LODOTRA 1

Lodotra-DL-May2012-02

SUMMARYOF PRODUCTCHARACTERISTICS

1. NAMEOF THEMEDICINAL PRODUCT

Lodotra1mgmodified-releasetablets

Lodotra2mgmodified-releasetablets

Lodotra5mgmodified-releasetablets

2. QUALITATIVEANDQUANTITATIVECOMPOSITION

Lodotra1mg:Eachmodified-releasetabletcontains 1mgofprednisone.

Lodotra2mg:Eachmodified-releasetabletcontains 2mgofprednisone.

Lodotra5mg:Eachmodified-releasetabletcontains 5mgofprednisone.

Thetabletscontain apprx.40mglactose.

Forafulllistofexcipients,seesection6.1.

3. PHARMACEUTICAL FORM

Modified-releasetablet

Lodotra1mg:

Pale yellowish-white,cylindricalmodified- releasetabletwith “NP1”embossedononeside.

Lodotra2mg:

Yellowish-white,cylindricalmodified- releasetabletwith “NP2”embossedon one side.

Lodotra5mg:

Lightyellow,cylindricalmodified- releasetabletwith “NP5”embossedononeside.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Lodotraisindicatedforthetreatmentofmoderate tosevere,active rheumatoid arthritisin

adultsparticularlywhen accompaniedbymorning stiffness.

4.2 Posologyand MethodofAdministration

Theappropriatedose dependsontheseverityoftheconditionandtheindividualresponse of

thepatient.Ingeneral,fortheinitiation ofthetherapy10mgprednisone isrecommended.In

certaincases,ahigherinitialdose mightberequired(e.g.15or20mg prednisone).

Dependingontheclinicalsymptomsandthepatient’s response,theinitialdose canbe

reduced instepstoa lowermaintenancedose.

When changingoverfromthestandardregimen(glucocorticoid administration inthemorning)

to Lodotraadministeredatbedtime(atabout10pm),thesamedose(inmg prednisone

equivalent)should bemaintained.Followingthechange-over,thedosemaybeadjusted

accordingtotheclinicalsituation.

Fordosesnotrealisable/practicable with thisstrength otherstrengthsofthismedicinalproduct

areavailable.Forlong-termtherapyofrheumatoid arthritis,theindividualdose ofupto 10mg

prednisonedailyshould beadjustedaccording totheseverityofthecourse ofthedisease.

Dependingonthetreatmentresult,thedosecanbereducedin stepsof1mgevery2-4

weekstoreachtheappropriatemaintenancedose.

In ordertodiscontinuethe therapywith Lodotra,thedose should bereducedin stepsof1mg

every2-4 weeks,with monitoring ofpituitary-adrenalaxisparametersifnecessary.

Lodotra-DL-May2012-02

Method ofAdministration:

Lodotrashould betakenatbedtime(atabout10pm),with oraftertheeveningmealandbe

swallowedwholewith sufficientliquid.Ifmorethan 2-3hourshave passed sincetheevening

meal,itisrecommendedtotakeLodotra with alightmealorsnack(e.g.aslice ofbread with

cheese).Lodotrashouldnotbeadministeredinthefastedstate.Thiscouldresultin areduced

bioavailability.

Lodotraisdesignedtorelease theactive substance with adelayofapproximately4-6 hours

afterintake,thereleaseoftheactive substanceandthepharmacologicaleffectswillstart

duringthenight.

Lodotramodified-releasetabletsconsistofaprednisone-containingcore andaninertcoating.

Delayedrelease ofprednisone is dependentonanintactcoating.Forthisreason,the

modified-releasetabletsarenotto bebroken,divided orchewed.

Because ofinsufficientdataontolerabilityand efficacy,theuseinchildrenand adolescentsis

notrecommended.

In patientswith hypothyroidismorhepaticcirrhosis,comparativelylowdoses maybesufficient

oradosereductionmaybenecessary.

4.3 Contraindications

Lodotraiscontraindicated inpatientswith hypersensitivityto prednisone orto anyofthe

excipients(seesection6.1).

4.4 SpecialWarnings andPrecautionsforUse

Aprednisone-basedpharmacotherapyshould onlybegivenwhen absolutelynecessaryand

should beaccompaniedbyappropriate anti-infectioustherapyinthepresenceofthefollowing

conditions:

- Acuteviralinfections(herpeszoster,herpessimplex,varicella,herpetickeratitis),

- HBsAg-positive chronicactive hepatitis,

- Approximately8weeksbeforeand 2weeksafterimmunisationwith livevaccines,

- Systemic mycosesand parasitoses(e.g.nematodes),

- Poliomyelitis,

- LymphadenitisfollowingBCGinoculation,

- Acuteandchronicbacterialinfections,

- Historyoftuberculosis(caution:reactivation!)Duetotheirimmunosuppressive

propertiesglucocorticoids caninduceoraggravate infections.Suchpatientsshouldbe

monitoredcarefullye.g.byperformingatuberculin test.Patientsatspecialriskshould

receive atuberculostatictreatment.

In addition,aprednisone-basedpharmacotherapyshould onlybegivenwhennecessaryand

should beaccompaniedifrequiredbyappropriatetherapyin thepresenceofthefollowing

conditions:

- Gastrointestinalulcers,

- Severeosteoporosisandosteomalacia

- Hypertension thatisdifficulttocontrol,

- Severediabetesmellitus,

- Psychiatricdisorders(also ifin patient’shistory),

- Narrow-and wide-angleglaucoma,

- Cornealulcersandcornealinjuries.

Becauseoftheriskofintestinalperforation,prednisone mayonlybeused ifabsolutely

necessaryand with adequatemonitoring incasesof:

- Severeulcerative colitiswith imminentperforation,

- Diverticulitis,

- Entero-anastomoses(immediatelypostoperative).

Lodotracannotachieve thedesiredbloodconcentrationofprednisoneiftakenunderfasting

conditions.Therefore,Lodotrashould alwaysbetakenwith oraftertheeveningmealin order

Lodotra-DL-May2012-02

to ensure sufficientefficacy.In addition,lowplasmaconcentrationsmayoccurin6%-7%of

Lodotradoses asobservedacrossallpharmacokineticstudies and11%ina single

pharmacokineticstudywhen takenaccordingtotherecommendations.Thisshould be

consideredifLodotra isnotsufficientlyeffective.Inthesesituationsa switch toa conventional

immediate-releaseformulation maybeconsidered.

TheuseofthemedicalproductLodotramayleadto positive resultsintheeventofdoping test.

Lodotrashould notbesubstitutedbyprednisoneimmediate-releasetabletsin thesame

administrationregime because ofLodotra’sdelayedreleasemechanism.

In caseofsubstitution,termination,ordiscontinuingprolongedtreatment,thefollowingrisks

mustbeconsidered:Recurrenceoftherheumatoid arthritisdisease activity,acuteadrenal

failure(especiallyin stressfulsituations,e.g.duringinfections,afteraccidents,with increased

physicalstrain),cortisone withdrawalsyndrome.

Lodotrashould notbegivenasforacute indications insteadofprednisoneimmediate-release

tabletsdueto itspharmacologicalproperties.

DuringtheuseofLodotra,apossiblyincreasedneedforinsulin ororalanti-diabetics should be

considered.Patientswith diabetesmellitus shouldtherefore betreatedunderclosemonitoring.

Duringthetreatmentwith Lodotra,regularbloodpressurechecksarerequiredin patientswith

hypertensionthatisdifficulttocontrol.

Patientswith severecardiac insufficiencyhave tobecloselymonitoredbecause oftheriskof

deteriorationofthecondition.

Sleep disorderisdocumentedto occurmorefrequentlywith Lodotrathanwith conventional

immediatereleaseformulations which are takenin themorning.Ifinsomnia occursanddoes

notimprove,aswitch toa conventionalimmediate releaseformulationmaybeadvisable.

Thetreatmentwith Lodotra canalsomasksignsandsymptomsofanexistingordeveloping

infectionandthusmayrenderdiagnosticeffortsmoredifficult.

