SLOW - K

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ודילערשואוקדבנונכותותואירבהדרשמ י"עעבקנהז ןולעטמרופ יאמב 3102

SLOW-K ®

(potassiumchloride)

600 mgsugar-coatedtablets

Prescribing Information

1 Tradename

SLOW-K ®

600 mgsugar-coatedslowreleasetablets.

2 Descriptionandcomposition

Onesugar-coatedtabletcontains600mgpotassiumchlorideasactivesubstanceequivalentto

8mmol potassium ion (K +

).

Pharmaceuticalform

Slow-K,designedfororalpotassiumsupplementation,isasustained-releasedosageform

containingpotassiumchloride(KCl)finelydispersedinaneutralmatrix.Thisformulationis

intended to slow downreleaseofthe activesubstanceso that thelikelihood ofahigh localized

concentrationofKClwithinthegastro-intestinaltract(GIT)isreduced.Thereleaseofthe

activesubstanceislargelypH-independentandoccursataratesufficienttoensurecomplete

absorptionduringitstransitthroughtheGIT.Theinsolublematrixisexcretedinasoftened

form in the feces.

Activesubstance

Potassiumchloride

Activemoiety

Potassium

Excipients

Cetostearylalcohol,gelatin,magnesiumstearate,acacia,titaniumdioxide(E171),purified

talc,sucrose,DispersedBuff70753(redironoxide(E172),yellowironoxide(E172),

titaniumdioxide), carnaubawax.

3 Indications

Treatmentand prevention of hypokalaemia.

4 Dosageandadministration

Generalrules

Theusualdietaryintakeofpotassiumbytheaverageadultis50to100mmolperday.Asa

rule,potassiumdepletionsufficienttocausehypokalemiadoesnotoccuruntilatleast

200mmol of potassiumhas been lostfrom the total bodystore.

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Dosagemustbeadjustedto theindividual needs ofeach patient and to the cause and degreeof

themanifestorpotentialhypokalemicstate.Whereintermittentdiuretictherapyisbeingused,

itis advisableto give Slow-K on theinterveningdays betweenadministrations of thediuretic.

Ifthedosageexceeds20mmolK +

,itshouldbetakenindivideddoses,sothatnotmorethan

20mmol is given inasingle dose.

GeneralPopulations

Dependingonthepatient’sindividualneeds,adailydosageof2to3sugar-coatedtablets(16

to 24mmol K +

) should generallyprovesufficient forthe prevention ofhypokalemia.

Whencorrectinghypokalemia,dosesof40to50upto100mmolK +

(correspondingto5to6

upto12sugar-coatedtablets)mayberequired,dependingontheinitialplasmaK +

concentration.Theresponsetothetreatmentshouldpreferablybemonitoredbyrepeated

determinationofplasmapotassium,andSlow-Kshouldbecontinueduntilthehypokalemia

has been corrected.

Specialpopulations

Renalimpairment

Inpatientwithmildtomoderaterenalimpairment,SlowKshouldbegivenwithextreme

cautionwithfrequentserumpotassiummonitoringduetoincreasedriskofhyperkalemia.

Slow-Kiscontraindicatedinpatientswithsevererenalimpairment(seealsosection5

Contraindications).

Hepaticimpairment

Nostudieshavebeenperformedinhepaticallyimpairedpatients.However,Slow-Kshouldbe

givenwithcautionduetoincreasedlikelihoodofelectrolytedisturbancesinpatientswith

hepaticimpairment (seealso section 5 Contraindications).

Pediatrics

Safetyandeffectivenessinchildrenhavenotbeenestablished,Slow-Kisthereforenot

recommendedforpediatric use.

Geriatrics(olderthan65years)

Slow-Kshouldbegivenwithcautionandwithfrequentserumpotassiummonitoringdueto

increased risk ofhyperkalemia.

Method ofadministration

Slow-Kisadvisedtobegivenwithorafterfoodtominimizegastricirritation.The

sugar-coatedtabletsmustnotbecrushed,chewed,orsucked,butshouldbeswallowedwhole

with an adequateamountof fluid while thepatientis sittingupright.

5 Contraindications

Hypersensitivitytopotassiumadministration,asfound,forexample,inadynamia

episodicahereditariaandcongenitalparamyotonia,orhypersensitivitytoanyofthe

excipients.

