ETHYPHARM KETOPROFEN SR

Main information

  • Trade name:
  • ETHYPHARM KETOPROFEN SR
  • Dosage:
  • 200mg Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ETHYPHARM KETOPROFEN SR
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0549/009/002
  • Authorization date:
  • 08-02-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PA0549/009/002

CaseNo:2034767

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

EthypharmSA

17-21rueSt.Mattieu,78550Houdan,France

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

ETHYPHARMKETOPROFENSR200mgprolongedreleasehardcapsules

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/04/2007until14/04/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EthypharmKetoprofenSRCapsule200mg

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontainsketoprofen200mg.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Prolonged-releasecapsule,hard.

Capsule,hard,withopaquegreycapandopaquewhitebody,containingoff-whitesphericalmicrogranules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomatictreatmentof:

chronicinflammatoryrheumatism,suchasrheumatoidarthritisandankylosingspondylitis,

osteoarthritis.

4.2Posologyandmethodofadministration

Oraluse.

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.4).

Adultsandadolescentsovertheageof15years:

Theusualdailydoseis200mg,however100mgmaybesufficientinsomepatients.

Nodatahavebeenprovidedinchildrenintheseindications,sothisproductshouldonlybeusedinadultsand

adolescentsovertheageof15.

Adoseof100mgisparticularlyrecommendedinelderlypatients,inpatientswithchroniccongestiveheartfailureand

inpatientswithrenalimpairment(creatinineclearance30-50ml/min)orwithhepaticimpairment(seesection4.4

“Specialwarningsandspecialprecautionsforuse”).

Thecapsuleshouldbeswallowedwholewithfoodoncedaily,withalargeglassofwater.

4.3Contraindications

hypersensitivitytoketoprofenortoanyoftheexcipients,

lasttrimesterofpregnancy(seesection4.6“Pregnancyandlactation”),

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steroidalanti-inflammatoryagents(NSAIDs)oracetylsalicylicacid,

historyofgastrointestinalbleedingorperforation,relatedtopreviousNSAIDstherapy,

Active,orhistoryofrecurrentpepticulcer/haemorrhage(twoormoredistinctepisodesofprovenulcerationor

bleeding),

severehepaticfailure,

severerenalfailure,

severeuncontrolledheartfailure

gastrointestinalbleeding,cerebrovascularbleedingorotheractivebleeding.

4.4Specialwarningsandprecautionsforuse

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.2,andGIandcardiovascularrisksbelow).

TheuseofEthypharmKetoprofenSRwithconcomitantNSAIDsincludingcyclooxygenase-2selectiveinhibitors

shouldbeavoided.

Patientswithasthmaassociatedwithchronicrhinitis,chronicsinusitisand/ornasalpolyposisaremorelikelytoexhibit

allergicreactionsaftertakingacetylsalicylicacidand/ornon-steroidalanti-inflammatoryagentsthanthegeneral

population.Administrationofthisproductmayinduceanattackofasthma(seesection4.3“Contraindications”).

Gastrointestinaleffects

GIbleeding,ulcerationorperforation,whichcanbefatal,hasbeenreportedwithallNSAIDsatanytimeduring

treatment,withorwithoutwarningsymptomsoraprevioushistoryofseriousGIevents.

TheriskofGIbleeding,ulcerationorperforationishigherwithincreasingNSAIDdoses,inpatientswithahistoryof

ulcer,particularlyifcomplicatedwithhaemorrhageorperforation(seesection4.3),andintheelderly.Thesepatients

shouldcommencetreatmentonthelowestdoseavailable.Combinationtherapywithprotectiveagents(e.g.misoprostol

orprotonpumpinhibitors)shouldbeconsideredforthesepatients,andalsoforpatientsrequiringconcomitantlowdose

aspirin,orotherdrugslikelytoincreasegastrointestinalrisk(seebelowand4.5).

PatientswithahistoryofGItoxicity,particularlywhenelderly,shouldreportanyunusualabdominalsymptoms

(especiallyGIbleeding)particularlyintheinitialstagesoftreatment.

Cautionshouldbeadvisedinpatientsreceivingconcomitantmedicationswhichcouldincreasetheriskofulcerationor

bleeding,suchasoralcorticosteroids,anticoagulantssuchaswarfarin,selectiveserotonin-reuptakeinhibitorsoranti-

plateletagentssuchasaspirin(seesection4.5).