Evenwith lowdoses,long-termuseofLodotraresultsin anincreasedriskofinfection.These

possible infectionsmayalso bebroughtaboutbymicroorganismsthatrarelycause infection

undernormalcircumstances (so-calledopportunisticinfections).

Certain viraldiseases(varicella,measles)maytakeamoreseverecoursein patientstreated

withglucocorticoids.Immunosuppressedindividualswithoutpriorvaricella ormeaslesinfection

areatparticularrisk.Ifsuchindividuals,while beingtreatedwith Lodotra,have contactwith

personsinfectedwith varicella ormeasles,apreventive treatmentshouldbeinitiated,if

required.

Vaccinationswith inactivatedvaccinesaregenerallypossible.However,ithasto betakeninto

accountthattheimmuneresponseandconsequentlythesuccessofthevaccinationmaybe

impairedwith higherdoses ofglucocorticoids.

In caseoflong-termtherapywith Lodotra,regularmedicalfollow-ups(including

ophthalmologicexaminationsatthreemonthintervals)areindicated;ifcomparativelyhigh

doses aregiven,sufficientsupplyofpotassiumsupplementsandrestrictionofsodiumhave to

beensuredandserumpotassiumlevelshave tobemonitored.

Ifduringthetreatmentwith Lodotrahighlevelsofphysicalstress arecausedbycertainevents

(accidents,surgicalprocedureetc.),atemporarydose increasemaybecome necessary.

Dependingonthedurationofthetreatmentandthedosage used,a negative impacton

calciummetabolismmustbeexpected.Osteoporosisprophylaxisisthereforerecommended

and is particularlyimportantifotherriskfactorsare present(includingfamilialpredisposition,

advancedage,postmenopausalstatus,insufficientintakeofprotein andcalcium,excessive

smoking,excessive alcoholconsumption,aswellasreduced physicalactivity).The

prophylaxisisbasedona sufficientsupplyofcalciumand vitaminD,aswellas onphysical

activity.In caseofpre-existingosteoporosis,anadditionaltherapyshouldbeconsidered.

Lodotra-DL-May2012-02

Themedicinalproductcontains lactosemonohydrate.Patientswith rare hereditaryproblems

ofgalactose intolerance,theLapplactasedeficiencyorglucose-galactosemalabsorption

should nottakethismedicine.

When usinghighdosesofprednisoloneforanextended periodoftime(30mg/dayfora

minimumof4 weeks),reversible disturbancesofspermatogenesiswereobservedthat

persistedforseveralmonthsafterdiscontinuationofthemedicinalproduct.

4.5 Interactionswith otherMedicinalProductsand otherFormsofInteraction

Cardiacglycosides:Theeffectoftheglycosidescanbeenhancedbypotassiumdeficiency.

Saluretics/laxatives:Potassiumexcretionisenhanced.

Antidiabetic agents:Theblood sugarlowering effectisreduced.

Coumarinderivatives:The efficacyofcoumarin anticoagulantsmaybereduced orenhanced.

Non-steroidalantiphlogistic/antirheumaticagents,salicylatesand indomethacin:Theriskof

gastrointestinalhaemorrhagesisincreased.

Non-depolarisingmusclerelaxants:Muscle relaxationmaybeprolonged.

Atropineandotheranticholinergics:TheconcurrentuseofLodotramayresultin additional

increases inintraocularpressure.

Praziquantel:Glucocorticoids maylowerthepraziquantelconcentrationsintheblood.

Chloroquine,hydroxychloroquine,mefloquine:Thereisanincreasedriskofoccurrence of

myopathies,cardiomyopathies.

Somatropin:Theefficacyofsomatropinmaybereduced.

Oestrogens(e.g.oralcontraceptives):Mayenhancetheefficacyofglucocorticoids.

Liquorice:Inhibitionofthe metabolismofglucocorticoids is possible.

Rifampicin,phenytoin,barbiturates,bupropionand primidone:Theefficacyofglucocorticoids

isreduced.

Cyclosporine:Thebloodlevelsofcyclosporineare increased.There isanincreasedriskof

seizures.

AmphotericineB:Theriskofhypokalaemiamaybe increased.

Cyclophosphamide:Theeffectsofcyclophosphamidemaybeenhanced.

ACEinhibitors:Increased riskofoccurrenceofblood countchanges.

Aluminiumandmagnesiumantacids:Theabsorptionofglucocorticoids isreduced.However,

due tothedelayedrelease mechanismofLodotra aninteractionbetween prednisone and

aluminium/magnesiumantacids is unlikely.

Impactondiagnosticmethods:Skinreactionscausedbyallergytestingmaybesuppressed.

TheTSHincreasefollowingtheadministrationofprotirelinmaybereduced.

4.6 Pregnancyand Lactation

Duringpregnancy,Lodotra should onlybeusedwhen thebenefitsoutweigh thepotentialrisks.

Thelowesteffective dose ofLodotra neededtomaintain adequate disease controlshould be

used.

Animalstudies indicatethatadministrationofpharmacologicaldosesofglucocorticoidsduring

pregnancymayincreasethefoetusriskofintrauterinegrowthretardation,adultcardiovascular

and/ormetabolicdiseaseandmayhave aneffectontheglucocorticoid receptordensity,and

neurotransmitterturnoverorneurobehaviouraldevelopment.

Prednisone hascausedcleftpalateformationinanimalexperiments(seesection5.3).Thereis

anongoingdiscussionon thepossibilityofanincreasedriskoforalcleftformationinthe

humanfoetusasaresultoftheadministrationofglucocorticoids duringthefirsttrimester.

Ifglucocorticoids areadministeredtowardstheendofpregnancy,there isariskofatrophyof

thefoetaladrenalcortex,which maynecessitatereplacementtherapyin the newborn,which

Lodotra-DL-May2012-02

hastobeslowlyreduced.

Glucocorticoids passin smallamountsinto breastmilk(upto 0.23%ofanindividualdose).

Fordosesupto10mgdaily,theamounttakenvia breastmilklies belowthedetection

threshold.Sofar,nodamageto infantshasbeen reported.Nevertheless,glucocorticoids

should onlybeprescribed when thebenefitstomotherand child outweightherisks.

Becausethemilk/plasmaconcentrationratio increaseswith doses above 10 mg/day(e.g.

25%oftheserumconcentrationarefoundinthebreastmilkwith 80mg prednisone daily),itis

recommendedtodiscontinue breastfeedinginsuch cases.

4.7 EffectsonAbilityto Drive andUseMachines

No studies ontheeffectsontheabilityto drive and usemachineshave beenperformed.

4.8 UndesirableEffects

Thefrequencyand severityoftheundesirableeffectslistedbelowdependondosageand

duration oftreatment.IntherecommendeddoserangeforLodotra(low-dose corticoid therapy

with dailydoses rangingfrom1to10mg),thelistedundesirable effectsoccurlessfrequently

with lowerseveritycomparedto dosesabove 10mg.

Thefollowingundesirable effectsmayoccurdependingonthedurationoftreatmentandthe

dosage:

verycommon(≥1/10);common(≥1/100to<1/10);uncommon(≥1/1000to<1/100);rare(≥

1/10000to<1/1000);veryrare(<1/10000),notknown(cannotbeestimatedfromthe

available data)

Blood and lymphatic systemdisorders:

Common:Moderate leucocytosis,lymphopoenia,eosinopoenia,polycythaemia

Immunesystemdisorders:

Common:Reducedimmune defence,masking ofinfections,exacerbationoflatentinfections

Rare:Allergicreactions

Endocrine disorders:

Common:Adrenalsuppressionand inductionofCushing'ssyndrome(typicalsymptoms:

moon-shapedface,upperbodyobesityand plethora)

Rare:Disturbedsexualhormonesecretion(amenorrhoea,impotence),disturbanceofthe

thyroidfunction

Metabolismand nutritionaldisorders:

Common:Sodiumretentionwithoedema,increasedpotassiumexcretion(caution:

arrhythmias),increasedappetite andweightgain,reducedglucosetolerance,diabetes

mellitus,hypercholesterolaemia and hypertriglyceridaemia

Psychiatricdisorders:

Common:Insomnia

Rare:Depression,irritability,euphoria,increasedimpulse,psychosis

Nervoussystemdisorders:

