PALONOSETRON ACCORD 250mcg injectible solution medication leaflet

Palonosetron Accord 250 micrograms solution for injection

Each ml of solution contains 50 micrograms of palonosetron (as hydrochloride).

Each vial of 5 ml of solution contains 250 micrograms of palonosetron (as hydrochloride).

For the full list of excipients, see section 6.1.

Solution for injection.

A clear colourless solution, practically free from foreign particles, pH 3.0 to 3.9, osmlolarity 260-320 mOsm/l.

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

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

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

Adults250 micrograms palonosetron administered as a single intravenous bolus approximately 30 minutes beforethe start of chemotherapy. Palonosetron Accord should be injected over 30 seconds.

The efficacy of palonosetron in the prevention of nausea and vomiting induced by highly emetogenicchemotherapy may be enhanced by the addition of a corticosteroid administered prior to chemotherapy.

No dose adjustment is necessary for the elderly.

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.

Children and adolescents (aged 1 month to 17 years):20 micrograms/kg (the maximum total dose should not exceed 1,500 micrograms) palonosetron administeredas a single 15 minutes intravenous infusion beginning approximately 30 minutes before the start ofchemotherapy.

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

For intravenous use.

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

At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QTc interval. Aspecific thorough QT/QTc study was conducted in healthy volunteers for definitive data demonstrating theeffect 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 patientswho have or are likely to develop prolongation of the QT interval. These conditions include patients with apersonal or family history of QT prolongation, electrolyte abnormalities, congestive heart failure,bradyarrhythmias, conduction disturbances and in patients taking anti-arrhythmic agents or other medicinalproducts that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and hypom agnesemiashould be corrected prior to 5-HT3-antagonist administration.

Interference with serotonergic medicinal products

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) andserotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotoninsyndrome-like symptoms is advised.

As palonosetron may increase large bowel transit time, patients with a history of constipation or signs ofsubacute intestinal obstruction should be monitored following administration. Two cases of constipation withfaecal impaction requiring hospitalisation have been reported in association with palonosetron750 micrograms.

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

This medicinal product contains less than 1 mmol sodium (23 mg) per vial that is to say 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 P450 isoenzymeat clinically relevant concentrations.

Chemotherapeutic agents

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

Metoclopramide

In a clinical study, no significant pharmacokinetic interaction was shown between a single intravenous doseof 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 and rifampicin) andinhibitors (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-HT3 antagonists and otherserotonergic drugs (including SSRIs and SNRIs).

Other medicinal products

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

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

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

As there are no data concerning palonosetron excretion in breast milk, breast-feeding should be discontinuedduring 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 drivingor operating machines.

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

In the clinical studies the following adverse drug reactions (ADRs) were observed as possibly or probablyrelated 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) ADRs were reported post-marketing.

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

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

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

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

Psychiatric disorders Anxiety, euphoric mood

Nervous system Headache, Dizziness Somnolence, insomnia,disorders paraesthesia,hypersomnia, peripheralsensory neuropathy

Eye disorders Eye irritation, amblyopia

Ear and labyrinth Motion sickness, tinnitusdisorders

Cardiac disorders Tachycardia,bradycardia,extrasystoles,myocardial ischaemia,sinus tachycardia, sinusarrhythmia,supraventricularextrasystoles

Vascular disorders Hypotension,hypertension, veindiscolouration, veindistended

Respiratory, thoracic Hiccupsand mediastinaldisorders

Gastrointestinal Constipation diarrhoea Dyspepsia, abdominaldisorders pain, abdominal painupper, dry mouth,flatulence

Hepatobiliary disorders Hyperbilirubinaemia

Skin and subcutaneous Dermatitis allergic,tissue disorders pruritic rash

Musculoskeletal and Arthralgiaconnective tissuedisorders

Renal and urinary Urinary retention,disorders glycosuria

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

Investigations Elevated transaminases-,electrocardiogram QTprolonged

* 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). Thefollowing common or uncommon adverse reactions were reported for palonosetron, none were reported at afrequency of >1%.

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

Nervous system disorders Headache Dizziness, dyskinesia

Cardiac disorder Electrocardiogram, QT prolongedconduction disorder, sinustachycardia

Respiratory, thoracic and Cough, dyspnoea, epistaxismediastinal disorders

Skin and subcutaneous tissue Dermatitis, allergic, pruritus, skindisorders 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 4 chemotherapycycles.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed 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 palonosetron, 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 palonosetron 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 moderately emetogenicchemotherapy that included cisplatin ≤50 mg/m2, carboplatin, cyclophosphamide ≤1,500 mg/m2 anddoxorubicin >25 mg/m2, palonosetron 250 micrograms and 750 micrograms were compared withondansetron 32 mg (half-life 4 hours) or dolasetron 100 mg (half-life 7.3 hours) administered intravenouslyon Day 1, without dexamethasone.

In a randomised, double-blind study with a total of 667 patients receiving highly emetogenic chemotherapythat included cisplatin ≥ 60 mg/m2, cyclophosphamide > 1,500 mg/m2 and dacarbazine, palonosetron250 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 andvomiting. The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours. Resultsfor the studies on moderately emetogenic chemotherapy and for the study on highly emetogenicchemotherapy are summarised in the following tables.

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

Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in controlledclinical studies, 875 patients enrolled in the three phase 3 trials continued in an open label safety study andwere treated with palonosetron 750 micrograms for up to 9 additional cycles of chemotherapy. The overallsafety was maintained during all cycles.

Table 1: Percentage of patientsa responding by treatment group and phase in the moderatelyemetogenic chemotherapy study versus ondansetron

Palonosetron Ondansetron Delta250micrograms 32milligrams(n= 189) (n= 185)% % %

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 % demonstrates non-inferiority between palonosetron 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 moderatelyemetogenic chemotherapy study versus dolasetron

Palonosetron Dolasetron Delta250 micrograms 100 milligrams(n= 185) (n= 191)% % %

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 % demonstrates non-inferiority between palonosetron 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 emetogenicchemotherapy study versus ondansetron

Palonosetron Ondansetron Delta250 micrograms 32 milligrams(n= 223) (n= 221)% % %

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 % demonstrates non-inferiority between palonosetron and comparator.c Chi-square test. Significance level at α=0.05.

The effect of palonosetron on blood pressure, heart rate, and electrocardiogram (ECG) parameters including

QTc were comparable to ondansetron and dolasetron in chemotherapy induced nausea and vomiting (CINV)clinical studies. In non-clinical studies palonosetron possesses the ability to block ion channels involved inventricular 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, placeboand positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECGeffects of intravenous administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in 221 healthysubjects. The study demonstrated no effect on QT/QTc interval duration as well as any other ECG interval atdoses up to 2.25 mg. No clinically significant changes were shown on heart rate, atrioventricular (AV)conduction and cardiac repolarisation.

Prevention of chemotherapy induced nausea and vomiting (CINV):

The safety and efficacy of palonosetron intravenously at single doses of 3mcg/kg and 10 mcg/kg wasinvestigated in the 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 ormoderately emetogenic chemotherapy. No safety concerns were raised at either dose level. The primaryefficacy variable 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. Efficacyafter palonosetron 10 mcg/kg compared to palonosetron 3 mcg/kg was 54.1 % and 37.1 % respectively.

The efficacy of palonosetron for the prevention of chemotherapy-induced nausea and vomiting in paediatriccancer patients was demonstrated in a second non-inferiority pivotal trial comparing a single intravenousinfusion of palonosetron versus an intravenous ondansetron regimen. A total of 493 paediatric patients, aged64 days to 16.9 years, receiving moderately (69.2 %) or highly emetogenic chemotherapy (30.8 %) weretreated with palonosetron 10 mcg/kg (maximum 0.75 mg), palonosetron 20 mcg/kg (maximum 1.5 mg) orondansetron (3 x 0.15 mg/kg, maximum total dose 32 mg) 30 minutes prior to the start of emetogenicchemotherapy during Cycle 1. Most patients were non-naive to chemotherapy (78.5 %) across all treatmentgroups. Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m2),ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids, includingdexamethasone, were administered with chemotherapy in 55 % of patients. The primary efficacy endpointwas Complete Response in the acute phase of the first cycle of chemotherapy, defined as no vomiting, noretching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based ondemonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron. Non -inferiority criteria 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 %.

In the palonosetron 10 mcg/kg, 20 mcg/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-Haenszeltest) of the difference in CR0-24h between palonosetron 20 mcg/kg and ondansetron was [-11.7 %, 12.4 %],the 20 mcg/kg palonosetron dose demonstrated non-inferiority to ondansetron.

While this study demonstrated that paediatric patients require a higher palonosetron dose than adults toprevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the establishedprofile 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 intravenously at single dosesof 1mcg/kg and 3 mcg/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 16years of age (47 patients)undergoing elective surgery. No safety concerns were raised in either treatment group. The proportion ofpatients without emesis during 0-72 hours post-operatively was similar after palonosetron 1 mcg/kg or3 mcg/kg (88 % vs 84 %).

The second paediatric, trial was a multicenter, double-blind, double-dummy, randomised, parallel group,active control, single-dose non-inferiority study, comparing intravenous palonosetron (1 mcg/kg, max0.075 mg) versus intravenous. ondansetron. A total of 670 paediatric surgical patients participated, age30 days 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 % ofpatients in the palonosetron group and 82.7 % in the ondansetron group. Given the prespecified non-inferiority margin of -10 %, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidenceinterval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7 %], thereforenon-inferiority was not demonstrated. No new safety concerns were raised in either treatment 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. Meanmaximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-∞) are generallydose-proportional over the dose range of 0.3-90 mcg/kg in healthy subjects and in cancer patients.

