Aloxi 500 micrograms soft capsules

Each capsule contains 500 micrograms palonosetron (as hydrochloride).

Excipient(s):

Each capsule contains 14.21 milligrams sorbitol.

For a full list of excipients, see section 6.1.

Soft capsule.

Light beige, opaque, oval, soft gelatine capsules, imprinted with black logo “AlO”, filled with a clear yellowish solution.

Aloxi is indicated for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults.

Aloxi should be used only before chemotherapy administration.

Posology

Adults

500 micrograms palonosetron administered orally approximately one hour before the start of chemotherapy.

Elderly population

No dose adjustment is necessary for the elderly.

Paediatric population

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.

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 oral use.

Aloxi can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients.

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 QT corrected (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 concomitant use of palonosetron with medicinal products that increase the QT interval or in patients who have or are likely to develop prolongation of the QT interval.

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

Aloxi contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product. Aloxi capsules may also contain a trace of lecithin derived from soya. Therefore, patients with known hypersensitivity to peanut or soya, should be monitored closely for signs of an allergic reaction.

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 medicinal products

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.

Other medicinal products

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

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 so 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.

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

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.

In clinical studies at a dose of 500 micrograms (total 161 patients) the most frequently observed adverse reaction, at least possibly related to Aloxi, was headache (3.7 %).

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).

In post marketing very rare cases (<1/10,000) of hypersensitivity reactions occurred with palonosetron solution for injection for intravenous use.

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 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.

Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT₃) antagonists, ATC code: A04AA05

Palonosetron is a selective high-affinity receptor antagonist of the 5HT₃ receptor.

In a multicentre, randomised, double-blind active control clinical trial of 635 patients set to receive moderately emetogenic cancer chemotherapy. A single-dose of 250 mcg, 500 mcg, or 750 mcg oral palonosetron capsules given one hour prior to moderately emetogenic chemotherapy was compared to a single-dose of 250 mcg intravenous Aloxi given 30 minutes prior to chemotherapy. Patients were randomised to either dexamethasone or placebo in addition to their assigned treatment. The majority of patients in the study were women (73 %), white (69 %), and naïve to previous chemotherapy (59 %). The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours. Efficacy was based on demonstrating non-inferiority of oral palonosetron doses compared to the approved intravenous formulation. Non-inferiority criteria were met if the lower bound of the two-sided 98.3 % confidence interval for the difference in complete response rates of oral palonosetron dose minus approved intravenous formulation was larger than -15 %. The non-inferiority margin was 15 %.

As shown in Table 1, oral Aloxi capsules 500 micrograms demonstrated non-inferiority to the active comparator during the 0 to 24 hour and 0 to 120 hour time intervals; however, for the 24 to 120 hour time period, non-inferiority was not shown.

Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in controlled clinical trials, 217 patients were enrolled in a multicentre, open label safety study and were treated with palonosetron capsules 750 micrograms for up to 4 cycles of chemotherapy in a total of 654 chemotherapy cycles. Approximately 74 % of patients also received single dose oral or intravenous dexamethasone 30 minutes before chemotherapy. Complete Response was not formally evaluated for the repeat cycle application. However, in general the antiemetic effect for the 0-24 hour interval was similar throughout the consecutively repeated cycles and the overall safety was maintained during all cycles.

Table 1: Proportion of patients^a responding by treatment group and phase

^a Intent-to-treat cohort

^b The study was designed to show non-inferiority. A lower bound greater that -15 % demonstrates non-inferiority between Aloxi oral and comparator Aloxi intravenous

^c Chi-square test. Significance levels at alpha 0.0167 (adjusted for multiple comparisons).

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 repolarization.

Paediatric population

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV):

The safety and efficacy of Palonosetron i.v at single doses of 3µg/kg and 10µg/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 µg/kg compared to palonosetron 3µg/kg was 54.1% and 37.1% respectively. Pharmacokinetic information is provided in section 5.2.

Prevention of Post Operative Nausea and Vomiting (PONV):

The safety and efficacy of Palonosetron i.v at single doses of 1µg/kg and 3µg/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 µg/kg or 3 µg/kg (88% vs 84%).

Please see section 4.2 for information on paediatric use.

Absorption

Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97 %. After single oral doses using buffered solution mean maximum palonosetron concentrations (C_max) and area under the concentration-time curve (AUC0-) were dose proportional over the dose range of 3.0 to 80 µg/kg in healthy subjects.

In 36 healthy male and female subjects given a single oral dose of palonosetron capsules 500 micrograms, maximum plasma palonosetron concentration (C_max) was 0.81 ± 0.17 ng/ml (mean ± SD) and time to maximum concentration (Tmax) was 5.1 ± 1.7 hours. In female subjects (n=18), the mean AUC was 35 % higher and the mean C_max was 26 % higher than in male subjects (n=18).

In 12 cancer patients given a single oral dose of palonosetron capsules 500 micrograms one hour prior to chemotherapy, C_max was 0.93 ± 0.34 ng/ml and Tmax was 5.1 ± 5.9 hours. The AUC was 30 % higher in cancer patients than in healthy subjects.

A high fat meal did not affect the C_max and AUC of oral palonosetron. Therefore, Aloxi capsules may be taken without regard to meals.

Distribution

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.

Biotransformation

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.

Elimination

Following administration of a single oral 750 micrograms dose of [¹⁴C]-palonosetron to six healthy subjects, 85 % to 93 % of the total radioactivity was excreted in urine, and 5 % to 8 % was eliminated in feces. The amount of unchanged palonosetron excreted in the urine represented approximately 40 % of the administered dose. In healthy subjects given palonosetron capsules 500 micrograms, the terminal elimination half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients, t½ was 48 ± 19 hours. After a single-dose of approximately 0.75 mg intravenous palonosetron, the total body clearance of palonosetron in healthy subjects was 160 ± 35 ml/h/kg (mean ± SD) and renal clearance was 66.5 ± 18.2 ml/h/kg.

Pharmacokinetics in special populations

Elderly

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

Gender

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

Paediatric patients

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 3μg/kg and 10μg/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.

Renal impairment

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 dose 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 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.

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 15 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.

Capsule content:

Mono/diglycerides of caprylic/capric acid

Polyglycerol oleate

Glycerol

Purified water

Butylhydroxyanisole (BHA)

Capsule shell:

Gelatin

Sorbitol (E420)

Glycerol

Titanium dioxide (E171)

Printing Ink:

Iron oxide black (E172)

Polyvinyl acetate phthalate

Macrogol 400

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Polyamide/aluminium/PVC blister containing one or five soft capsules.

Not all pack sizes may be marketed.

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

Helsinn Birex Pharmaceuticals Limited.

Damastown

Mulhuddart

Dublin 15

Ireland

EU/1/04/306/002

EU/1/04/306/003

22 March 2005/23 March 2010

February 2012

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