Document: Palonosetron Reig Jofre solution for injection ENG SmPC change

• Palonosetron Reig Jofre Solution for injection SmPC
• Palonosetron Reig Jofre solution for injection ENG SmPC

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^{SUMMARY OF PRODUCT CHARACTERISTICS}

Palonosetron Reig Jofre 250 micrograms solutionforinjection.

Each mlof solutioncontains 50 micrograms palonosetron (as hydrochloride).

Each vialof 5mlof solution contains 250 micrograms palonosetron(as hydrochloride).

Excipient(s) with known effect:

Each vial contains less than 1 mmol sodium (23 mg) (see section 4.4).

Forthe fulllistof excipients, see section 6.1.

Solutionfor injection. Clear, colourless solution.

The pH is between 4.5 and 5.5 and osmolality is between 250 and 375 mOsm/kg.

Palonosetron Reig Jofre isindicatedin adultsfor:

• 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 Reig Jofre is indicated in paediatric patients 1 month of age and older for:

Palonosetron Reig Jofre should be usedonlybefore chemotherapyadministration.This medicinalproductshouldbe administered by a healthcare professionalunderappropriate medicalsupervision.

Posology

Adults

250 micrograms palonosetron administered as a singleintravenousbolus approximately30 minutes beforethe startofchemotherapy. Palonosetron Reig Jofreshouldbe injectedover30 seconds.

Theefficacyof Palonosetron Reig Jofre intheprevention ofnauseaand vomitinginduced by highlyemetogenic chemotherapymaybe enhanced bytheaddition ofa corticosteroidadministered priorto chemotherapy.

Elderly people

No dose adjustmentis necessaryforthe elderly.

Paediatric population

Children and Adolescents (aged 1 month to 17 years):

20 micrograms/kg (the maximum total dose should not exceed 1500 micrograms) palonosetron administered as a single 15 minute intravenous infusion beginning approximately 30 minutes before the start of chemotherapy.

Thesafetyand efficacy of Palonosetron Reig Jofre in children aged less than 1 month have not been established. No data are available. There are limited data on the use of Palonosetron Reig Jofre in the prevention of nausea and vomiting in children under 2 years of age.

Hepatic impairment

No dose adjustmentis necessaryforpatients with impairedhepatic function.

Renalimpairment

No dose adjustmentis necessaryforpatients with impairedrenalfunction.

No dataare available forpatients withend stage renaldiseaseundergoinghaemodialysis.

Method of administration Forintravenous use.

Hypersensitivityto the active substance orto anyof the excipientslistedin section 6.1.

As palonosetron mayincreaselarge boweltransittime, patients witha historyof constipation or signs of subacuteintestinalobstruction shouldbe monitoredfollowingadministration.Two cases of constipation withfaecalimpactionrequiringhospitalisation have been reportedinassociation with palonosetron750 micrograms.

Atalldose levelstested,palonosetron did notinduce clinicallyrelevantprolongation of the QTc interval. A specificthorough QT/QTc studywas conductedin healthyvolunteers fordefinitive data demonstratingthe effectofpalonosetronon QT/QTc(see section 5.1).

However,as forother5-HT₃antagonists, caution should be exercised inthe use ofpalonosetronin patients who have or arelikelyto develop prolongationof the QTinterval.These conditions include patients with a personalorfamilyhistoryof QTprolongation, electrolyteabnormalities, congestive heartfailure, bradyarrhythmias, conduction disturbances and inpatientstakinganti-arrhythmic agents or othermedicinalproductsthatleadto QTprolongation or electrolyteabnormalities. Hypokalemia and hypomagnesemia should be corrected priorto 5-HT3-antagonistadministration.

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone or in combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.

Palonosetron Reig Jofre should notbe usedtopreventortreatnausea and vomitingin the days followingchemotherapy ifnotassociated withanotherchemotherapyadministration.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, but if the maximum dose for children are administered (6 vials) the sodium content corresponds to 1.2 mmol sodium (27.90 mg).

Palonosetronis mainly metabolisedby CYP2D6, withminorcontribution by CYP3A4 and CYP1A2 isoenzymes. Based on in vitrostudies, palonosetron does notinhibitor induce cytochrome P450 isoenzyme at clinicallyrelevantconcentrations.

Chemotherapeutic agents

In preclinicalstudies,palonosetron did notinhibitthe antitumouractivityof thefive chemotherapeutic agents tested(cisplatin, cyclophosphamide, cytarabine,doxorubicin and mitomycin C).

Metoclopramide

In a clinicalstudy, no significantpharmacokineticinteraction was shown betweena singleintravenous dose ofpalonosetronand steadystate concentration oforal metoclopramide, which is aCYP2D6inhibitor.

CYP2D6 inducersandinhibitors

In a population pharmacokinetic analysis, ithas been shown thatthere wasno significanteffecton palonosetronclearance when co-administered with CYP2D6 inducers (dexamethasone and rifampicin) and inhibitors(includingamiodarone, celecoxib, chlorpromazine, cimetidine,doxorubicin, fluoxetine, haloperidol, paroxetine, quinidine, ranitidine, ritonavir,sertraline orterbinafine).

Corticosteroids

Palonosetronhas beenadministeredsafelywith corticosteroids.

Serotonergic Drugs (e.g. SSRIs and SNRIs)

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

Other medicinalproducts

Palonosetronhas beenadministeredsafelywith analgesics, antiemetic/antinauseants, antispasmodics and anticholinergic medicinalproducts.

Pregnancy

ForPalonosetron no clinicaldata on exposed pregnancies are available. Animalstudiesdo notindicate director indirectharmfuleffects withrespectto pregnancy, embryonal/foetaldevelopment, parturition or postnataldevelopment. Onlylimited datafromanimalstudies areavailableregardingthe placental transfer(see section 5.3).

Thereis no experience of palonosetronin human pregnancy. Therefore, palonosetron shouldnot be usedin pregnantwomen unlessit is considered essentialby thephysician.

Breast-feeding

As there are no data concerningpalonosetron excretionin breastmilk, breast-feedingshould be discontinued duringtherapy.

Fertility

Thereare no dataconcerningthe effectof palonosetronon fertility.

No studieson the effects on the abilityto drive and usemachines have been performed.

Sincepalonosetron mayinduce dizziness, somnolenceor fatigue, patientsshould be cautioned when drivingor operatingmachines.

In clinicalstudiesin adults at a doseof 250 micrograms(total633 patients)the mostfrequentlyobserved adversereactions,at leastpossiblyrelatedto Palonosetron Reig Jofre, were headache (9%) and constipation (5 %).

Intheclinicalstudiesthefollowingadversereactions(ARs)wereobservedas possiblyor probably relatedtoPalonosetron Reig Jofre. Thesewereclassifiedas common(≥1/100to<1/10)or uncommon(≥1/1,000to <1/100).Veryrare (<1/10,000)adversereactions were reported post-marketing.

Withineach frequencygrouping, adversereactions arepresented belowin orderofdecreasing seriousness.

System organ class	Common ARs (≥1/100 to<1/10)	Uncommon ARs (≥1/1,000 to <1/100)	Very rare ARs° (<1/10,000)
Immune system disorders			Hypersensitivity, anaphylaxis, anaphylactic/ anaphylactoid reactions and shock
Metabolism and nutrition disorders		Hyperkalaemia, metabolic disorders, hypocalcaemia, hypokalaemia, anorexia, hyperglycaemia, appetite decreased
Psychiatric disorders		Anxiety, euphoric mood
Nervous system disorders	Headache Dizziness	Somnolence, insomnia, paraesthesia, hypersomnia, peripheral sensory neuropathy
Eye disorders		Eye irritation, amblyopia
Ear and labyrinth disorders		Motion sickness, tinnitus
Cardiac disorders		Tachycardia, bradycardia, extrasystoles, myocardial ischaemia, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles
Vascular disorders		Hypotension, hypertension, vein discolouration, vein distended
Respiratory, thoracic and mediastinal disorders		Hiccups
Gastrointestinal disorders	Constipation Diarrhoea	Dyspepsia, abdominal pain, abdominal pain upper, dry mouth, flatulence
Hepatobiliary disorders		Hyperbilirubinaemia
Skin and subcutaneous tissue disorders		Dermatitis allergic, pruritic rash
Musculoskeletal and connective tissue disorders		Arthralgia
Renal and urinary disorders		Urinary retention, glycosuria
General disorders and administration site conditions		Asthenia, pyrexia, fatigue, feeling hot, influenza like illness	Injection site reaction*
Investigations		Elevated transaminases-, electrocardiogram QT prolonged

° Frompost-marketingexperience

* Includes the following:burning, induration, discomfortand pain

Paediatric population

In paediatric clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic 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 were reported at a frequency of >1%.

System organ class	Common ARs (≥1/100 to<1/10)	Uncommon ARs (≥1/1,000 to <1/100)
Nervous system disorders	Headache	Dizziness, dyskinesia
Cardiac disorders		Electrocardiogram QT prolonged conduction disorder, sinus tachycardia
Respiratory, thoracic and mediastinal disorders		Cough, dyspnoea, epistaxis
Skin and subcutaneous tissue disorders		Dermatitis allergic, pruritus, skin disorder, urticaria
General disorders and administration site conditions		Pyrexia, infusion site pain, infusion site reaction, pain

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in <to be completed nationally).

No case ofoverdose has been reported.

Doses ofup to 6 mghave been used in clinicalstudies.The highestdose group showed a similar incidence ofadverse reactions comparedtothe otherdose groupsand no doseresponseeffects were observed. In the unlikelyeventofoverdose with Palonosetron Reig Jofre,this should be managed with supportive care. Dialysis studies have notbeen performed, however, due tothelarge volume of distribution, dialysis is unlikelytobe an effectivetreatmentforPalonosetron Reig Jofreoverdose.

Paediatric population

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

Pharmacotherapeuticgroup:Antiemetics and antinauseants,serotonin(5HT₃)antagonists.ATCcode: A04AA05

Palonosetronisa selective high-affinityreceptorantagonistof the 5HT₃receptor.

In two randomised, double-blind studies with a totalof 1,132 patients receivingmoderately emetogenicchemotherapythatincludedcisplatin≤50mg/m², carboplatin, cyclophosphamide≤1,500 mg/m²anddoxorubicin>25 mg/m²,palonosetron250 micrograms and 750microgramswere compared with ondansetron32 mg(half-life 4 hours)ordolasetron 100 mg(half-life 7.3 hours) administered intravenouslyon Day1, withoutdexamethasone.

In a randomised, double-blind studywith a totalof 667patients receivinghighlyemetogenic chemotherapythatincludedcisplatin≥ 60 mg/m², cyclophosphamide > 1,500 mg/m²and dacarbazine, palonosetron250 micrograms and 750 micrograms were comparedwith ondansetron 32 mg administered intravenouslyon Day1. Dexamethasonewas administered prophylacticallybefore chemotherapyin 67% ofpatients.

Thepivotalstudies werenotdesigned to assess efficacyof palonosetronin delayed onsetnauseaand vomiting. The antiemetic activitywas observed during0-24 hours, 24-120 hoursand 0-120 hours. Resultsfor thestudies on moderatelyemetogenic chemotherapyand forthestudyon highly emetogenic chemotherapyare summarisedinthefollowingtables.

Palonosetron was non-inferiorversusthe comparatorsin theacute phaseof emesisbothin moderately and highlyemetogenic setting.

Although comparative efficacyof palonosetronin multiple cycles has notbeen demonstrated in controlledclinicalstudies,875 patientsenrolledinthethree phase 3trialscontinued inan open label safetystudyand weretreated withpalonosetron 750 micrograms for up to9 additionalcycles of chemotherapy. Theoverallsafetywas maintainedduringallcycles.

Table 1: Percentageof patients^aresponding by treatmentgroupandphase inthe Moderately Emetogenic Chemotherapy study versus ondansetron

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

^a Intent-to-treatcohort.

Table 2: Percentageof patients^aresponding by treatmentgroupandphase inthe Moderately Emetogenic Chemotherapy studyversus dolasetron

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

^a Intent-to-treatcohort.

Table 3: Percentageof patients^aresponding by treatmentgroupandphase intheHighly Emetogenic Chemotherapy study versus ondansetron

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

^a Intent-to-treatcohort.

Theeffectofpalonosetronon blood pressure,heartrate, and ECGparameters includingQTc were comparableto ondansetronand dolasetron in CINVclinicalstudies. In non-clinicalstudies palonosetronpossessestheabilitytoblockion channels involved in ventricularde-and re-polarisation and toprolongactionpotentialduration.

Theeffectofpalonosetronon QTc intervalwasevaluatedin a double blind,randomised, parallel, placebo and positive (moxifloxacin)controlled trialinadultmen and women. Theobjective was to evaluate the ECGeffectsof IVadministered palonosetron at singledoses of0.25, 0.75 or2.25 mgin 221 healthysubjects.Thestudydemonstrated no effecton QT/QTc intervalduration as wellas any otherECGintervalat dosesup to 2.25 mg. No clinicallysignificantchanges wereshown on heartrate, atrioventricular(AV)conduction and cardiacrepolarisation.

