Aloxi 250 micrograms (n= 185)		Dolasetron 100 milligrams (n= 191)	Delta
	%	%	%
Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b
0 - 24 hours	63.0	52.9	10.1	[-1.7 %, 21.9 %]
24 - 120 hours	54.0	38.7	15.3	[3.4 %, 27.1 %]
0 - 120 hours	46.0	34.0	12.0	[0.3 %, 23.7 %]
Complete Control (Complete Response and No More Than Mild Nausea) p-value c
0 - 24 hours	57.1	47.6	9.5	NS
24 - 120 hours	48.1	36.1	12.0	0.018
0 - 120 hours	41.8	30.9	10.9	0.027
No Nausea (Likert Scale) p-value c
0 - 24 hours	48.7	41.4	7.3	NS
24 - 120 hours	41.8	26.2	15.6	0.001
0 - 120 hours	33.9	22.5	11.4	0.014

Aloxi 250 micrograms (n= 223)		Ondansetron 32 milligrams (n= 221)	Delta
	%	%	%
Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b
0 - 24 hours	59.2	57.0	2.2	[-8.8 %, 13.1 %]
24 - 120 hours	45.3	38.9	6.4	[-4.6 %, 17.3 %]
0 - 120 hours	40.8	33.0	7.8	[-2.9 %, 18.5 %]
Complete Control (Complete Response and No More Than Mild Nausea) p-value c
0 - 24 hours	56.5	51.6	4.9	NS
24 - 120 hours	40.8	35.3	5.5	NS
0 - 120 hours	37.7	29.0	8.7	NS
No Nausea (Likert Scale) p-value c
0 - 24 hours	53.8	49.3	4.5	NS
24 - 120 hours	35.4	32.1	3.3	NS
0 - 120 hours	33.6	32.1	1.5	NS

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION