Sildenafil
andDapoxetine
Tablets

Effectsof sildenafilon otherdrugs: In vitrostudies:Sildenafilis a weakinhibitorof thecytochromeP450isoforms1A2,2C9, 2C19,2D6,2E1 and 3A4 (IC 50 > 150mM).Givensildenafilpeakplasmaconcentrationsof approximately
1µM afterrecommended
doses,it isunlikelythatsildenafilwillaltertheclearanceof substratesof theseisoenzymes.

S~AMAGRAi<COMPOSITION:Eachfilm coatedtabletcontains:
SildenafilCitrateequivalentto Sildenafil
DapoxetineHydrochlorideequivalentto Dapoxetine

relateddiuretics,ACE inhibitorsand calciumchannelblockers.The AUC of the active
metabolite,N-desmethylsildenafil,was increased62% by loop and potassium-sparing
diureticsand 102%by non-specificbeta-blockers.Theseeffectson the metaboliteare notexpectedto beof clinicalconsequence.

100mg
60mg

DESCRIPTION
Sildenafil : A selective inhibitor of cyclic guanosine monophosphate(cGMP)-specificphosphodiesterase
type5 (PDE5).
Dapoxetine: A short acting serotoninreuptakeinhibitor(SSRI)developedspecificallyfor
the treatmentof prematureejaculation.
CLINICALPHARMACOLOGY
Mechanismof Action : Sildenafi/ : The physiologicmechanismof erection of the penisinvolvesreleaseof nitricoxide(NO)in the corpuscavernosumduringsexualstimulation.NO
then activatesthe enzymeguanylatecyclase,which results in increasedlevels of cyclic
guanosinemonophosphate(cGMP), producingsmooth muscle relaxation in the corpus
cavernosumand allowinginflowof blood.Sildenafilhasno directrelaxanteffecton isolated
human corpus cavernosum,but enhances lhe effect of nitric oxide (NO) by inhibiting
phosphodiesterasetype 5 (PDE5), which is responsiblefor degradationof cGMP in thecorpuscavernosum.Whensexualstimulationcauseslocalreleaseof NO,inhibitionof PDE5bysildenafilcausesincreasedlevelsof cGMPin the corpuscavernosum,resultingin smoothmusclerelaxationand inflowof bloodto the corpuscavernosum.Sildenafilat recommended
doseshasnoeffectin the absenceof sexualstimulation.
Dapoxetine: Dapoxetineexhibits its efficacy by primarily inhibiting the reuptakeof theserotonintransporter.It was also shown to bind and inhibit the reuptaketransportersof
dopamineandnorepinephrine.
Pharmacokinetics
Si/denafi/:Absorptionand Distribution:Sildenafilis rapidlyabsorbed.Maximumobserved
plasmaconcentrationsare reachedwithin 30 to 120 minutes(median60 minutes)of oraldosingin the fastedstate.Whensildenafilis takenwith a highfat meal,the rateof absorption
is reduced,with a meandelayin T maxof 60 minutesand a meanreductionin C maxof 29%.
The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating
distributioninto the tissues.Sildenafiland its majorcirculatingN-desmethylmetaboliteareboth approximately96% boundto plasmaproteins.Proteinbindingis independentof total
drugconcentrations.
Basedupon measurementsof sildenafil in semenof healthyvolunteers90 minutesafter
dosing,lessthan0.001% of the administereddosemayappearinthe semenof patients:
MetabolismandExcretion:Sildenafilis clearedpredominantlybythe CYP3A4(majorroute)
and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating
metaboliteresultsfromN-desmethylationof sildenafil,and is itselffurthermetabolized.This
metabolitehasa PDEselectivityprofilesimilarto sildenafiland an in vitro potencyfor PDE5
approximately50% of the parent drug. Plasma concentrationsof this metabolite areapproximately40% of those seen for sildenafil,so that the metaboliteaccountsfor about
20%of sildenafil'spharmacologiceffects.
After either oral or intravenous administration,sildenafil is excreted as metabolites
predominantlyin the feces (approximately80%of administeredoral dose) and to a lesser
extent in the urine (approximately13%of the administeredoral dose). Similar values forpharmacokineticparameterswere seenin normalvolunteersand in the patientpopulation,usinga populationpharmacokineticapproach
Dapoxetine:Dapoxetineis rapidly absorbedafter oral administrationwith a peakplasma
concentration(T~.) occurringbetween1.4and2.0 hours.Thisis followedby a rapiddecline