Allformsofhyperkalemia,sinceafurtherincreaseintheserumpotassiumconcentration

insuchpatientscanproducearrhythmiaandcardiacarrest.Hyperkalemiamaycomplicate

anyofthefollowingconditions:markedrenalfailure,conditionsinvolvingintensivecell

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destruction(e.g.trauma,burns,massivehemolysis,rhabdomyolysis,tumorlysis),

untreatedAddison’sdisease,hyporeninemichypoaldosteronism,aswellas

decompensatedcases ofmetabolicacidosis andacute dehydration.

Hyperkalemicperiodicparalysis:Itisaninheritedautosomaldominantdisorderwhich

affectssodiumchannelsinmusclecellsandtheabilitytoregulatepotassiumlevelsinthe

blood.Thetermhyperkalemicismisleadingsincepatientsareoftennormokalemicduring

attacks.Thefactthatattacksareprecipitatedbypotassiumadministrationbestdefinesthe

disease.

Severerenal failure, evenwhen itis notyet associated with manifest hyperkalemia.

Concomitanttreatmentwithpotassium-sparingdiuretics(spironolactone,triamterene,

amiloride) (seealso section 8Interactions).

Furthermore,andaswithallothersustained-releaseformsofpotassiumchloride,Slow-K

iscontraindicatedinanypatientsinwhomthereiscauseforarrestordelayintablet

passagethrough theGIT.Thesestates include:

Partialorcompleteesophagealobstruction,e.g.bycarcinomas(esophageal,

postcricoidal,thyroidal),aorticaneurysm,left-atrialenlargement,inflammatory

strictureduetorefluxesophagitis,andesophagealdisplacementduetocardiac

surgery(e.g. valvereplacement).

StenosisoratonyinanypartoftheGIT(e.g.pyloricstenosis,intestinal

strictures).

6 Warningsandprecautions

Gastrointestinaldisorders

IfapatienttreatedwithSlow-Kdevelopspronouncednausea,severevomiting,severe

abdominalpainsorflatulence,diarrheaorgastro-intestinalhemorrhage,thepreparation

shouldbewithdrawnatonce,becausethesesignsandsymptomsmaypointtothepresenceof

ulceration orperforation in theGIT (seealso section 7 Adversedrugreactions).

Suchrisksmaybeincreasedinpatientswithesophagealstasis,knownpepticand/orgastric

ulcers,delayedintestinaltransit,orintestinalischemiaduetogeneralizedatherosclerotic

vasculardisease.

Sinceanticholinergicdrugsmayreducegastrointestinalmotility,theyshouldbeprescribed

withgreatcarewhengivenconcomitantlywithsolidoralpotassiumpreparations,particularly

in high dosage(seealso section 8Interactions).

Patientswithostomiesmayhaveanalteredintestinaltransittimeandarebettertreatedwith

otherforms of potassiumsalts.

Hyperkalemia

Inpatientswithimpairedmechanismsforexcretingpotassium,theadministrationof

potassiumsaltscanproducehyperkalemiaandcardiacarrest.Thisarisesmostcommonlyin

patientsgivenpotassiumbythei.v.route,butitmayalsooccurinpatientsreceiving

potassiumorally.Potentiallyfatalhyperkalemiacandeveloprapidlyandmaybe

asymptomatic.Theuseofpotassiumsaltsinpatientswithchronicrenaldisease,oranyother

conditionwhichimpairspotassiumexcretion,requiresparticularlycarefulmonitoringofthe

serum potassiumconcentration and appropriate dosageadjustments.

Slow-Kshouldbeusedwithcautioninpatientsreceivinganydrugknowntohaveapotential

forhyperkalemia,suchasACEinhibitors,angiotensin-II-receptor-antagonists,NSAIDs(e.g.

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indomethacin),beta-blockers,heparin,digoxinandciclosporin(seealsosection

8Interactions).

Metabolicacidosis

Hypokalemiainpatientswithmetabolicacidosisshouldbemanagednotwithpotassium

chloride,butwithanalkalinizingpotassiumsalt,suchaspotassiumbicarbonate,potassium

citrate, orpotassiumacetate.