WhenGIbleedingorulcerationoccursinpatientsreceivingEthypharmKetoprofenSR,thetreatmentshouldbe

withdrawn.

NSAIDsshouldbegivenwithcaretopatientswithahistoryofgastrointestinaldisease(ulcerativecolitis,Crohn’s

disease)astheseconditionsmaybeexacerbated(seesection4.8–undesirableeffects).

Cardiovascularandcerebrovasculareffects

Appropriatemonitoringandadvicearerequiredforpatientswithahistoryofhypertensionand/ormildtomoderate

congestiveheartfailureasfluidretentionandoedemahavebeenreportedinassociationwithNSAIDtherapy.

ClinicaltrialandepidemiologicaldatasuggestthatuseofsomeNSAIDs(particularlyathighdosesandinlongterm

treatment)maybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexamplemyocardial

infarctionorstroke).Thereareinsufficientdatatoexcludesuchariskforketoprofen.

Patientswithuncontrolledhypertension,congestiveheartfailure,establishedischaemicheartdisease,peripheral

arterialdisease,and/orcerebrovasculardiseaseshouldonlybetreatedwithketoprofenaftercarefulconsideration.

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cardiovasculardisease(e.g.hypertension,hyperlipidaemia,diabetesmellitus,smoking).

Urineoutputandrenalfunctionshouldbecloselymonitoredinpatientswithrenalorhepaticimpairment,inpatientson

diuretictreatment,followingmajorsurgerywhichinvolvedhypovolaemia,andparticularlyintheelderly.

TheelderlyhaveanincreasedfrequencyofadversereactionstoNSAIDsespeciallygastrointestinalbleedingand

perforationwhichmaybefatal(seesection4.2).Intheelderly,ashalf-lifeofNSAIDsislonger,dosesshouldbe

reduced(seesection4.2.“Posologyandmethodofadministration”)

Duringlong-termtreatment,monitoringofbloodcountandhepaticandrenalfunctionisrecommended.

Skinreactions

Seriousskinreactions,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

epidermalnecrolysis,havebeenreportedveryrarelyinassociationwiththeuseofNSAIDSs(see4.8).Patientsappear

tobeathighestriskforthesereactionsearlyinthecourseoftherapy:theonsetofthereactionoccurringinthemajority

ofcaseswithinthefirstmonthoftreatment.EthypharmKetoprofenSRshouldbediscontinuedatthefirstappearance

ofskinrash,mucosallesions,oranyothersignofhypersensitivity.

Patientswithaprevioushistoryofphotosensitivityorphototoxicityreactionsshouldbecarefullymonitored.

Ketoprofen,asanyotherNSAID,maymasksymptomsofanunderlyinginfectiousdisease.

Theuseofketoprofen,aswithanydrugknowntoinhibitcyclooxygenase/prostaglandinsynthesis,mayimpairfertility

andisnotrecommendedinwomenattemptingtoconceive.Inwomenwhohavedifficultyconceivingorwhoare

undergoinginvestigationofinfertility,withdrawalofketoprofenshouldbeconsidered.

EthypharmKetoprofenSRisaslowreleaseformulation,thereforethistreatmentisnotsuitablewhenaquickonsetof

efficacyatthebeginningofthetreatmentisrequired.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Certainsubstancesortherapeuticclasseshaveapotentialtocontributetotheoccurrenceofhyperkalaemia:potassium

salts,potassium-sparingdiuretics,angiotensin-convertingenzymeinhibitors,non-steroidalanti-inflammatorydrugs

(NSAIDs),heparins(oflowmolecularweightornon-fractionated),cyclosporinandtacrolimus,andtrimethoprim.

Theoccurrenceofhyperkalaemiamaydependupontheexistenceofacombinationoffactors.

Thisriskisincreasedbycombinedadministrationoftheabove-namedsubstances.

Concomitantadministrationofketoprofenwiththefollowingproductscallsforstrictmonitoringofthepatient’s

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Combinationstobeavoided:

OtherNSAIDs(includingsalicylatesathighdoses):increasedriskofgastrointestinalulcerandhaemorrhage

(duetoadditivesynergiceffects).

Oralanticoagulants:increasedriskofahaemorrhagiceffectoftheoralanticoagulant(duetoinhibitionof

plateletfunctionanddamagetothegastroduodenalmucosabyNSAIDs).

Ifthecombinationcannotbeavoided,closeclinicalobservationandmonitoringoflaboratoryvaluesarerequired.

Heparins:(bytheparenteralroute):increasedriskofhaemorrhage(duetoinhibitionofplateletfunctionand

damagetothegastroduodenalmucosabyNSAIDs).

Ifthecombinationcannotbeavoided,itcallsforcloseclinicalobservation(andmonitoringoflaboratoryvaluesfor

nonfractionatedheparins).

Lithium:(reportedwithdiclofenac,ketoprofen,indomethacin,phenylbutazone,piroxicam):elevationoftheblood

lithiumlevels,whichmayattaintoxiclevels(viareducedrenalexcretionoflithium).

Ifnecessary,bloodlithiumlevelsshouldbecloselymonitoredandthedosageoflithiumadjustedduringthecombined

treatmentandafterwithdrawaloftheNSAID.

Methotrexate(atdosesabove15mg/week):Increasedhaematotoxicityofmethotrexate(duetoareductionof

renalclearanceofmethotrexatebyanti-inflammatoryagentsingeneralanddisplacementofmethotrexatefromits

plasmaproteinbindingsitesbyNSAIDs).

Methotrexateshouldnotbeadministeredlessthan12hoursbeforethestartoraftertheendofaketoprofentreatment.

Ticlopidine:increasedriskofhaemorrhage(duetosynergyoftheinhibitoryeffectsonplateletaggregation).

Ifthecombinationcannotbeavoided,closeclinicalobservationandmonitoringoflaboratoryvalues(including

bleedingtime)arerequired.

Combinationstobeadministeredwithprecaution:

Diuretics,angiotensinconvertingenzymeinhibitors:acuterenalfailureindehydratedpatients(reduced

glomerularfiltrationduetodecreasedrenalprostaglandinsynthesis).

Additionally,theantihypertensiveeffectisreduced.

Thepatientshouldbehydratedandrenalfunctionmonitoredatthestartoftreatment.

Corticosteroids:increasedriskofgastrointestinalulcerationorbleeding(seesection4.4).

Anti-coagulants:NSAIDsmayenhancetheeffectsofanti-coagulants,suchaswarfarin(seesection4.4).

Anti-plateletagentsandselectiveserotoninreuptakeinhibitors(SSRIs):increasedriskofgastrointestinalbleeding

(seesection4.4).

Methotrexateatlowdoses(lessthan15mg/week):increasedhaematotoxicityofmethotrexate(duetoa

reductionofrenalclearanceofmethotrexatebyanti-inflammatoryagentsingeneralanddisplacementofmethotrexate

fromitsplasmaproteinbindingsites).

Weeklymonitoringofbloodcountisrecommendedduringthefirstweeksofcombinedtreatment.

Closerobservationisnecessaryintheeventofany(evenmild)impairmentofrenalfunctionandinelderlysubjects.

Pentoxifylline:increasedriskofhaemorrhage.

Clinicalobservationshouldbeincreasedandbleedingtimemonitoredmorefrequently.

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anaemiaeightdaysafterthestartoftheNSAIDtreatment.

Fullbloodcountandreticulocytecountarerecommendedeightto15daysafterthestartoftheNSAIDtreatment.

Combinationstobegivendueconsideration:

Beta-blockers:(byextrapolationfromreportedinteractionwithindomethacin):reducedantihypertensiveeffect

(inhibitionofvasodilatorprostaglandinsbyNSAIDs).

Cyclosporin,tacrolimus:riskofadditivenephrotoxiceffects,particularlyinelderlysubjects.

Intrauterinecontraceptivedevice:thereisacontroversialpossibilityofdecreasedefficacyoftheintrauterine

contraceptivedevice.

Thrombolytics:increasedriskofhaemorrhage.

4.6Pregnancyandlactation

Pregnancy:

Noparticularmalformationeffectshavebeenreportedinhumans.Howeverclinicalexperienceofuseinpregnancyis

limited.

Duringthelasttrimesterofpregnancy,allprostaglandinsynthesisinhibitorsmayexposethefoetusto:

cardiopulmonarytoxicity(pulmonaryhypertensionwithprematureclosureoftheductusarteriosus),

renaldysfunctionwhichmayprogresstorenalfailurewitholigoamnios;

exposethemotherandchild,attheendofpregnancy,topossibleprolongationofbleedingtime;

inhibituterinecontractionsanddelay/prolongdelivery.

Consequently,NSAIDsshouldbeadministeredonlyifnecessaryduringthefirsttwotrimestersofpregnancy.Withthe

exceptionofveryrestrictedobstetricaluseswhichrequirespecialisedmonitoring,prescriptionofNSAIDsis

contraindicatedinthelasttrimesterofpregnancy.

Lactation:

SinceNSAIDsareexcretedinbreastmilk,theiruseshouldbeavoidedduringbreast-feedingasaprecautionary

measure.

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbewarnedthatthereisapossibilityofdizziness,drowsinessandblurredvision.

4.8Undesirableeffects

ClinicaltrialandepidemiologicaldatasuggestthatuseofsomeNSAIDs(particularlyathighdosesandinlongterm

treatment)maybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexamplemyocardial

infarctionorstroke)(seesection4.4).

Oedema,hypertension,andcardiacfailure,havebeenreportedinassociationwithNSAIDtreatment.

Themostcommonly-observedadverseeventsaregastrointestinalinnature.Pepticulcers,perforationorGIbleeding,

sometimesfatal,particularlyintheelderly,mayoccur(seesection4.4).Nausea,vomiting,diarrhoea,flatulence,

constipation,dyspepsia,abdominalpain,melaena,haematemesis,ulcerativestomatitis,exacerbationofcolitisand

Crohn’sdisease(seesection4.4-Specialwarningsandprecautionsforuse)havebeenreportedfollowing

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4.9Overdose

Inadultsandadolescents,themainsignsofoverdoseareheadache,dizziness,drowsiness,nausea,vomiting,diarrhoea

andabdominalpain.Inseriousintoxication,hypotensionandrespiratorydepressionandgastrointestinalhaemorrhage

havebeenobserved.

Thepatientshouldbetransferredimmediatelytoaspecialisedhospitalunitwheresymptomatictreatmentshouldbe

instituted.Owingtotheslowreleasecharacteristicsoftheproduct,ketoprofenwillcontinuetobeabsorbed16hours

afteringestion.

Evacuationofgastriccontentoradministrationofactivatedcharcoalmaybeperformedinordertoreducethe

absorptionofketoprofen.

Thereisnospecificantidote.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Propionicacidderivates:ATCCode:M01AE03

Systemorganclass Common

(1-10%) Uncommon

(0.1-1%) Rare

(0.01-0.1%) Veryrare/isolatedreports

(less0.01%)

Blood and the lymphatic

systemdisorders Leukopenia, anaemia,

thrombocytopenia,

pancytopenia,

agranulocytosis

Psychiatricdisorders Mooddisorder

Nervoussystemdisorders Headache,

dizziness,

drowsiness,

somnolence

Eyedisorders Blurredvision

Earandlabyrinthdisorders tinnitus

Cardiacdisorders Congestiveheartfailure,

hypertension

Respiratory, thoracic and

mediastinaldisorders Possibleasthmaticattacks,

particularlyinpatientswith

known allergy to

acetylsalicylicacidandother

NSAIDs

Gastrointestinaldisorders Nausea, vomiting,

diarrhoea,constipation,

abdominal pain,

gastrointestinal

discomfort,gastralgia Peptic ulcer,

gastrointestinal

bleeding, intestinal

perforation

Hepatobiliarydisorders Elevation of

transaminases levels,

hepatitis

Skinandsubcutaneoustissue

disorders Eruption,rash,

pruritis exacerbated chronic

urticaria,alopecia Bullous eruption (Steven

Johnson,Lyellsyndrome),

Angioedema, erythema

multiform,photosensitivity

Renalandurinarydisorders Abnormalrenalfunction

tests,acuterenalfailure,

interstitial nephritis,

nephroticsyndrome Oedema (especially in

patientswithhypertension)

General disorders and

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Ithasthefollowingproperties:

analgesicactivity,

antipyreticactivity,

anti-inflammatoryactivity,

inhibitionofplateletfunctions.