Paediatric population

Prevention of Chemotherapy Induced NauseaandVomiting(CINV):

Thesafetyand efficacyof Palonosetroni.vat single doses of3µg/kgand 10µg/kgwas investigated in the first clinicalstudyin 72 patients in the followingage groups, >28 days to 23 months(12 patients), 2 to 11 years (31patients), and 12to 17 years ofage (29patients),receivinghighlyor moderatelyemetogenic chemotherapy. No safetyconcerns were raised ateitherdose level.The primaryefficacyvariable was the proportion ofpatients witha complete response(CR, definedas no emetic episode and norescue medication) duringthefirst24 hours afterthe startof chemotherapyadministration. Efficacyafter palonosetron10 µg/kgcomparedto palonosetron 3µg/kgwas 54.1%and 37.1%respectively.

The efficacy of Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in paediatric cancer patients was demonstrated in a second non-inferiority pivotal trial comparing a single intravenous infusion of palonosetron versus an i.v. ondansetron regimen. A total of 493 paediatric patients, aged 64 days to 16.9 years, receiving moderately (69.2%) or highly emetogenic chemotherapy (30.8%) were treated with palonosetron 10 μg/kg (maximum 0.75 mg), palonosetron 20 μg/kg (maximum 1.5 mg) or ondansetron (3 x 0.15 mg/kg , maximum total dose 32 mg) 30 minutes prior to the start of emetogenic chemotherapy during Cycle 1. Most patients were non-naïve to chemotherapy (78.5%) across all treatment groups. Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m2), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients. The primary efficacy endpoint was Complete Response in the acute phase of the first cycle of chemotherapy, defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstrating 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 μg/kg, 20 μg/kg and ondansetron groups, the proportion of patients with CR0-24h was 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 adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults (see section 4.8). Pharmacokineticinformation isprovidedinsection 5.2.

Prevention of PostOperative Nausea and Vomiting(PONV):

Two paediatric trials were performed. 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%).

The second paediatric trial was a multicenter, double-blind, double-dummy, randomised, parallel group, active control, single-dose non-inferiority study, comparing i.v. palonosetron (1 μg/kg, max 0.075 mg) versus I.V. ondansetron. A total of 670 paediatric surgical patients participated, age 30 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% of patients 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-inferiority confidence 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 either treatment group.

Please see section 4.2 forinformationon paediatric use.

Absorption

Followingintravenousadministration,an initialdecline in plasma concentrationsis followed by slow eliminationfromthe bodywith a meanterminalelimination half-life of approximately40 hours. Meanmaximumplasma concentration (C_max)and area underthe concentration-timecurve (AUC0-∞)are generallydose-proportionaloverthe doserange of 0.3–90 μg/kgin healthysubjects and in cancer patients.

Followingintravenousadministration ofpalonosetron0.25 mgonce everyotherdayfor 3 dosesin 11 testicularcancerpatients,the mean (±SD)increasein plasma concentrationfromDay 1 to Day5 was 42 ±34 %. Afterintravenous administration ofpalonosetron 0.25 mgonce dailyfor3 daysin 12 healthysubjects,the mean (±SD)increase in plasma palonosetronconcentrationfromDay1 to Day3 was 110±45 %.

Pharmacokinetic simulations indicatethatthe overallexposure(AUC0-∞)of 0.25 mgintravenous palonosetronadministeredonce dailyfor 3consecutive days was similartoa single intravenous dose of 0.75 mg, although C_maxof the 0.75 mgsingle dose was higher.

Distribution

Palonosetronat therecommended dose is widelydistributedinthe bodywith a volume of distribution of approximately6.9 to7.9 l/kg. Approximately62 %of palonosetronis boundtoplasma proteins.

Biotransformation

Palonosetroniseliminatedby dualroute,about40 %eliminated through the kidneyand with approximately50 %metabolisedto formtwo primarymetabolites,which have less than 1 %of the 5HT₃receptorantagonistactivityof palonosetron.In vitrometabolismstudieshave shownthat CYP2D6 and toa lesserextent, CYP3A4 and CYP1A2isoenzymes are involved inthe metabolismof palonosetron.However, clinicalpharmacokinetic parameters are notsignificantlydifferentbetween poor and extensive metabolisers ofCYP2D6 substrates. Palonosetrondoes notinhibitorinduce cytochrome P450 isoenzymes atclinicallyrelevantconcentrations.

Elimination

After a singleintravenousdose of10 micrograms/kg[¹⁴C]-palonosetron,approximately80 % ofthe dose wasrecovered within144 hours in the urinewithpalonosetronrepresentingapproximately40 % of the administereddose, asunchanged active substance. Aftera single intravenous bolus administrationin healthysubjectsthetotalbody clearance ofpalonosetron was 173 ±73 ml/min and renalclearance was53 ±29 ml/min.Thelowtotalbodyclearanceand large volume of distribution resulted in aterminalelimination half-life in plasma of approximately40 hours.Ten percentof patients have a mean terminalelimination half-life greaterthan 100hours.