Treatment monitoring

Periodicserumpotassiumdeterminationsarerecommendedduringlong-termpotassium

supplementation,especiallyinclinicalconditions,whichcarryariskofhyperkalemia(e.g.

impairment of renalfunction, heart disease) (seealso section 8Interactions).

Inaddition,carefulattentionshouldbepaidtotheacid-basebalance,tootherserum

electrolytelevels(e.g.magnesium,seebelow),totheECG,andtotheclinicalstatusofthe

patient.

Whenbloodsamplesaretakenforanalysisofplasmapotassium,itisimportanttobearin

mindthatartifactualelevationscanoccurafteranimproperveinpuncturetechniqueorasa

resultofin vitrohemolysis of the sample.

Other

Insomepatients,diuretic-inducedmagnesiumdeficiencywillpreventtherestorationof

intracellulardeficitsofpotassium,sothathypomagnesemiashouldbecorrectedatthesame

time as hypokalemia.

Slow-Kcontainssucrose(=saccharose).Patientswithrarehereditarydisorderslike

fructose-intolerance,glucose-galactosemalabsorption,orsucrase-isomaltaseinsufficiency

should not usethis medicine.

7 Adversedrugreactions

Adversedrug reactionsfrom post-marketing experience(frequencynot known)

Thefollowingadversedrugreactionshavebeenderivedfrompost-marketingexperiencewith

Slow-K.Becausethesereactionsarereportedvoluntarilyfromapopulationofuncertainsize,

itisnotpossibletoreliablyestimatetheirfrequencywhichisthereforecategorizedasnot

known.AdversedrugreactionsarelistedaccordingtosystemorganclassesinMedDRA.

Within each system organ class, ADRs arepresented in order ofdecreasing seriousness.

Table 7-1 Adversedrugreactions frompost-marketingexperience(frequency

notknown)

Gastrointestinaldisorders

Gastrointestinalobstruction, gastrointestinalhemorrhage, gastrointestinalulcer,withorwithout

perforationoftheupper orlower GIT, delayedintestinaltransit orobstruction in the GIT. Nausea,

flatulence,vomiting, abdominalpain, diarrhea

Skinandsubcutaneoustissue disorders

Urticarial, rash,pruritus

Metabolism andnutritiondisorders

Hyperkalemia:eitherwith renalpotassiumexcretionorwithinternaldisposal

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8 Interactions

Observed Interactionsresulting in acontraindication

Potassium-sparing diuretics

Concomitanttreatmentwithpotassium-sparingdiuretics(spironolactone,triamterene,

amiloride)iscontraindicated(seealsosection5Contraindications).Drugswhichinterfere

withpotassiumexcretionmaypromote hyperkalemiawhengiven togetherwith Slow-K.

Anticipated interactionsresultingin concomitant usenot beingrecommended

Drugs causing hyperkalemia

Slow-Kshouldbeusedwithcautioninpatientsreceivinganydrugknowntohaveapotential

forhyperkalemia,suchasACEinhibitors,angiotensin-II-receptor-antagonists,NSAIDs(e.g.

indomethacin),beta-blockers,heparin,digoxinciclosporin(seealsosection6Warningsand

precautions).

Interactionstobeconsidered

Drugs causing hyperkalemia

Otherdrugssuchasdirectrenininhibitors(e.g.aliskerin)andprotonpumpinhibitorscan

causehyperkalemiawhenusedconcomitantlywithSlow-K.Thus,cautionshouldexercisein

theirconcomitant use.

Anticholinergics:Sinceanticholinergicdrugsmayreducegastrointestinalmotility,they

shouldbeprescribedwithgreatcarewhengivenconcomitantlywithsolidoralpotassium

preparations, particularlyin high dosage(seealso section 6Warnings andprecautions).

9 Womenofchild-bearingpotential,pregnancy,breast-feeding

andfertility

Women of child-bearing potential

Thereareno special recommendations.

Pregnancy

ForSlow-K no clinical dataon exposedpregnancies areavailable.

Thereisnoindicationinanimalstudiesofdirectorindirectharmfuleffectswithrespectto

pregnancy,embryonal/foetaldevelopment,parturitionorpostnataldevelopment(seealso

section 13 Non-clinical safetydata).

Asageneralrule,nodrugsshouldbetakenduringthefirst3monthsofpregnancy,andthe

benefitsandrisksoftakingdrugsshouldbecarefullyconsideredthroughoutthewholeof

pregnancy. Pregnancyis associated withgastrointestinal hypomotility.