Allthesepropertiesresultfromthereductionofprostaglandinsynthesisbyinhibitionofthecyclo-oxygenasepathway.

5.2Pharmacokineticproperties

EthypharmKetoprofenSRisapH-independentprolonged-releaseformofketoprofenintendedforaonce-a-day

therapeuticdosageregimen.

Theketoprofenmicrogranulesaredispersedgraduallyintheintestinaltract.

Absorption

Afteroraladministration,ketoprofenisalmostcompletelyabsorbedfromtheintestinaltractbutundergoesfirst-pass

metabolism.

Amaximumplasmaconcentrationofabout2.7µg/mlisattainedabout6hoursafteradministrationofadoseof200

mg;significantlevelsarefoundatthe24thhour.Theproductdoesnotaccumulateafterrepeatedadministrationinthe

courseoftreatment.

Thedegreeofabsorptionisnotinfluencedbyconcomitantfoodintake.

Distribution

EthypharmKetoprofenSRcapsuleprocurescontinuous,regularimpregnationwithketoprofen.

Ketoprofenis99%boundtoplasmaproteins.

Ketoprofendiffusesintosynovialfluid,wherelevelshigherthantheserumconcentrationsarefoundmorethan4hours

afteroraladministration.

Itcrossestheplacentalbarrier.

Metabolism

Twoprocessesareinvolvedinthebiotransformationofketoprofen:oneveryminor(hydroxylation),andtheother

largelypredominant(conjugationwithglucuronicacid).

Lessthan1%ofthedoseofketoprofenadministeredisrecoveredinunchangedformintheurine,whereasthe

glucuronidemetaboliteaccountsforabout65to75%.

Excretion

Thedrugisexcretedasmetabolitesessentiallybytheurinaryroute.Therateofexcretionisrapid,since50%ofthe

doseadministerediseliminatedinthefirst6hours,regardlessoftherouteofadministration.Theprolonged-release

formdoesnotaltertherenalexcretionprocesses.

Thehalf-lifefortheterminaleliminationphaseisabout7hours.

Inthe5daysafteroraladministration,75to90%ofthedoseisexcretedbythekidneysand1to8%inthefaeces.

Populationsatrisk

Theeliminationofketoprofenisdecreasedintheelderlyandthehalf-lifeisprolonged.

Thehalf-lifeinpatientswithrenalinsufficiencyincreaseswiththeseverityoftheimpairment(seesection4.2

“Posologyandmethodofadministration”).

5.3Preclinicalsafetydata

Insubchronicandchronicexperiments,ketoprofenresultedintheformationoflesionsandulcerationinthe

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Inseveralinvitroandinvivomutagenicitytestsketoprofenhadnosignificantpositiveeffects.Long-termexperiments

inratsandmiceshowednoevidenceofacarcinogenicpotentialofketoprofen.

Experimentsinvariousanimalspeciesshowednoevidenceofateratogeniceffectofketoprofen.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sucrose,

Maizestarch,

EudragitNE30D(PolyacrylateDispersion30%),

EudragitRS30D(Poly[ethylacrylate,methylmethacrylate,trimethylammonioethylmethacrylatechloride]1:2:0.1

(dispersion30%)),

EudragitRL30D(Poly[ethylacrylate,methylmethacrylate,trimethylammonioethylmethacrylatechloride]1:2:0.2

(dispersion30%)),

Triethylcitrate,

Colloidalanhydroussilica,

Talc

Capsuleshell:titaniumdioxide(E171),gelatin,blackironoxide(E172).

Printingink:shellac,potassiumhydroxide,blackironoxide(E172).

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Prolonged-releasecapsule,hardinPVC/Aluminiumblisters,packof10,14,15,28,30,100.

Prolonged-releasecapsule,hardinPolypropylenecontainer:30,100capsules.

Notallpacksizesandcontainermaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ETHYPHARMSA

17/21,rueSaintMatthieu

F-78550Houdan

FRANCE

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:08February2002

Dateoflastrenewal:16April2004

10DATEOFREVISIONOFTHETEXT

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