in plasmaconcentration,to about5%of peakconcentrationat 24 hours.Boththe areaunder
the curve(AUC)andC~, increasedproportionatelywith dosesupto.100mg.Themeaninitial
half-lifeof dapoxetineaftera single doseis 0.5to 0.8 hoursandthis decreasedslightlyto 0.4
to 0.6 hoursafter multipledosesfor 6 days.Theterminalhalf-lifeof dapoxetinewas 15to 19
hoursaftera singledoseand20to 24 aftermultipledoses.
Dapoxetineundergoeshepatic metabolismto 2 metabolites,desmethyldapoxetineanddidesmethyldapoxetine,
both of which have muchlower plasmaconcentrationscomparedwith dapoxetine.Informationon specificisoenzymesinvolvedin metabolismand volumeof
distributionanddetailson excretionhadnot beenpublishedat presstime.
INDICATIONS:Forthe treatmentof maleerectiledysfunctionandprematureejaculation.
CONTRAINDICATIONSContraindicatedin patientswith a knownhypersensitivityto anycomponentof the tablet.
Consistentwith its knowneffectson the nitric oxide/cGMPpathway,Sildenafilwas shownto
potentiatethe hypotensiveeffectsof nitrates,andits administrationto patientswhoareusingorganic nitrates, either regularly and/or intermittently, in any form is therefore
contraindicated.Sildenafilis not indicatedfor usein womenand individualsbelow 18yearsof age.
WARNINGS&PRECAUTIONSDrugInteractions:Sildenafil:Effectsof otherdrugsonsi/denafi/
In vitrostudies:Sildenafilmetabolismis principallymediatedbythecytochromeP450(CYP)
isoforms3A4(majorroute)and2C9 (minorroute).Therefore,inhibitorsof theseisoenzymes
mayreducesildenafilclearance.
In vivostudies:Cimetidine(800mg),a non-specificGYPinhibitor,causeda 56%increasein
plasmasildenafil concentrationswhen co-administeredwith sildenafil (50 mg) to healthy
volunteers.
StrongerCYP3A4inhibitors such as ketoconazoleor itrac011azole
would be expectedto
havestill greater effects, and populationdata from patientsin clinical trials did indicatea
reductionin sildenafilclearancewhen it was co-administeredwith CYP3A4inhibitors(suchas ketoconazole,erythromycin, or cimetidine). It can be expected that concomitantadministrationof CYP3A4 inducers, such as rifampin, will decrease plasma levels ofsildenafil.
Ritonavir,a highly potentP450 inhibitor,resultedin 300%increasein sildenafil C maxand
1000% increase in sildenafil plasma AUC. Single doses of antacid (magnesiumhydroxide/aluminiumhydroxide)did notaffectthe bioavailabilityof sildenafil.
Pharmacokineticdata from patients in clinical trials showed no effect on sildenafil
pharmacokineticsof CYP2C9inhibitors(suchas tolbutamide,warfarin),CYP2D6inhibitors(such as selective serotonin reuptake inhibitors,tricyclic antidepressants),thiazide andIn vivostudies:Nosignificantinteractionswereshownwithtolbutamide(250mg)orwarfarin(40mg),bothofwhicharemetabolizedbyCYP2C9.
Sildenafil(50mg)didnotpotentiatetheincreaseinbleedingtimecausedbyaspirin(150mg).
Sildenafil(50mg)did not potentiatethe hypotensiveeffectof alcoholin healthyvolunteers
withmeanmaximumbloodalcohollevelsof 0.08%.
No interactionwas seenwhensildenafil(100mg)was co-administeredwith amlodipinein
hypertensivepatients.Themeanadditionalreductionon supinebloodpressure(systolic.8mmHg;diastolic.7 mmHg)was of a similar magnitudeto that seen when sildenafilwas
administeredaloneto healthyvolunteers.
Analysisof the safetydatabaseshowedno differencein the side effect profilein patientstakingsildenafilwithandwithoutanti-hypertensive
medication.
In a studyof healthymalevolunteers,sildenafil(100 mg) did not affect the steadystate
pharmacokinetics
of !he HIVproteaseinhibitors,saquinavirandritonavir.bothof whichare
CYP3A4substrates.
General: Thereis no controlledclinicaldata on the safetyor efficacyof sildenafilin thefollowinggroups:if prescribed,thisshouldbedonewithcaution.
• Patientswhohavesuffereda myocardialinfarction,stroke,orlife-threatening
arrhythmiawithinthelast6months:• Patientswithrestinghypotension(BP<90/50)or hypertension(BP> 170/11O):• Patientswithcardiacfailureor coronaryarterydiseasecausingunstableangina;• Patientswithretinitispigmentosa(aminorityof these patientshavegeneticdisordersof retinalphosphodiesterases).