Inpregnantwomen,therefore,soliddosageformsoforalpotassiumshouldonlybegivenif

such therapyis considered essential.

Breast-feeding

Theexcretion ofpotassium in milk has not been studied in animals or human.

ThenormalK +

contentofhumanmilkisabout13mmol/L.Sinceoralpotassiumbecomes

part ofthe body’s potassium pool, as longas bodypotassiumis not excessive, the contribution

ofSlow-K can beexpected to havelittle orno effect on thepotassiumlevel in human milk.

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Slow-Kshouldonlybegivenduringbreast-feedingwhentheexpectedbenefittothemother

outweighs thepotentialrisk to thebaby.

Fertility

Thereareno special recommendations.

10 Overdosage

Signsandsymptoms

Theclinicalpictureofacuteoverdosage(intoxication)withpotassiumischaracterizedchiefly

byhyperkalemiatogetherwithcardiovascularandneuromusculardisturbances,which,inthe

presenceof renal impairment, mayalreadydevelop followingrelativelylow doses of Slow-K.

Cardiovascular system

Ventriculararrhythmias,bundle-branchblockandventricularfibrillation,accompaniedby

hypotension andshock, possiblyleadingto cardiacarrest.

Besideselevationoftheserumpotassiumconcentration,typicalECGchangesarealso

encountered(increasedamplitudeandpeakingofTwave,disappearanceofPwave,widening

ofQRScomplex, and STsegment depression).

Centralnervoussystemand muscles

Paraesthesiae,convulsions,areflexia,flaccidparalysisofstriatedmusclesleadingpossiblyto

respiratoryparalysis.

Treatment

Incases of acutepoisoning, remove and/or inactivate excess potassium by:

Inductionofvomiting

Gastric lavage

Administrationofcationexchangeresinbymouthorgastricinstillation(e.g.20gsodium

polystyrenesulfonate with 20 mL70%sorbitolsolution.

Inmoderatelyseverehyperkalemia(plasmapotassiumbetween6.5and8mmol/L,aswellas

Twavepeakingas the onlyECG abnormality):

Promotetranscellularshiftofpotassiumbyadministeringi.v.300to500mL/hourof10%

dextrosesolution containing10 to 20 units of insulin per 1,000 mL.

Correctacidosis,ifpresent,withi.v.sodiumbicarbonate(44to132mmol/Lofglucose

solution).

Correct hyponatraemiaand hypovolaemia, if present.

Inseverehyperkalemia(plasmapotassiumexceeding8mmol/LorECGabnormalities

includingabsenceofPwave,presenceofwidenedQRScomplex,disappearanceofTwave,

orventriculararrhythmia):

Infuseglucose(with insulin)and/or bicarbonate i.v. as described above.

Administer10to30mL10%calciumgluconatei.v.over1to5minutesundercontinuous

ECGmonitoring;administercationexchangeresinbyhighretentionenemaasfollows:30

to50gsodiumpolystyrenesulfonatesuspendedin100mLwarmaqueoussorbitol

solutionshouldbekeptinthesigmoidcolonforseveralhours,ifpossible.Thecolonis

thenirrigatedwithanon-sodium-containingsolutiontoremovetheresin.Repeated

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enemas can beadministered, ortheresingivenrepeatedlybymouth, in order to maintain a

physiological potassium concentration.

Hemodialysisorperitonealdialysismaybeofuse,particularlyinpatientswithrenal

failure.

When treatinghyperkalemia, itshould bebornein mind that, in patients who havebeen

stabilized on digitalis, loweringthe serum potassium concentration too rapidlycan

producedigitalis toxicity.

