ALOXI 500mcg capsule me medication leaflet

Aloxi 500 micrograms soft capsules

Each capsule contains 500 micrograms palonosetron (as hydrochloride).

Excipient(s):

Each capsule contains 7 mg sorbitol.

For the full list of excipients, see section 6.1.

Soft capsule.

Plain, light beige, opaque, round to oval, soft gelatine capsules, filled with a clear yellowish solution.

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

Aloxi should be used only before chemotherapy administration.

AU dults500 micrograms palonosetron administered orally approximately one hour before the start ofchemotherapy.

EU lderly population

No dose adjustment is necessary for the elderly.

PU aediatric population

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

HU epatic impairment

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

RU enal 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.

For oral use.

Aloxi can be taken with or without food.

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

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

At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QTcorrected (QTc) interval. A specific thorough QT/QTc study was conducted in healthy volunteers fordefinitive 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 inpatients who have or are likely to develop prolongation of the QT interval. These conditions includepatients with a personal or family history of QT prolongation, electrolyte abnormalities, congestiveheart failure, bradyarrhythmias, conduction disturbances and in patients taking anti-arrhythmic agentsor other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemiaand 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 incombination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI)and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients forserotonin syndrome-like symptoms is advised.

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

Aloxi contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not takethis 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 forsigns of an allergic reaction.

Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2isoenzymes. Based on in vitro studies, palonosetron does not inhibit or induce cytochrome P450isoenzyme at clinically relevant concentrations.

UChemotherapeutic medicinal products U

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

UMetoclopramide U

In a clinical study, no significant pharmacokinetic interaction was shown between a singleintravenous dose of palonosetron and steady state concentration of oral metoclopramide, which is a

CYP2D6 inhibitor.

UCYP2D6 inducers and inhibitorsU

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

CU orticosteroidsU

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-HT3antagonists and other serotonergic drugs (including SSRIs and SNRIs).

OU ther medicinal products U

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

For Palonosetron, no clinical data on exposed pregnancies are available. Animal studies do notindicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development,parturition or postnatal development. Only limited data from animal studies are available regardingthe placental transfer (see section 5.3). There is no experience of palonosetron in human pregnancy sopalonosetron 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 bediscontinued 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 whendriving or operating machines.

In clinical studies at a dose of 500 micrograms (total 161 patients) the most frequently observedadverse 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 probablyrelated to Aloxi. These were classified as common (≥1/100 to <1/10) or uncommon (≥1/1,000 to<1/100).

System Organ Class Common ARs Uncommon ARs

Psychiatric disorders Insomnia

Nervous system disorders Headache

Eye disorders Eye swelling

Cardiac disorders Atrioventricular block first degree,atrioventricular block second degree

Respiratory, thoracic and mediastinal Dyspnoeadisorders

Gastrointestinal disorders Constipation, nausea

Musculoskeletal and connective tissue Myalgiadisorders

Investigations Blood bilirubin increased

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 similarincidence of adverse reactions compared to the other dose groups and no dose response effects wereobserved. 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 isunlikely 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 receivemoderately emetogenic cancer chemotherapy. A single-dose of 250 mcg, 500 mcg, or 750 mcg oralpalonosetron capsules given one hour prior to moderately emetogenic chemotherapy was compared toa single-dose of 250 mcg intravenous Aloxi given 30 minutes prior to chemotherapy. Patients wererandomised to either dexamethasone or placebo in addition to their assigned treatment. The majorityof 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 theapproved 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 palonosetrondose minus approved intravenous formulation was larger than -15 %. The non-inferiority margin was15 %.

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

Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated incontrolled clinical trials, 217 patients were enrolled in a multicentre, open label safety study and weretreated with palonosetron capsules 750 micrograms for up to 4 cycles of chemotherapy in a total of654 chemotherapy cycles. Approximately 74 % of patients also received single dose oral orintravenous dexamethasone 30 minutes before chemotherapy. Complete Response was not formallyevaluated for the repeat cycle application. However, in general the antiemetic effect for the 0-24 hourinterval was similar throughout the consecutively repeated cycles and the overall safety wasmaintained during all cycles.