Pharmacokineticsin specialpopulations

Elderly people

Age does not affectthe pharmacokinetics ofpalonosetron. No dosage adjustmentis necessaryin elderlypatients.

Gender

Genderdoesnot affectthepharmacokineticsof palonosetron. No dosage adjustmentis necessary based on gender.

Paediatric population

Single-dose i.v. Palonosetron 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/kg a dose-proportional increase in mean AUC was observed. Following single dose intravenous infusion of Palonosetron 20 μg/kg, peak plasma concentrations (CT) reported at the end of the 15 minute infusion were highly variable in all age groups and tended to be lower in patients < 6 years than in older paediatric patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to 30 hours across 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 intravenous infusion of Palonosetron at 20 μg/kg over 15 min and in Adult Cancer Patients receiving 3 and 10 μg/kg palonosetron doses via intravenous bolus.

	Paediatric Cancer Patientsa				Adults Cancer Patientsb
	<2 y	2 to <6 y	6 to <12 y	12 to <17 y	3.0 μg/kg	10 μg/kg
	N=3	N=5	N=7	N=10	N=6	N=5
AUC0-∞, h·μg/L	69.0 (49.5)	103.5 (40.4)	98.7 (47.7)	124.5 (19.1)	35.8 (20.9)	81.8 (23.9)
t½, 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
Clearance c, L/h/kg	0.31 (34.7)	0.23 (51.3)	0.19 (46.8)	0.16 (27.8)	0.10 (0.04)	0.13 (0.05)
Volume of distributionc, d, L/kg	6.08 (36.5)	5.29 (57.8)	6.26 (40.0)	6.20 (29.0)	7.91 (2.53)	9.56 (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.

Renalimpairment

Mild tomoderate renalimpairmentdoes notsignificantlyaffectpalonosetron pharmacokinetic parameters. Severe renalimpairmentreducesrenalclearance,howevertotalbodyclearanceinthese patients is similarto healthysubjects. No dosage adjustmentis necessaryin patients withrenalinsufficiency. No pharmacokinetic datain haemodialysis patients are available.

Hepatic impairment

Hepaticimpairmentdoes notsignificantlyaffecttotalbody clearance of palonosetroncomparedto the healthysubjects.Whiletheterminalelimination half-life and mean systemic exposure ofpalonosetron is increased in the subjectswith severe hepaticimpairment, thisdoes notwarrantdose reduction.

Effectsin non-clinicalstudies were observed onlyat exposures considered sufficientlyinexcess ofthe maximumhuman exposureindicatinglittlerelevanceto clinicaluse.

Non-clinicalstudiesindicate thatpalonosetron, onlyatveryhigh concentrations, mayblockion channelsinvolved in ventricularde-and re-polarisation and prolongaction potentialduration.

Animalstudiesdo notindicate director indirectharmfuleffects with respectto pregnancy, embryonal/foetaldevelopment, parturition orpostnataldevelopment. Onlylimiteddatafromanimal studiesare available regardingthe placentaltransfer(see section 4.6).

Palonosetronis notmutagenic. High doses ofpalonosetron(each dose causingat least30 times the human therapeuticexposure)applied dailyfor two years causedan increasedrateof livertumours, endocrine neoplasms (inthyroid, pituitary, pancreas, adrenalmedulla)and skintumours in ratsbut not in mice.Theunderlyingmechanisms are notfullyunderstood, butbecause ofthe high doses employed and since Palonosetron Reig Jofreis intendedfor singleapplicationin humans, thesefindings are notconsidered relevant for clinicaluse.

Mannitol

Disodium edetate (dihydrate)

Sodium citrate (dihydrate) (to adjust pH)

Citric acid monohydrate (to adjust pH)

Water for injections

This medicinalproductmustnotbe mixed withothermedicinalproducts.

24 months.

Upon openingof the vial, use immediatelyand discardany unused solution.

This medicinalproductdoes notrequire any specialstorage conditions.

Type I glass vialwith chlorobutylsiliconised fluorotec rubberstopperand aluminiumcap. Available inpacks of1 vialcontaining5 mlof solution.

Single use only, any unused solution shouldbe discarded.

Anyunused productor waste materialshould be disposed of in accordance withlocalrequirements.

Marketing Authorisation Holder

Laboratorio Reig Jofre, S.A.

C/Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain

To be completed nationally

Date offirstauthorisation:To be completed nationally

Date oflatestrenewal:To be completed nationally

2016-08-03