11 Clinicalpharmacology

Pharmacodynamics(PD)

Pharmacotherapeuticgroup: Potassiumsupplement, ATC code: A12BA01

Potassium,asthemostabundantintracellularcation,playsanessentialroleinseveral

importantphysiologicalfunctions,includingtransmissionofnerveimpulses,contractionof

cardiac,skeletal,andsmooth-muscletissues,andmaintenanceofnormalrenalfunction.It

alsoaidsintheregulationofosmoticpressureandtheacid-basedbalance.Concentrationsof

rangeinintracellularfluidfrom130to150upto160mmol/Landinplasmafrom3.5to

5mmol/L.Althoughthereisnouniformcorrelationbetweenplasmaconcentrationsof

potassiumandtotalbodystores,clinicalsignsofK +

deficiencyareusuallyobserved

whenevertheplasmapotassiumconcentrationfallsbelow3.5mmol/L(hypokalemia).These

signsinclude:impairedneuromuscularfunction,whichmayvaryfromminimalweaknessto

frankparalysis;intestinaldilatationandileus;and,morefrequently,abnormalitiesmyocardial

functionwithdisturbedECGpatternscharacterizedbyaprolongedPRinterval,an

exaggerated Uwave,abroad and flat T wave,andadepressed ST segment.

Hypokalemiacanbepreventedand/orcorrectedbygivingsupplementarypotassium.Apart

fromincreasingdietaryintakeofpotassium-richfoods,whichmaynotalwaysbepracticable,

asuitablealternativeistoadministerSlow-K.Inviewofthefrequencywithwhichdeficitsof

andCL -

coexist,potassiumchlorideisthepreferredsaltformostoftheclinicalconditions

associated with hypokalemia.

Pharmacokinetics(PK)

Absorption

WhenSlow-Kisgiveninasingledoseof5or6sugar-coatedtabletsequivalentto40or

48mmolK +

,KClisgraduallyreleasedoveraperiodofapprox.4hoursduringitstransit

throughtheGIT.ThepatternofitsabsorptionissuchthatrenalexcretionoftheKCloccurs

30-60 minutes later thanwhen the same doseis given in theform of asolution.

Elimination

Inthepresenceofnormalpotassiumbalance,approx.90%ofthepotassiumsuppliedby

Slow-K is excreted viathe kidneyswithin 8hours, and morethan 98%within 24 hours.

Specialpopulation

ElderlyPatients

Nopharmacokineticsstudiesofpotassiumchloridearereportedinelderlypopulation.

However,thesepatientsaremorelikelytodevelophyperkalemiaduetophysiological

changes, andreduced renal function.

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Pediatrics

No pharmacokinetics studies of potassium chloride arereported in thepediatric population.

Hepaticimpairment

Nopharmacokineticsstudiesofpotassiumchloridearereportedinpatientswithhepatic

impairment.

Renalimpairment

Potassiumisalmostcompletelyexcretedviaurineanditsexcretionratehighlycorrelateswith

the glomerular filtration rate. Consideringthe possibilityof hyperkalemiain thesepatients and

severityofoutcome,Slow-Kiscontraindicatedinpatientswithsevererenalimpairment.If

usedinpatientswithmildtomoderaterenalimpairment,extremecautionalongwithfrequent

serum potassiummonitoringis recommended.

12 Clinicalstudies

No recent clinical trials havebeen conducted with Slow-K.

13 Non-clinicalsafetydata

Preclinicaldatadonotsupportaspecialhazardforhumansbasedonconventionalstudiesof

acutetoxicity,repeateddosetoxicity,genotoxicity,carcinogenicpotentialandtoxicityto

reproduction.

Theacuteandrepeated-doseoraltoxicityofpotassiumchloride(KCl)inanimalsislow.

Gastrointestinalirritanteffectshavebeenobservedinrhesusmonkeysathighoraldosagesof

Slow-K.Somepositiveresultsininvitrogenotoxicityassayswereattributedtoveryhigh

concentrationsofKCl.CarcinogenicitystudiesinratsadministeredKClin-feedwere

negative.Limitedinformationfromoraldevelopmentalstudiesinrodentsindicatesthereisno

illeffectonoffspring.ThereisnoevidencefromanimalexperimentsthatoralKClexertsany

teratogeniceffects or reproductivetoxicitywhichwould berelevant to man.

14 Pharmaceuticalparticulars

Incompatibilities

Not applicable.

Specialprecautionsfor storage

Storebelow 30°C.

Slow-K must be kept outof thereach and sight ofchildren.

Instructionsfor useand handling

No special requirements.

Manufacturer:

Novartis Pharmaceuticals UKLtd., UK

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ForNovartis PharmaA.G., Basle, Switzerland

LicenseHolder:

Novartis PharmaServices AG,36 Shacham St., Petach-Tikva