A thoroughmedicalhistoryand physicalexaminationshouldbe undertakento diagnose
erectile dysfunction,determine potential underlyingcauses, and identify appropriate
treatment.There is a degree of cardiacrisk associatedwith sexual activity; therefore,
physiciansmaywishto considerthe cardiovascular
statusof theirpatientspriorto initiating
anytreatmentforerectiledysfunction.
Agentsfor the treatmentof erectiledysfunctionshouldbe usedwithcautionin patientswith
anatomicaldeformationof the penis(suchas angulation,cavernosalfibrosisor Peyronie'sdisease),or in patientswhohaveconditions,whichmaypredisposethemto priapism(suchassicklecellanaemia,multiplemyeloma,orleukaemia).
The safety and efficacyof combinationsof sildenafilwith other treatmentsfor erectile
dysfunctionhave not been studied. Therefore,the use of such combinationsis notrecommended.
Sildenafilhasnoeffectonbleedingtimewhentakenaloneorwithaspirin.Invitrostudieswith
humanplateletsindicatethat sildenafilpotentiatesthe antiaggregatoryeffect of sodium
nitroprusside(a nitricoxidedonor).Thereis no safetyinformationon the administrationof
sildenafilto patientswithbleedingdisordersor activepepticulceration.Therefore.Sildenafil
should be administeredwith caution to these patients.Simultaneousadministrationof
sidenafilto patientstakingalpha-blockertherapymayleadto symptomatichypotensionin
somepatients.Therefore,sidenafildosesabove25 mgshouldnotbe takenwithin4 hoursof
takinganalpha-blocker.
A minority of patientswith the inherited condition,retinitis pigmentosa,have genetic
disordersof retinalphosphodiesterases.
Thereis nosafetyinformationontheadministrationof sildenafil to patients with retinitis pigmentosa.Therefore, sildenafil should be
administeredwithcautionto thesepatients.
Prolongederectiongreaterthan4 hoursandpriapism(painfulerectionsgreaterthan6 hours
in duration)havebeenreportedinfrequentlysincemarketapprovalof sildenafil.Intheeventof anerectionthat persistslongerthan4 hours,the patientshouldseekimmediatemedicalassistance.If priapismis nottreatedimmediately,
peniletissuedamageandpermanentlossof potencycouldresult.
Theuseof sildenafiloffersno protectionagainstsexuallytransmitteddiseases.Counselingof patientsaboutthe protectivemeasuresnecessaryto guardagainstsexuallytransmitted
diseases,includingtheHumanImmunodeficiency
Virus(HIV),maybeconsidered.
Dapoxetine: Currently,there are no documenteddrug-drugir.teractionsassociatedwith
dapoxetine.Coadministrationof dapoxetinewith ethanoldid not produceany significant
pharmacoki
neticchanges.
Pregnancy:Therearenoadequateandwell-controlledstudiesof combinationof Sildenafil
andDapoxetineinpregnantwomen.It is notindicatedinwomen.
Lactation:Combinationof SildenafilandDapoxetineis notindicatedin nursingmothers.
PaediatricUse:Combinationof SildenafilandDapoxetineis notindicatedinchildren.
ADVERSEREACTIONS
Sildenafil:The mostfrequentside effectsreportedwith sildenafiluse includeheadache,
flushing,dyspepsia,nasalcongestion,abnormalvision(mildand transient,predominantly
colortinge to vision,but also increasedsensitivityto light or blurredvision), urinarytract
infection,diarrhea,dizziness, and rash. Serious cardiovascular,cerebrovascularandvasculareventshave been reportedin temporalassociationwith sildenafil·use.It is notpossibleto determinewhetherthese eventsare related directlyto sildenafil,to sexualactivity,to thepatient'sunderlyingcardiovasculardisease,to a combinationof thesefactors,ortootherfactors.
Dapoxetine:Themostcommonadverseeventsassociatedwithdapoxetinewerenausea,diarrhea,dizziness,andheadache.
DOSAGE:
Therecommended
doseis oncedailyapproximately1hourbeforesexualactivity.
STORAGE:Storeat a temperaturebelow30°C.,Protectfrom
light&moisture.
KEEPOUTOFTHEREACHOFCHILDRENPRESENTATION:
Availablein blisterof4 tablets.

A product of:~la;anta

pltarma limitedRegd./Corp.Off.: Ajanta House,Charkop,Kandivli(W), Mumbai400 067.

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