Common:Headache

Rare:Pseudotumorcerebri,manifestation ofa latentepilepsyand increasedpredispositionto

developseizuresin casesofmanifestepilepsy

Eye disorders:

Common:Cataract,especiallywith posteriorsubcapsularopacity,glaucoma

Rare:Aggravation ofsymptomsassociatedwith cornealulcer,promotionofviral,fungaland

bacterialeye inflammations

Vasculardisorders:

Uncommon:Hypertension,increasedriskofarteriosclerosisandthrombosis,vasculitis(also

as withdrawalsyndromefollowinglong-termtherapy)

Lodotra-DL-May2012-02

Disordersofthegastrointestinaltract:

Uncommon(noconcomitantNSAIDs):Gastrointestinalulcerations,gastrointestinal

haemorrhages

Rare:Pancreatitis

Skin andsubcutaneoustissuedisorders:

Common:Striaerubrae,atrophy,telangiectasia,increasedcapillaryfragility,petechiae,

ecchymoses

Uncommon:Hypertrichosis,steroid acne,delayedhealingofwounds,rosacea-like(perioral)

dermatitis,changesin skin pigmentation

Rare:Hypersensitivityreactions,e.g.drugexanthema

Musculoskeletaland connective tissuedisorders:

Common:Muscularatrophyand weakness,osteoporosis(dose-related,mayoccurevenwith

short-termuse)

Rare:Asepticosteonecrosis(humeralandfemoralhead)

4.9 Overdose

Acuteintoxications withLodotraarenotknown.In caseofoverdosing,anincreasein

undesirable effects,especiallyendocrine,metabolicand electrolyte-relatedeffects,canbe

expected(seesection4.8).

There is noknownantidoteforprednisone.

5. PHARMACOLOGICALPROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeuticgroup:Glucocorticoids

ATCcode:H02AB07

Prednisone is anon-fluorinatedglucocorticoidforsystemictherapy.

Prednisone showsa dose-dependenteffectonthe metabolismofalmostalltissues.Under

physiologicalconditions,these effectsarevitaltomaintain homoeostasisoftheorganismat

restand understress,aswellas forthecontroloftheactivities oftheimmunesystem.

In dosestypicallyprescribedforLodotra,prednisone hasanimmediateanti-inflammatory

(antiexsudative and antiproliferative)effectandadelayedimmunosuppressive effect.Itinhibits

chemotaxisandtheactivityofimmunecellsas wellas therelease and effectofmediatorsof

inflammatoryand immune reactions,e.g.oflysosomalenzymes,prostaglandins and

leucotrienes.

Prolongedtherapywith high dosesresultsin impairedresponse oftheimmune systemand of

theadrenalcortex.Themineralotropiceffectthatispronouncedinhydrocortisone isstill

detectable inprednisoneandmayrequiremonitoringofserumelectrolyte levels.

In patientswith rheumatoid arthritis,pro-inflammatorycytokinessuchastheinterleukinsIL-1

and IL- 6 andtumornecrosisfactoralpha (TNFα)reach peakplasmalevelsin theearly

morninghours(e.g.IL-6between 7to 8am).Cytokineconcentrationswereshown to

decrease afteradministration ofLodotraandsubsequentnight-timerelease ofprednisone

(with startofabsorptionbetween 2-4amandC

between 4-6 am).

Theefficacyand safetyofLodotrawas assessedin two randomised,double-blindcontrolled

studies inpatientswith active rheumatoid arthritis.

thefirststudy , amulti-centrerandomiseddouble-blindphaseIIIstudyof12weekduration

in atotalof288patientspre-treatedwith prednisoneorprednisolone,thegroup switchingto

Lodotraatthesame dose showeda meanreductionof23%inthedurationofmorning

stiffnesswhereastheduration inthereferencegroupdid notchange.Detailsarepresentedin

thefollowingtable.

Lodotra-DL-May2012-02

Relative change inthedurationofmorning stiffnessafter12weeksoftreatment:

Relative change[%] Lodotra

(n=125) Prednisone IR

(n=129)

Mean

(SD)

Median

(min,max) –23

(89)

–34

–100,500) 0

(89)

–13

–100,610)

In asubsequentopenlabelextensionphase(9monthstreatment)themean relative change in

theduration ofmorningstiffnesscomparedto baselinewas about−50%.

Change inthedurationofmorningstiffnessafter12monthstreatmentwith Lodotra:

DurationofMorning

stiffness[min] Lodotra

Mean

(SD) N

0 months

Startofthestudy 156

(97) 107

12months

Endofopenlabelphase 74

(92) 96

Inthesamestudy,after12weeksoftreatment,amediandecreaseofthepro-inflammatory

cytokineIL-6of29%was observedinthegrouptreatedwith Lodotra,whereasnochangewas

observedin thecomparatorgroupwhoreceivedstandardprednisone.After12months of

treatmentwith Lodotrathe IL-6 levelremainsstable.

Change intheIL-6 levelafter12months:

IL-6

[IU/L] Lodotra

median

(min,max) N

0 months

Startofthestudy 860

(200,23000) 142

12months

Endofopenlabelphase 470

(200,18300) 103

Values<200IU/L weresetto 200IU/Lforstatisticalanalyses

TheefficacyofLodotragiven on top ofaDMARD was confirmed in a second randomised,

placebo-controlled trial in patients insufficientlyrespondingto DMARD therapyalone. At

12weeks theLodotrapatients had asignificantlyhigherACR20 and ACR50 response rate

(46.8%and 22.1%,respectively)compared to placebo patients (29.4%and10.1%,

respectively).Therewasalso a greatermean changein DAS 28 scores from baseline(5.2 for

theLodotragroupand 5.1 forthe placebogroup)to week 12 in theLodotragroup(−1.2 points)

as compared with that seen in theplacebogroup (−0.7 pointchange).

Lodotra-DL-May2012-02

Inaddition, after12 weeks of therapythe mean duration ofmorningstiffness was 86.0 minutes

(-66 minutes change) in theLodotragroupand 114.1 minutes (-42.6 minutes change) in the

placebogroup.Lodotracould be safelyusedin combination with other DMARDs.

5.2 PharmacokineticProperties

Absorption:

Lodotraareprednisone-containingmodified-releasetablets.Prednisone isreleasedbetween

4-6 hoursfollowingintakeofLodotra.Subsequently,prednisone israpidlyand almost

completelyabsorbed.

Distribution:

Peakserumlevelsarereachedapproximately6-9 hoursafterintake.

Metabolism:

More than 80%oftheprednisone is convertedtoprednisolone byfirst-passhepaticmetabo-

lism.Theratio ofprednisone toprednisolone isapproximately1:6to1:10.Prednisone itself

exertsnegligible pharmacologiceffects.Prednisolone is theactive metabolite.Thecompounds

arereversiblybound to plasmaproteins with highaffinityfortranscortin (corticosteroid binding

globulin,CBG)andlowaffinityforplasma albumin.

Inthelowdose range(up to5mg),approximately6%offreeprednisolone is present.Metabo-

liceliminationisdose linearinthisrange.Inthedoserangeabove 10mg,thebindingcapacity

oftranscortinisincreasinglyexhaustedandmorefreeprednisolone is present.Thismayresult

in afastermetabolicelimination.

Elimination:

Prednisolone is primarilyeliminatedbyhepaticmetabolism,toapproximately70%by

glucoronidationandto approximately30%bysulphatation.Thereisalsoconversion to

11ß,17ß-dihydroxyandrosta-1,4-dien-3-one andto 1,4-pregnadien-20-ol.Themetabolites

exhibitnohormonalactivityand undergoprimarilyrenalelimination.Negligible amountsof

prednisone and prednisolone arefoundunchanged intheurine.Theplasma eliminationhalf-

life ofprednis(ol)oneisapproximately3 hours.Inpatientswith severehepatic dysfunctionthe

half-lifemaybeprolonged and adosereductionshould beconsidered.The durationofthe

biologicaleffectsofprednis(ol)one exceedsthedurationofthepresencein theserum.

Bioavailability

Abioavailabilitystudyin 27healthysubjectsconductedin 2003revealedthefollowingresults

in comparisonwith aprednisone immediate-release tablet:

Parameter Lodotra 5mg:

2.5hoursafter

a lightmeal Lodotra 5mg:

Immediatelyafter

a meal Reference

preparation

5 mg fasted

Maximumplasma

concentration(C

): ng/ml 20.2

(18.5;21.9) 21.8

(20.0;23.7) 20.7

(19.0;22.5)

Time ofmaximumplasma

concentration

):h 6.0

(4.5; 10.0) 6.5

(4.5; 9.0) 2.0

(1.0; 4.0)

Durationofthe delayofdrug

release (t

): h 4.0

(3.5; 5.0) 3.5

(2.0; 5.5) 0.0

(0.0; 0.5)

Areaunder theconcentration-

time curve (AUC

–∞ ):

ngxh/ml 110

(101;119) 123

(114;133) 109

(101;118)

Valuesareleast-squaregeometricmeans andrange

Lodotra-DL-May2012-02

Figure:Mean plasmalevelsofprednisone afterasingle doseof5mgprednisone

administeredasLodotra 5mgoranimmediate-releasetablet.5mg

immediate-releasetablet(A:fasted,intakeat2 am),Lodotra5mg(B:2.5

hours afteralighteveningmeal)andLodotra5 mg(C:immediatelyafter

a fulleveningmeal).

TheplasmaconcentrationprofilesofLodotra areverysimilarto animmediate-release tablet,

with theimportantdifferencethattheLodotra profile is delayedwith 4 –6 hoursafterdrug

intake.Lowerplasma concentrationshave beenobservedin 6-7%ofdoses.

DoseproportionalitywasdemonstratedforLodotra 1mg,2mg and 5mg based onAUCand

.

5.3 Pre-clinicalSafetyData

Subchronic/chronictoxicity

Lightand electronmicroscopicchangesin theLangerhans’isletcellsofratswereobserved

followingdailyintraperitonealadministrationof33mg/kgbwover7to14daysin rats.In

rabbits,experimentalliverdamage couldbeproducedbyadministering2to3mg/kg bw/day

for2to 4weeks.Histotoxiceffects(myonecroses)werereportedfollowingseveralweeksof

administrationof0.5to 5mg/kgbwinguinea pigsand 4mg/kg bwin dogs.

Mutagenic andtumour-formingpotential

Thetoxicityobservedinanimalstudieswith prednisone was associatedwith exaggerated

pharmacologicalactivity.Nogenotoxiceffectsofprednisone have beenobservedin

conventionalgenotoxicitytests.

Reproductive toxicity

In animalreproductionstudies,glucocorticoids such asprednisone have been shown to

inducemalformations(cleftpalate,skeletalmalformations).Withparenteraladministration,

minoranomalies ofskull,jawandtonguewerefound inrats.Intrauterinegrowth retardation

was observed(also seesection 4.6).

Similareffectsareconsideredunlikelyto occurinpatientsattherapeuticdoses.

6. PHARMACEUTICAL PARTICULARS

6.1 ListofExcipients

Lodotra-DL-May2012-02

Tabletcore:

Colloidalanhydroussilica

Croscarmellosesodium

Lactosemonohydrate

Magnesiumstearate

PovidoneK29/32

RedferricoxideE172

Tabletshell:

Colloidalanhydroussilica

Calciumhydrogenphosphate dihydrate

Glyceroldibehenate

Magnesiumstearate

PovidoneK29/32

YellowferricoxideE172

6.2 Incompatibilities

Notapplicable.

6.3 SpecialPrecautionsforStorage

Do notstore above 25°C.

NatureandContentsofContainer

HDPEcontainerswith 30and100modified-release tablets.

(Notallpacksizes maybe marketed).

7.Manufacturer:HorizonPharma,Germany.

8.Registrationholderandnumbers:

Lodotra1: 5833355541

Lodotra2: 5833555545

Lodotra5: 5833155548

Rafa LaboratoriesLtd.P.O.Box405 Jerusalem91003.

Theformat ofthis leafletwas determined bytheMinistryof Health that checkedand approved

its content inMay2012.