Table 1: Proportion of patientsa responding by treatment group and phase

Aloxi Oral Aloxi Intravenous Delta500 micrograms 250 micrograms(n=160) (n=162)% % %

Complete Response (No Emesis and No Rescue Medication) 98.3 % CIb0-24 hours 76.3 70.4 5.9 [-6.5 %, 18.2 %]24-120 hours 62.5 65.4 -2.9 [-16.3 %, 10.5 %]0-120 hours 58.8 59.3 -0.5 [-14.2 %, 13.2 %]

Complete Control (Complete Response and No More Than Mild Nausea) p-valuec0-24 hours 74.4 68.5 5.9 NS24-120 hours 56.3 62.3 -6.0 NS0-120 hours 52.5 56.2 -3.7 NS

No Nausea (Likert Scale) p-valuec0-24 hours 58.8 57.4 1.4 NS24-120 hours 49.4 47.5 1.9 NS0-120 hours 45.6 42.6 3.0 NSa Intent-to-treat cohortb The study was designed to show non-inferiority. A lower bound greater that -15 % demonstrates non-inferiority between Aloxi oral and comparator Aloxi intravenousc 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 ventricularde- 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 toevaluate the ECG effects of IV administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in221 healthy subjects. The study demonstrated no effect on QT/QTc interval duration as well as anyother ECG interval at doses up to 2.25 mg. No clinically significant changes were shown on heartrate, atrioventricular (AV) conduction and cardiac repolarization.

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 inthe first 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 moderatelyemetogenic chemotherapy. No safety concerns were raised at either dose level. The primary efficacyvariable was the proportion of patients with a complete response (CR, defined as no emetic episodeand 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.

The efficacy of Aloxi for the prevention of chemotherapy-induced nausea and vomiting in paediatriccancer patients was demonstrated in a second non-inferiority pivotal trial comparing a singleintravenous infusion of palonosetron versus an i.v. ondansetron regimen. A total of 493 paediatricpatients, aged 64 days to 16.9 years, receiving moderately (69.2%) or highly emetogenicchemotherapy (30.8%) were treated with palonosetron 10 µg/kg (maximum 0.75 mg), palonosetron20 µg/kg (maximum 1.5 mg) or ondansetron (3 x 0.15 mg/kg , maximum total dose 32 mg) 30minutes prior to the start of emetogenic chemotherapy during Cycle 1. Most patients were non-naïveto chemotherapy (78.5%) across all treatment groups. Emetogenic chemotherapies administeredincluded doxorubicin, cyclophosphamide (<1500 mg/m2), ifosfamide, cisplatin, dactinomycin,carboplatin, and daunorubicin. Adjuvant corticosteroids, including dexamethasone, were administeredwith chemotherapy in 55% of patients. The primary efficacy endpoint was Complete Response in theacute phase of the first cycle of chemotherapy, defined as no vomiting, no retching, and no rescuemedication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstratingnon-inferiority of intravenous palonosetron compared to intravenous ondansetron. Non-inferioritycriteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete

Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%. Inthe palonosetron 10 µg/kg, 20 µg/kg and ondansetron groups, the proportion of patients with CR0-24hwas 54.2%, 59.4% and 58.6%. Since the 97.5% confidence interval (stratum adjusted Mantel-

Haenszel test) of the difference in CR0-24h between palonosetron 20 µg/kg and ondansetron was [-11.7%, 12.4%], the 20 µg/kg palonosetron dose demonstrated non-inferiority to ondansetron.

While this study demonstrated that paediatric patients require a higher palonosetron dose than adultsto prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with theestablished profile in adults (see section 4.8). Pharmacokinetic information is provided in section 5.2.

Prevention of Post Operative Nausea and Vomiting (PONV):

Two paediatric trials were performed. The safety and efficacy of Palonosetron i.v at single doses of1µg/kg and 3µg/kg was compared in the first clinical study in 150 patients in the following agegroups, >28 days to 23 months (7 patients), 2 to 11 years (96 patients), and 12 to 16 years of age (47patients) undergoing elective surgery. No safety concerns were raised in either treatment group. Theproportion of patients without emesis during 0-72 hours post-operatively was similar afterpalonosetron 1 µg/kg or 3 µg/kg (88% vs 84%).

The second paediatric trial was a multicenter, double-blind, double-dummy, randomised, parallelgroup, active control, single-dose non-inferiority study, comparing i.v. palonosetron (1 µg/kg, max0.075 mg) versus i.v. ondansetron. A total of 670 paediatric surgical patients participated, age 30 daysto 16.9 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, andno antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% ofpatients in the palonosetron group and 82.7% in the ondansetron group. Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiorityconfidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5,1.7%], therefore non-inferiority was not demonstrated No new safety concerns were raised in eithertreatment group.

Please see section 4.2 for information on paediatric use.

AU bsorption

Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching97 %. After single oral doses using buffered solution mean maximum palonosetron concentrations(Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportional over the doserange of 3.0 to 80 µg/kg in healthy subjects.