Following intravenous administration of palonosetron 0.25 mg once every other day for 3 doses in11 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 healthysubjects, the mean (± SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was110 ± 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 dose of0.75 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 ofapproximately 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 approximately50 % metabolised to form two primary metabolites, which have less than 1 % of the 5HT3 receptorantagonist activity of palonosetron. In vitro metabolism studies have shown that CYP2D6 and to a lesserextent, CYP3A4 and CYP1A2 isoenzymes are involved in the metabolism of palonosetron. However,clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolisersof CYP2D6 substrates. Palonosetron does not inhibit or induce cytochrome P450 isoenzymes at clinicallyrelevant concentrations.

After a single intravenous dose of 10 micrograms/kg [14C]-palonosetron, approximately 80 % of the dosewas recovered within 144 hours in the urine with palonosetron representing approximately 40 % of theadministered dose, as unchanged active substance. After a single intravenous bolus administration in healthysubjects the total body clearance of palonosetron was 173 ± 73 ml/min and renal clearance was53 ± 29 ml/min. The low total body clearance and large volume of distribution resulted in a terminalelimination half-life in plasma of approximately 40 hours. Ten percent of patients have a mean terminalelimination half-life greater than 100 hours.

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 based ongender.

Single-dose intravenous palonosetron pharmacokinetic data was obtained from a subset of paediatric cancerpatients (n=280) that received 10 mcg/kg or 20 mcg/kg. When the dose was increased from 10 mcg/kg to20 mcg/kg a dose-proportional increase in mean AUC was observed. Following single dose intravenousinfusion of palonosetron 20 mcg/kg, peak plasma concentrations (CT) reported at the end of the 15 minuteinfusion were highly variable in all age groups and tended to be lower in patients < 6 years than in olderpaediatric patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to30 hours across age groups after administration of 20 mcg/kg.

The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. Thereare no apparent differences in volume of distribution when expressed as L/kg.

Table 4: Pharmacokinetic parameters in paediatric cancer patients following intravenous infusion ofpalonosetron at 20 mcg/kg over 15 min and in Adult Cancer Patients receiving 3 and 10 mcg/kgpalonosetron doses via intravenous bolus.

Paediatric cancer patientsa Adults cancer patientsb<2y 2 to <6 y 6 to <12 y 12 to <17 y 3.0 mcg/kg 10 mcg/kg

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

AUC0- ∞ , 69.0 (49.5) 103.5 (40.4) 98.7 (47.7) 124.5 (19.1) 35.8 (20.9) 81.8 (23.9)h.mcg/Lt1/2, hours 24.0 28 23.3 30.5 56.4 (5.81) 49.8 (14.4)

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

Clearancec, 0.31 (34.7) 0.23 (51.3) 0.19 (46.8) 0.16 (27.8) 0.10 (0.04) 0.13 (0.05)

L/h/kg

Volume of 6.08 (36.5) 5.29 (57.8) 6.26 (40.0) 6.20 (29.0) 7.91 (2.53) 9.56 (4.21)distributionc,d, L/kga PK parameters expressed as geometric mean (CV) except forT1/2, 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 both10 mcg /kg and 20 mcg /kg dose groups combined. In adults, different dose levels are indicated in columntitle.d Vss (steady state) is reported for paediatric cancer patients, whereas Vz (elimination) is reported for adultcancer patients.

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 tohealthy subjects. No dose adjustment is necessary in patients with renal insufficiency. No pharmacokineticdata 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 palonosetron isincreased 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 themaximum human exposure indicating little relevance to clinical use.

Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ion channelsinvolved 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/foetaldevelopment, parturition or postnatal development. Only limited data from animal studies are availableregarding the placental transfer (see section 4.6).

Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 30 times the humantherapeutic exposure) applied daily for two years caused an increased rate of liver tumours, endocrineneoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but not in mice. Theunderlying mechanisms are not fully understood, but because of the high doses employed and sincepalonosetron is intended for single application in humans, these findings are not considered relevant forclinical use.

Mannitol,

Citric acid monohydrate,

Sodium citrate,

Disodium edetate,

Sodium hydroxide (for pH adjustment),

Hydrochloric acid, concentrated (for pH adjustment),

Water for injections.

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

3 years

Upon opening of the vial, it should be used immediately.

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

6 ml type I tubular clear glass vial, closed with chlorobutyl rubber stopper and sealed with a flip-offaluminium seal.

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

Single use only, any unused solution should be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/16/1104/001

Date of first authorisation: 26th May 2016

Date of latest renewal: 12 February 2021

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

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