ALOXI 250mcg / 5ml solution for injection medication leaflet

Aloxi 250 micrograms solution for injection.

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.

Solution for injection.

Clear, colourless solution.

Aloxi is indicated in adults for:

* the prevention of acute nausea and vomiting associated with highly emetogenic cancerchemotherapy,

* the prevention of nausea and vomiting associated with moderately emetogenic cancerchemotherapy.

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

* the prevention of acute nausea and vomiting associated with highly emetogenic cancerchemotherapy and prevention of nausea and vomiting associated with moderately emetogeniccancer chemotherapy.

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

Adults250 micrograms palonosetron administered as a single intravenous bolus approximately 30 minutesbefore 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 emetogenicchemotherapy may be enhanced by the addition of a corticosteroid administered prior tochemotherapy.

Elderly people

No dose adjustment is necessary for the elderly.

Children and Adolescents (aged 1 month to 17 years):20 micrograms/kg (the maximum total dose should not exceed 1500 micrograms) palonosetronadministered as a single 15 minute intravenous infusion beginning approximately 30 minutes beforethe start of chemotherapy.

The safety and efficacy of Aloxi in children aged less than 1 month have not been established. Nodata are available. There are limited data on the use of Aloxi in the prevention of nausea and vomitingin children under 2 years of age.

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

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 intravenous use.

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 QTcinterval. A specific thorough QT/QTc study was conducted in healthy volunteers for definitive datademonstrating 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.

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

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.

Chemotherapeutic agents

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

Metoclopramide

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.

CYP2D6 inducers and inhibitors

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).

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).

Other medicinal products

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. Therefore, palonosetron should not beused 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 in adults at a dose of 250 micrograms (total 633 patients) the most frequentlyobserved 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 probablyrelated 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 decreasingseriousness.

System organ class Common ARs Uncommon ARs Very rare ARs°(≥1/100 to<1/10) (≥1/1,000 to <1/100) (<1/10,000)

Immune system disorders Hypersensitivity,anaphylaxis,anaphylactic/anaphylactoid reactionsand shock

Metabolism and nutrition Hyperkalaemia, metabolicdisorders disorders, hypocalcaemia,hypokalaemia, anorexia,hyperglycaemia, appetitedecreased

Psychiatric disorders Anxiety, euphoric mood

Nervous system disorders Headache Somnolence, insomnia,

Dizziness paraesthesia, hypersomnia,peripheral sensoryneuropathy

Eye disorders Eye irritation, amblyopia

Ear and labyrinth disorders Motion sickness, tinnitus

Cardiac disorders Tachycardia, bradycardia,extrasystoles, myocardialischaemia, sinustachycardia, sinusarrhythmia,supraventricularextrasystoles

Vascular disorders Hypotension, hypertension,vein discolouration, veindistended

Respiratory, thoracic and Hiccupsmediastinal disorders

Gastrointestinal disorders Constipation Dyspepsia, abdominal pain,

Diarrhoea abdominal pain upper, drymouth, flatulence

Hepatobiliary disorders Hyperbilirubinaemia

Skin and subcutaneous Dermatitis allergic, pruritictissue disorders rash

Musculoskeletal and Arthralgiaconnective tissue disorders

Renal and urinary disorders Urinary retention,glycosuria

General disorders and Asthenia, pyrexia, fatigue, Injection site reaction*administration site feeling hot, influenza likeconditions illness

Investigations Elevated transaminases-,electrocardiogram QTprolonged° From post-marketing experience

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

In paediatric clinical trials for the prevention of nausea and vomiting induced by moderately or highlyemetogenic 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 werereported at a frequency of >1%.

System organ class Common ARs Uncommon ARs(≥1/100 to<1/10) (≥1/1,000 to <1/100)

Nervous system disorders Headache Dizziness, dyskinesia

Cardiac disorders Electrocardiogram QTprolongedconduction disorder, sinustachycardia

Respiratory, thoracic and Cough, dyspnoea, epistaxismediastinal disorders

Skin and subcutaneous tissue Dermatitis allergic, pruritus,disorders skin disorder, urticaria

General disorders and Pyrexia, infusion site pain,administration site conditions infusion site reaction, pain

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

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 adult clinical studies. 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.

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

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 moderatelyemetogenic chemotherapy that included cisplatin ≤50 mg/m2, carboplatin, cyclophosphamide≤1,500 mg/m2 and doxorubicin >25 mg/m2, palonosetron 250 micrograms and 750 micrograms werecompared 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 emetogenicchemotherapy that included cisplatin ≥ 60 mg/m2, cyclophosphamide > 1,500 mg/m2 and dacarbazine,palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mgadministered intravenously on Day 1. Dexamethasone was administered prophylactically beforechemotherapy in 67 % of patients.

The pivotal studies were not designed to assess efficacy of palonosetron in delayed onset nausea andvomiting. 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 highlyemetogenic chemotherapy are summarised in the following tables.

Palonosetron was non-inferior versus the comparators in the acute phase of emesis both in moderatelyand highly emetogenic setting.

Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated incontrolled clinical studies, 875 patients enrolled in the three phase 3 trials continued in an open labelsafety study and were treated with palonosetron 750 micrograms for up to 9 additional cycles ofchemotherapy. 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

Aloxi Ondansetron250 micrograms 32 milligrams(n= 189) (n= 185) Delta% % %

Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b0 - 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 c0 - 24 hours 76.2 65.4 10.8 NS24 - 120 hours 66.7 50.3 16.4 0.0010 - 120 hours 63.0 44.9 18.1 0.001

No Nausea (Likert Scale) p-value c0 - 24 hours 60.3 56.8 3.5 NS24 - 120 hours 51.9 39.5 12.4 NS0 - 120 hours 45.0 36.2 8.8 NSa Intent-to-treat cohort.b The study was designed to show non-inferiority. A lower bound greater than -15 % demonstratesnon-inferiority between Aloxi and comparator.c Chi-square test. Significance level at α=0.05.

Table 2: Percentage of patients a responding by treatment group and phase in the Moderately

Emetogenic Chemotherapy study versus dolasetron

Aloxi Dolasetron250 micrograms 100 milligrams(n= 185) (n= 191) Delta% % %

Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b0 - 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 c0 - 24 hours 57.1 47.6 9.5 NS24 - 120 hours 48.1 36.1 12.0 0.0180 - 120 hours 41.8 30.9 10.9 0.027

No Nausea (Likert Scale) p-value c0 - 24 hours 48.7 41.4 7.3 NS24 - 120 hours 41.8 26.2 15.6 0.0010 - 120 hours 33.9 22.5 11.4 0.014a Intent-to-treat cohort.b The study was designed to show non-inferiority. A lower bound greater than -15 % demonstratesnon-inferiority between Aloxi and comparator.c Chi-square test. Significance level at α=0.05.

Table 3: Percentage of patients a responding by treatment group and phase in the Highly

Emetogenic Chemotherapy study versus ondansetron

Aloxi Ondansetron250 micrograms 32 milligrams(n= 223) (n= 221) Delta% % %

Complete Response (No Emesis and No Rescue Medication) 97.5 % CI b0 - 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 c0 - 24 hours 56.5 51.6 4.9 NS24 - 120 hours 40.8 35.3 5.5 NS0 - 120 hours 37.7 29.0 8.7 NS

No Nausea (Likert Scale) p-value c0 - 24 hours 53.8 49.3 4.5 NS24 - 120 hours 35.4 32.1 3.3 NS0 - 120 hours 33.6 32.1 1.5 NSa Intent-to-treat cohort.b The study was designed to show non-inferiority. A lower bound greater than -15 % demonstratesnon-inferiority between Aloxi and comparator.c Chi-square test. Significance level at α=0.05.

The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc werecomparable to ondansetron and dolasetron in CINV clinical studies. In non-clinical studiespalonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarisationand 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 repolarisation.

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV):

The safety and efficacy of Palonosetron i.v at single doses of 3 µg/kg and 10 µg/kg was investigatedin the first clinical study in 72 patients in the following age groups, >28 days to 23 months (12patients), 2 to 11 years (31 patients), and 12 to 17 years of age (29 patients), receiving highly ormoderately emetogenic chemotherapy. No safety concerns were raised at either dose level. Theprimary efficacy variable was the proportion of patients with a complete response (CR, defined as noemetic episode and no rescue medication) during the first 24 hours after the start of chemotherapyadministration. 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 30days to 16.9 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching,and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2%of patients in the palonosetron group and 82.7% in the ondansetron group. Given the pre-specifiednon-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.

Following intravenous administration, an initial decline in plasma concentrations is followed by slowelimination 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 μg/kg in healthy subjects and in cancerpatients.

Following intravenous administration of palonosetron 0.25 mg once every other day for 3 doses in 11testicular cancer patients, the mean (± SD) increase in plasma concentration from Day 1 to Day 5 was42 ± 34 %. After intravenous administration of palonosetron 0.25 mg once daily for 3 days in 12healthy subjects, the mean (± SD) increase in plasma palonosetron concentration from Day 1 to Day 3was 110 ± 45 %.

Pharmacokinetic simulations indicate that the overall exposure (AUC0-∞) of 0.25 mg intravenouspalonosetron administered once daily for 3 consecutive days was similar to a single intravenous doseof 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 distributionof 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 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.

After a single intravenous dose of 10 micrograms/kg [14C]-palonosetron, approximately 80 % of thedose 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 bolusadministration in healthy subjects the total body clearance of palonosetron was 173 ± 73 ml/min andrenal clearance was 53 ± 29 ml/min. The low total body clearance and large volume of distributionresulted in a terminal elimination half-life in plasma of approximately 40 hours. Ten percent ofpatients have a mean terminal elimination half-life greater than 100 hours.

Elderly people

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

Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessarybased on 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 4: 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.

Adults Cancer

Paediatric Cancer Patientsa 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 dosage 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 30 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 dosesemployed and since Aloxi is intended for single application in humans, these findings are notconsidered relevant for clinical use.

Mannitol

Disodium edetate

Sodium citrate

Citric acid monohydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products.

5 years.

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

This medicinal product does not require any special storage conditions.

Type I glass vial with chlorobutyl siliconised rubber stopper and aluminium cap.

Available in packs of 1 vial containing 5 ml of solution.

Single use only, any unused solution should be discarded.

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

Helsinn Birex Pharmaceuticals Ltd.

Damastown

Mulhuddart

Dublin 15

Ireland

EU/1/04/306/001

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