In 36 healthy male and female subjects given a single oral dose of palonosetron capsules500 micrograms, maximum plasma palonosetron concentration (Cmax) 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), themean AUC was 35 % higher and the mean Cmax 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 priorto chemotherapy, Cmax 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 Cmax and AUC of oral palonosetron. Therefore, Aloxi capsules maybe taken without regard to meals.

DU istribution

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

BU iotransformation

Palonosetron is eliminated by dual route, about 40 % eliminated through the kidney and withapproximately 50 % metabolised to form two primary metabolites, which have less than 1 % of the5HT3 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 ofpalonosetron. However, clinical pharmacokinetic parameters are not significantly different betweenpoor and extensive metabolisers of CYP2D6 substrates. Palonosetron does not inhibit or inducecytochrome P450 isoenzymes at clinically relevant concentrations.

UElimination

Following administration of a single oral 750 micrograms dose of [14C]-palonosetron to six healthysubjects, 85 % to 93 % of the total radioactivity was excreted in urine, and 5 % to 8 % was eliminatedin feces. The amount of unchanged palonosetron excreted in the urine represented approximately40 % of the administered dose. In healthy subjects given palonosetron capsules 500 micrograms, theterminal elimination half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancerpatients, t½ was 48 ± 19 hours. After a single-dose of approximately 0.75 mg intravenouspalonosetron, 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.

UPharmacokinetics in special populations

Elderly people

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

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

Single-dose i.v. Aloxi pharmacokinetic data was obtained from a subset of paediatric cancer patients(n=280) that received 10 µg/kg or 20 µg/kg. When the dose was increased from10 µg/kg to 20 µg/kga dose-proportional increase in mean AUC was observed. Following single dose intravenous infusionof Aloxi 20 µg/kg, peak plasma concentrations (CT) reported at the end of the 15 minute infusion werehighly variable in all age groups and tended to be lower in patients < 6 years than in older paediatricpatients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to 30 hoursacross age groups after administration of 20 µg/kg.

The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults.

There are no apparent differences in volume of distribution when expressed as L/kg.

Table 2: Pharmacokinetic Parameters in Paediatric Cancer Patients following intravenousinfusion of Aloxi at 20 µg/kg over 15 min and in Adult Cancer Patients receiving 3 and 10 µg/kgpalonosetron doses via intravenous bolus.

Paediatric Cancer Patientsa Adults Cancer

Patientsb<2 y 2 to <6 y 6 to <12 12 to <17 3.0 10 µg/kgy y µg/kg

N=3 N=5 N=7 N=10 N=6 N=5

AUC0-∞, h·µg/L 69.0 103.5 98.7 124.5 35.8 81.8(49.5) (40.4) (47.7) (19.1) (20.9) (23.9)t½, hours 56.4 49.824.0 28 23.3 30.5 (5.81) (14.4)

N=6 N=14 N=13 N=19 N=6 N=5

Clearance c, L/h/kg 0.31 0.23 0.19 0.16 0.10 0.13(34.7) (51.3) (46.8) (27.8) (0.04) (0.05)

Volume of distribution c, d, L/kg 6.08 5.29 6.26 6.20 7.91 9.56(36.5) (57.8) (40.0) (29.0) (2.53) (4.21)a PK parameters expressed as Geometric Mean (CV) except for T½ which is median.b PK parameters expressed as Arithmetic mean (SD)c Clearance and Volume of distribution in paediatric patients were calculated weight-adjusted from both 10 µg/kg and 20 µg /kg dose groups combined. In adults, different dose levels are indicated in column title.d Vss is reported for paediatric cancer patients, whereas Vz is reported for adult cancer patients.

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

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to thehealthy subjects. While the terminal elimination half-life and mean systemic exposure of palonosetronis 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 ofthe maximum human exposure indicating little relevance to clinical use.

Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ionchannels 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 animalstudies 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 thehuman 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 notin mice.

The underlying mechanisms are not fully understood, but because of the high doses employed andsince Aloxi is intended for single application in humans, these findings are not considered relevant forclinical use.

CU apsule content:

Glycerol Monocaprylocaproate (type I)

Polyglycerol oleate

Glycerol

Purified water

Butylhydroxyanisole

UCapsule shell:

Gelatin

Sorbitol

Glycerol

Titanium dioxide

Not applicable.

4 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/1/04/306/003

EU/1/04/306/002

Date of first authorisation: 22 March 2005

Date of latest renewal: 23 March 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu