activella - novo-pi.com · 1 ——— warnings and precautions ——— • estrogens increase...

1

WARNINGS AND PRECAUTIONS Estrogensincreasetheriskofgallbladderdisease(5.4)Discontinueestrogenifseverehypercalcemia,lossofvision,

severehypertriglyceridemiaorcholestaticjaundiceoccurs(5.5,5.6,5.9,5.10)

Monitorthyroidfunctioninwomenonthyroidreplacementtherapy(5.11,5.18)

ADVERSE REACTIONS Mostcommonadversereactions(incidence5percent)arebackpain,headache,painintheextremity,nausea,diarrhea,gastroenteritis,insomnia,emotionallability,upperrespiratorytractinfection,sinusitis,nasopharyngitis,weightincrease,breastpain,post-menopausalbleeding,uterinefibroidvaginalhemorrhage,ovariancyst,endometrialthickening,viralinfection,moniliasisgenital,andaccidentalinjury.(6.1)To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-888-824-4336 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS Inducersand/orinhibitorsofCYP3A4mayaffectestrogendrug

metabolism(7.1)

USE IN SPECIFIC POPULATIONS NursingMothers:Estrogenadministrationtonursingwomen

hasbeenshowntodecreasethequantityandqualityofbreastmilk(8.3)

GeriatricUse:Anincreaseriskofprobabledementiainwomenover65yearsofagewasreportedintheWomensHealthInitiativeMemoryancillarystudiesoftheWomensHealthInitiative(5.3,8.5)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 10/2013

12 CLINICAL PHARMACOLOGY12.1 MechanismofAction12.2 Pharmacodynamics12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility

14 CLINICAL STUDIES14.1 EffectsonVasomotorSymptoms14.2 EffectsontheEndometrium14.3 EffectsonUterineBleedingorSpotting14.4 EffectsonBoneMineralDensity14.5 WomensHealthInitiativeStudies14.6 WomensHealthInitiativeMemoryStudy

15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 HowSupplied16.2 StorageandHandling

17 PATIENT COUNSELING INFORMATION17.1 AbnormalVaginalBleeding17.2 PossibleSeriousAdverseReactionswithEstrogen

PlusProgestinTherapy17.3 PossibleLessSeriousbutCommonAdverse

ReactionswithEstrogenPlusProgestinTherapy

*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA

1 INDICATIONS AND USAGE1.1 TreatmentofModeratetoSevereVasomotor

SymptomsduetoMenopause1.2 TreatmentofModeratetoSevereSymptomsofVulvar

andVaginalAtrophyduetoMenopause1.3 PreventionofPostmenopausalOsteoporosis

2 DOSAGE AND ADMINISTRATION2.1 TreatmentofModeratetoSevereVasomotor

SymptomsduetoMenopause2.2 TreatmentofModeratetoSevereSymptomsofVulvar

andVaginalAtrophyduetoMenopause2.3 PreventionofPostmenopausalOsteoporosis

3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS

5.1 CardiovascularDisorders5.2 MalignantNeoplasms5.3 ProbableDementia5.4 GallbladderDisease5.5 Hypercalcemia5.6 VisionAbnormalities5.7 AdditionofaProgestinWhenaWomanHasNotHad

aHysterectomy

5.8 ElevatedBloodPressure5.9 Hypertriglyceridemia5.10 HepaticImpairmentand/orPastHistoryofCholestatic

Jaundice5.11 Hypothyroidism5.12 FluidRetention5.13 Hypocalcemia5.14 ExacerbationofEndometriosis5.15 HereditaryAngioedema5.16 ExacerbationofOtherConditions5.17 LaboratoryTests5.18 Drug-LaboratoryTestInteractions

6 ADVERSE REACTIONS6.1 ClinicalTrialsExperience6.2 PostmarketingExperience

7 DRUG INTERACTIONS7.1 MetabolicInteractions

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 NursingMothers8.4 PediatricUse8.5 GeriatricUse8.6 RenalImpairment8.7 HepaticImpairment

10 OVERDOSAGE11 DESCRIPTION

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ACTIVELLA safely and effectively. See full prescribing information for ACTIVELLA.Activella (estradiol/norethindrone acetate) tablets, for oral useInitial U.S. Approval: 1998

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND

PROBABLE DEMENTIASee full prescribing information for complete boxed

warning

Estrogen Plus Progestin TherapyEstrogenplusprogestintherapyshouldnotbeused

for the prevention of cardiovascular disease or dementia (5.1, 5.3)

TheWomensHealthInitiative(WHI)estrogenplusprogestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) (5.1)

TheWHIestrogenplusprogestinsubstudyreportedincreased risks of invasive breast cancer (5.2)

TheWHIMemoryStudy(WHIMS)estrogenplusprogestin ancillary study of WHI reported an increased risk of probable dementia in postmeno-pausal women 65 years of age and older (5.3)

Estrogen-Alone Therapy Thereisanincreasedriskofendometrialcancerina

woman with a uterus who use unopposed estrogens (5.2)

Estrogen-alonetherapyshouldnotbeusedfortheprevention of cardiovascular disease or dementia (5.2, 5.3)

TheWHIestrogen-alonesubstudyreportedincreased risks of stroke and DVT (5.1)

TheWHIMSestrogen-aloneancillarystudyofWHIreported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.3)

RECENT MAJOR CHANGES Contraindications(4) 10/2013WarningsandPrecautions,HereditaryAngioedema(5.15) 10/2013

INDICATIONS AND USAGE Activellaisanestrogenandprogestincombinationindicatedinawomanwithauterusfor:Activella1mg/0.5mgand0.5mg/0.1mgareindicatedinawomanwithauterusfor:TreatmentofModeratetoSevereVasomotorSymptomsdueto

Menopause(1.1)PreventionofPostmenopausalOsteoporosis(1.3)

Activella1mg/0.5mgisalsoindicatedinawomanwithauterusfor:TreatmentofModeratetoSevereSymptomsofVulvarand

VaginalAtrophyduetoMenopause(1.2)

DOSAGE AND ADMINISTRATION Onetablettobetakenoncedaily(2)

DOSAGE FORMS AND STRENGTHS Activella(estradiol/norethindroneacetate)1mg/0.5mgtablet

(3)Activella(estradiol/norethindroneacetate)0.5mg/0.1mg

tablet(3)

CONTRAINDICATIONS Undiagnosedabnormalgenitalbleeding(4)Known,suspected,orhistoryofbreastcancer(4,5.2)Knownorsuspectedestrogen-dependentneoplasia(4,5.2)ActiveDVT,PE,orhistoryoftheseconditions(4,5.1)Activearterialthromboembolicdisease(forexample,strokeand

MI),orahistoryoftheseconditions(4,5.1)Knownanaphylacticreactionorangioedemaorhypersensitivity

toActivella(4)Knownliverimpairmentordisease(4,5.10)KnownproteinC,proteinS,orantithrombindeficiency,orother

knownthrombophilicdisorders(4)Knownorsuspectedpregnancy(4,8.1)

Activella (estradiol/norethindrone acetate) tablets 2

FULL PRESCRIBING INFORMATION

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND

PROBABLE DEMENTIAEstrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].TheWomensHealthInitiative(WHI)estrogenplus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].

Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5)]. In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen-Alone TherapyEndometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].

Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)]. The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)]. The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmeno-pausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment

1 INDICATIONS AND USAGE1.1 Treatment of Moderate to Severe Vasomotor

Symptoms due to Menopause1.2 Treatment of Moderate to Severe Symptoms of

Vulvar and Vaginal Atrophy due to MenopauseLimitation of UseWhen prescribing solely for the treatment of moderate to severesymptomsofvulvarandvaginalatrophyduetomenopause,topicalvaginalproductsshouldbeconsidered.

1.3 Prevention of Postmenopausal OsteoporosisLimitation of UseWhen prescribing solely for the prevention of postmenopausalosteoporosis, therapy should only be considered for women atsignificant risk of osteoporosis and non-estrogen medicationshouldbecarefullyconsidered.

2 DOSAGE AND ADMINISTRATIONUseofestrogen-alone,orincombinationwithaprogestin,shouldbe with the lowest effective dose and for the shortest durationconsistentwithtreatmentgoalsandrisksfortheindividualwoman.Postmenopausal women should be re-evaluated periodically asclinicallyappropriatetodetermineiftreatmentisstillnecessary.

2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

Activellatherapyconsistsofasingletablettobetakenoncedailyfor the treatmentofmoderate toseverevasomotorsymptomsduetomenopause.Activella1mg/0.5mgActivella0.5mg/0.1mg

2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause

Activellatherapyconsistsofasingletablettobetakenoncedailyfor the treatment of moderate to severe symptoms of vulvar andvaginalatrophyduetomenopause.Activella1mg/0.5mg

2.3 Prevention of Postmenopausal OsteoporosisActivellatherapyconsistsofasingletablettobetakenoncedailyforthepreventionofpostmenopausalosteoporosis.Activella1mg/0.5mgActivella0.5mg/0.1mg

3 DOSAGE FORMS AND STRENGTHSActivellatabletsareavailableintwostrengths:EachtabletofActivella1mg/0.5mgcontains1mgof

estradioland0.5mgofnorethindroneacetate.Thetabletsarewhite,round,bi-convex,film-coatedtabletsengravedwithNOVO288ononesideandtheAPISbullontheother.

EachtabletofActivella0.5mg/0.1mgcontains0.5mgofestradioland0.1mgofnorethindroneacetate.Thetabletsarewhite,round,bi-convex,film-coatedtabletsengravedwithNOVO291ononesideandtheAPISbullontheother.

4 CONTRAINDICATIONSActivella is contraindicated in women with any of the followingconditions:UndiagnosedabnormalgenitalbleedingKnown,suspected,orhistoryofbreastcancerKnown,pastorsuspectedestrogen-dependentneoplasiaActiveDVT,PE,orhistoryoftheseconditionsActivearterialthromboembolicdisease(forexamplestrokeand

MI),orahistoryoftheseconditionsKnownanaphylacticreactionorangioedemaorhypersensitivity

toActivella

KnownliverimpairmentordiseaseKnownproteinC,proteinS,orantithrombindeficiency,orother

knownthrombophilicdisordersKnownorsuspectedpregnancy

5 WARNINGS AND PRECAUTIONS5.1 Cardiovascular DisordersAnincreasedriskofPE,DVT,strokeandMIhasbeenreportedwithestrogen plus progestin therapy. An increased risk of stroke andDVT has been reported with estrogen-alone therapy. Should anyoftheseoccurorbesuspected,estrogenwithorwithoutprogestintherapyshouldbediscontinuedimmediately.Riskfactorsforarterialvasculardisease(forexample,hypertension,diabetesmellitus,tobaccouse,hypercholesterolemia,andobesity)and/or venous thromboembolism (VTE) (for example, personal

historyorfamilyhistoryofVTE,obesity,andsystemiclupuserythe-matosus)shouldbemanagedappropriately.StrokeIn the WHI estrogen plus progestin substudy, a statisticallysignificant increased riskof strokewas reported inwomen50 to79yearsofagereceivingdailyCE(0.625mg)plusMPA(2.5mg)comparedtowomeninthesameagegroupreceivingplacebo(33versus25per10,000women-years)[seeClinicalStudies(14.5)].The increase in risk was demonstrated after the first year andpersisted.1Shouldastrokeoccurorbesuspected,estrogenplusprogestintherapyshouldbediscontinuedimmediately.IntheWHIestrogen-alone substudy, a statistically significant increased riskofstrokewas reported inwomen50 to79yearsofage receivingdailyCE (0.625mg)-alone compared towomen in the same agegroupreceivingplacebo(45versus33per10,000women-years).Theincreaseinriskwasdemonstratedinyear1andpersisted[seeClinical Studies (14.5)]. Should a stroke occur or be suspected,estrogen-alonetherapyshouldbediscontinuedimmediately.Subgroup analyses of women 50 to 59 years of age suggest noincreased risk of stroke for those women receiving CE (0.625mg)-aloneversusthosereceivingplacebo(18versus21per10,000women-years).1Coronary Heart DiseaseIntheWHIestrogenplusprogestinsubstudy,therewasastatisti-callynon-significantincreaseriskofcoronaryheartdisease(CHD)events(definedasnonfatalMI,silentMI,orCHDdeath)reportedinwomenreceivingdailyCE(0.625mg)plusMPA(2.5mg)comparedto women receiving placebo (41 versus 34 per 10,000 women-years)1 An increase in relative risk was demonstrated in year 1,andatrendtowarddecreasingrelativeriskwasreportedinyears2through5[seeClinicalStudies(14.5)].In the WHI estrogen-alone substudy, no overall effect on CHDeventswasreportedinwomenreceivingestrogen-alonecomparedtoplacebo2[seeClinicalStudies(14.5)].Subgroup analyses of women 50 to 59 years of age suggest astatistically non-significant reduction in CHD events (CE [0.625mg]-alonecomparedtoplacebo)inwomenwithlessthan10yearssincemenopause(8versus16per10,000women-years).1

In postmenopausal women with documented heart disease(n=2,763),average66.7yearsofage, inacontrolledclinical trialof secondary prevention of cardiovascular disease (Heart andEstrogen/Progestin Replacement Study [HERS]), treatment withdailyCE(0.625mgplusMPA(2.5mg)demonstratednocardiovas-cularbenefit.Duringanaveragefollow-upof4.1years, treatmentwithCEplusMPAdidnotreducetheoverallrateofCHDeventsinpostmenopausal women with established CHD. There were moreCHDeventsintheCEplusMPA-treatedgroupthanintheplacebogroupinyear1,butnotduringthesubsequentyears.Twothousand,three hundred and twenty-one (2,321) women from the originalHERStrialagreedtoparticipateinanopenlabelextensionofHERS,HERSII.Averagefollow-upinHERSIIwasanadditional2.7years,foratotalof6.8yearsoverall.RatesofCHDeventswerecomparableamongwomenintheCEplusMPAgroupandtheplacebogroupinHERS,HERSII,andoverall.Venous ThromboembolismIn the WHI estrogen plus progestin substudy, a statisticallysignificant2-foldgreaterrateofVTE(DVTandPE),wasreportedinwomenreceivingdailyCE(0.625mg)plusMPA(2.5mg)comparedto women receiving placebo (35 versus 17 per 10,000 women-years).Statistically significant increases in risk forbothDVT (26versus13per10,000women-years)andPE(18versus8per10,000women-years) were also demonstrated. The increase in VTE riskwasdemonstratedduringthefirstyearandpersisted3[seeClinicalStudies(14.5)].ShouldaVTEoccurorbesuspected,estrogenplusprogestintherapyshouldbediscontinuedimmediately.IntheWHIestrogen-alonesubstudy,theriskofVTEwasincreasedforwomenreceiving daily CE (0.625 mg)-alone compared to placebo (30versus22per10,000women-years),althoughonly the increasedrisk of DVT reached statistical significance (23 versus 15 per10,000women-years).TheincreaseinVTEriskwasdemonstratedduringthefirst2years4[seeClinicalStudies(14.5)].ShouldaVTEoccurorbesuspected,estrogen-alonetherapyshouldbediscon-tinued immediately. If feasible, estrogensshouldbediscontinuedatleast4to6weeksbeforesurgeryofthetypeassociatedwithanincreasedriskofthromboembolism,orduringperiodsofprolongedimmobilization.

5.2 Malignant NeoplasmsBreast CancerThemostimportantrandomizedclinicaltrialprovidinginformationabout breast cancer in estrogen plus progestin users is the WHIsubstudyofdailyCE(0.625mg)plusMPA(2.5mg).Afterameanfollow-up of 5.6 years, the estrogen plus progestin substudy


reportedanincreasedriskofinvasivebreastcancerinwomenwhotookdailyCEplusMPA. In thissubstudy,prioruseof estrogen-aloneorestrogenplusprogestintherapywasreportedby26percentofthewomen.Therelativeriskofinvasivebreastcancerwas1.24,andtheabsoluteriskwas41versus33casesper10,000women-years,forCEplusMPAcomparedwithplacebo[seeClinicalStudies(14.5)].Amongwomenwhoreportedprioruseofhormonetherapy,therelativeriskofinvasivebreastcancerwas1.86,andtheabsoluteriskwas46versus25casesper10,000women-years,forCEplusMPAcomparedwithplacebo.Amongwomenwhoreportednoprioruseofhormonetherapy,therelativeriskofinvasivebreastcancerwas1.09,andtheabsoluteriskwas40versus36casesper10,000women-years,forCEplusMPAcomparedwithplacebo.Inthesamesubstudy,invasivebreastcancerswerelarger,weremorelikelytobe node positive, and were diagnosed at a more advanced stagein the CE (0.625 mg) plus MPA (2.5 mg) group compared withtheplacebogroup.Metastaticdiseasewas rare,withnoapparentdifferencebetweenthetwogroups.Otherprognosticfactors,suchashistologicsubtype,gradeandhormonereceptorstatusdidnotdifferbetweenthegroups5[seeClinicalStudies(14.5)].Themostimportantrandomizedclinicaltrialprovidinginformationaboutbreastcancerinestrogen-aloneusersistheWHIsubstudyofdaily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy,after an average follow-up of 7.1 years, daily CE-alone was notassociatedwithanincreasedriskofinvasivebreastcancer[relativerisk(RR)0.806[seeClinicalStudies(14.5)].ConsistentwiththeWHIclinicaltrials,observationalstudieshavealsoreportedanincreasedriskofbreastcancer forestrogenplusprogestintherapy,andasmallerincreasedriskforestrogen-alonetherapy,afterseveralyearsofuse.Theriskincreasedwithdurationofuse,andappearedtoreturntobaselineoverabout5yearsafterstoppingtreatment(onlytheobservationalstudieshavesubstantialdataonriskafterstopping).Observationalstudiesalsosuggestthattheriskofbreastcancerwasgreater,andbecameapparentearlier,with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significantvariationintheriskofbreastcanceramongdifferentestrogenplusprogestincombinations,doses,orroutesofadministration.Theuseof estrogen-aloneandestrogenplusprogestinhasbeenreported to result in an increase in abnormal mammogramsrequiringfurtherevaluation.In a one-year trial among 1,176 women who received eitherunopposed1mgestradioloracombinationof1mgestradiolplusone of three different doses of NETA (0.1, 0.25, 0.5 mg), sevennewcasesofbreastcancerwerediagnosed,twoofwhichoccurredamongthegroupof295womentreatedwithActivella1.0mg/0.5mg and two of which occurred among the group of 294 womentreatedwith1mgestradiol/0.1mgNETA.Allwomenshouldreceiveyearlybreastexaminationsbyahealthcareproviderandperformmonthlybreastself-examinations.Inaddition,mammographyexaminationsshouldbescheduledbasedonpatientage,riskfactors,andpriormammogramresults.Endometrial CancerEndometrial hyperplasia (a possible precursor of endometrialcancer) has been reported to occur at a rate of approximately 1percentorlesswithActivella.An increased risk of endometrial cancer has been reported withtheuseofunopposedestrogentherapyinawomanwithauterus.Thereportedendometrialcancer riskamongunopposedestrogenusersisabout2to12timesgreaterthaninnonusers,andappearsdependent on duration of treatment and on estrogen dose. Moststudies show no significant increased risk associated with useofestrogens for less than1year.Thegreatest riskappears tobeassociatedwithprolongeduse,withincreasedrisksof15-to24-foldfor5to10yearsormore.Thisriskhasbeenshowntopersistforatleast8to15yearsafterestrogentherapyisdiscontinued.Clinicalsurveillanceofallwomenusingestrogen-aloneorestrogenplusprogestintherapyisimportant.Adequatediagnosticmeasures,includingdirectedorrandomendometrialsamplingwhenindicated,should be undertaken to rule out malignancy in postmenopausalwomenwithundiagnosedpersistentorrecurringabnormalgenitalbleeding.There is no evidence that the use of natural estrogens results ina different endometrial risk profile than synthetic estrogens ofequivalentestrogendose.Addingaprogestin toestrogentherapyinpostmenopausalwomenhasbeenshown to reduce the riskofendometrialhyperplasia,whichmaybeaprecursortoendometrialcancer.Ovarian CancerTheWHIestrogenplusprogestinsubstudyreportedastatisticallynon-significant increased riskofovariancancer.After an averagefollow-upof5.6years, the relative risk forovariancancer forCEplusMPAversusplacebowas1.58(95percentCI,0.77-3.24].The

absoluteriskforCEplusMPAversusplacebowas4versus3casesper10,000women-years.7Insomeepidemiologicstudies,theuseofestrogenplusprogestinandestrogen-onlyproducts,inparticularfor5ormoreyears,hasbeenassociatedwithanincreasedriskofovariancancer.However,thedurationofexposureassociatedwithincreased risk isnot consistent acrossall epidemiologic studies,andsomereportnoassociation.

5.3 Probable DementiaIn the WHIMS estrogen plus progestin ancillary study of WHI, apopulation of 4,532 postmenopausal women 65 to 79 years ofage was randomized to daily CE (0.625 mg) plus MPA (2.5 mg)orplacebo.After an average follow-up of 4 years, 40 women in the CE plusMPA and 21 women in the placebo group were diagnosed withprobabledementia.The relative riskofprobabledementia for theCEplusMPAversusplacebowas2.05(95percentCI,1.21-3.48).The absolute risk of probable dementia for CE plus MPA versusplacebowas45versus22casesper10,000women-years8[seeUseinSpecificPopulations(8.5),andClinicalStudies(14.6)].IntheWHIMSestrogen-aloneancillarystudyofWHI,apopulationof 2,947 hysterectomized women 65 to 79 years of age wasrandomized to daily CE (0.625 mg)-alone or placebo. After anaverage follow-up of 5.2 years, 28 women in the estrogen-alonegroup and 19 women in the placebo group were diagnosed withprobable dementia. The relative risk of probable dementia forCE-aloneversusplacebowas1.49(95percentCI,0.83-2.66).TheabsoluteriskofprobabledementiaforCE-aloneversusplacebowas37versus25casesper10,000women-years8[seeUseinSpecificPopulations(8.5),andClinicalStudies(14.6)]WhendatafromthetwopopulationsintheWHIMSestrogen-aloneand estrogen plus progestin ancillary studies were pooled asplannedintheWHIMSprotocol,thereportedoverallrelativeriskofprobabledementiawas1.76(95percentCI,1.19-2.60).Sincebothancillarystudieswereconductedinwomen65to79yearsofage,itisunknownwhetherthesefindingsapplytoyoungerpostmeno-pausalwomen8[seeUseinSpecificPopulations(8.5),andClinicalStudies(14.6)].

5.4 Gallbladder DiseaseA2-to4foldincreaseintheriskofgallbladderdiseaserequiringsurgery inpostmenopausalwomen receiving estrogenshasbeenreported.

5.5 HypercalcemiaEstrogen administration may lead to severe hypercalcemia inpatients with breast cancer and bone metastases. If hypercal-cemiaoccurs,useofthedrugshouldbestoppedandappropriatemeasurestakentoreducetheserumcalciumlevel.

5.6 Vision AbnormalitiesRetinalvascularthrombosishasbeenreportedinpatientsreceivingestrogens.Discontinuemedicationpendingexaminationifthereisasuddenpartialorcomplete lossofvision,orasuddenonsetofproptosis,diplopia,ormigraine.Ifexaminationrevealspapilledemaor retinal vascular lesions, estrogens should be permanentlydiscontinued.

5.7 Addition of a Progestin When a Woman Has Not Had a Hysterectomy

Studiesoftheadditionofaprogestinfor10ormoredaysofacycleofestrogenadministration,ordailywithestrogeninacontinuousregimen, have reported a lowered incidence of endometrialhyperplasia than would be induced by estrogen treatment alone.Endometrialhyperplasiamaybeaprecursortoendometrialcancer.There are, however, possible risks that may be associated withtheuseofprogestinswithestrogenscompared toestrogen-aloneregimens.Theseincludeanincreasedriskofbreastcancer.

5.8 Elevated Blood PressureIn a small number of case reports, substantial increases inblood pressure have been attributed to idiosyncratic reactions toestrogens.Inalarge,randomized,placebo-controlledclinicaltrial,ageneralizedeffectofestrogentherapyonbloodpressurewasnotseen.

5.9 HypertriglyceridemiaInwomenwithpre-existinghypertriglyceridemia,estrogentherapymaybeassociatedwithelevationsofplasmatriglyceridesleadingtopancreatitis.Considerdiscontinuationoftreatmentifpancreatitisoccurs.

5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in women with impairedliver function. For women with a history of cholestatic jaundiceassociated with past estrogen use or with pregnancy, caution

should be exercised, and in the case of recurrence, medicationshouldbediscontinued.

5.11 HypothyroidismEstrogenadministrationleadstoincreasedthyroid-bindingglobulin(TBG)levels.Womenwithnormalthyroidfunctioncancompensatefor the increased TBG by making more thyroid hormone, thusmaintaining free T4 and T3 serum concentrations in the normalrange.Womendependentonthyroidhormonereplacementtherapywho are also receiving estrogen may require increased doses oftheirthyroidreplacementtherapy.Thesewomenshouldhavetheirthyroidfunctionmonitoredtomaintaintheir freethyroidhormonelevelsinanacceptablerange.

5.12 Fluid RetentionEstrogensplusprogestinsmaycausesomedegreeoffluidretention.Womenwithconditionsthatmightbeinfluencedbythisfactor,suchasacardiacorrenalimpairment,warrantcarefulobservationwhenestrogensplusprogestinsareprescribed.

5.13 HypocalcemiaEstrogentherapyshouldbeusedwithcautioninwomenwithhypo-parathyroidismasestrogen-inducedhypocalcemiamayoccur.

5.14 Exacerbation of EndometriosisA few cases of malignant transformation of residual endometrialimplantshavebeenreported inwomentreatedpost-hysterectomywith estrogen-alone therapy. For women known to have residualendometriosispost-hysterectomy,theadditionofprogestinshouldbeconsidered.

5.15 Hereditary AngioedemaExogenousestrogensmayexacerbatesymptomsofangioedemainwomenwithhereditaryangioedema.

5.16 Exacerbation of Other ConditionsEstrogen therapy may cause an exacerbation of asthma, diabetesmellitus,epilepsy,migraine,porphyria,systemic lupuserythema-tosus,andhepatichemangiomasandshouldbeusedwithcautioninwomenwiththeseconditions.

5.17 Laboratory TestsSerumfolliclestimulatinghormone(FSH)andestradiollevelshavenot been shown to be useful in the management of moderate toseverevasomotorsymptomsandmoderatetoseveresymptomsofvulvarandvaginalatrophy.

5.18 Drug-Laboratory Test InteractionsAccelerated prothrombin time, partial thromboplastin time, andplateletaggregationtime;increasedplateletcount;increasedfactorsII,VIIantigen,VIIIcoagulantactivity,IX,X,XII,VII-Xcomplex,andbeta-thromboglobulin;decreasedlevelsofanti-factorXaandanti-thrombinIII,decreasedantithrombinIIIactivity,increasedlevelsoffibrinogenandfibrinogenactivity; increasedplasminogenantigenandactivity.IncreasedTBGlevelsleadingtoincreasedcirculatingtotalthyroidhormone levels as measured by protein-bound iodine (PBI), T4levels(bycolumnorbyradioimmunoassay),orT3levelsbyradio-immunoassay.T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsareunaltered.Womenonthyroid replacement therapy may require higher doses of thyroidhormone.Other binding proteins may be elevated in serum, for example,corticosteroid binding globulin (CBG), sex hormone-bindingglobulin(SHBG),leadingtoincreasedtotalcirculatingcorticoste-roidsandsexsteroids,respectively.Freehormoneconcentrations,suchastestosteroneandestradiol,maybedecreased.Otherplasmaproteins may be increased (angiotensinogen/rennin substrate,alpha-1antitrypsin,ceruloplasmin).Increased plasma high-density lipoprotein (HDL) and HDL2cholesterol subfraction concentration, reduced low-densitylipoprotein(LDL)cholesterolconcentration, increasedtriglyceridelevels.Impairedglucosetolerance.

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhereinthelabeling:CardiovascularDisorders[seeBoxedWarning,Warningsand

Precautions(5.1)]MalignantNeoplasms[seeBoxedWarning,Warningsand

Precautions,(5.2)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varyingconditions,adversereactionratesobservedintheclinicaltrialsofa drug cannot be directly compared to rates in the clinical trialsofanotherdrugandmaynotreflecttheratesobservedinpractice.


Adverse reactions reported with Activella 0.5 mg/0.1 mg byinvestigators during the Phase 3 study regardless of causalityassessmentareshowninTable2.

Table 2: All Treatment-Emergent Adverse Reactions Regardless of Relationship Reported at a Frequency of 5 percent with Activella 0.5 mg/0.1 mg

Activella0.5mg/0.1mg

(n=194)Placebo(n=200)

Body as a Whole

BackPain 10% 4%

Headache 22% 19%

Paininextremity 5% 4%

Digestive System

Nausea 5% 4%

Diarrhea 6% 6%

Respiratory System

Nasopharyngitis 21% 18%

Urogenital System

Endometrialthickening 10% 4%

Vaginalhemorrhage 26% 12%

6.2 Postmarketing ExperienceThefollowingadversereactionshavebeenidentifiedduringpost-approval use of Activella. Because these reactions are reported

voluntarily from a population of uncertain size, it is not alwayspossible to reliablyestimate their frequencyorestablishacausalrelationshiptodrugexposure.

Genitourinary SystemChanges in vaginal bleeding pattern and abnormal withdrawalbleedingorflow;breakthroughbleeding;spotting;dysmenorrhea,increaseinsizeofuterineleiomyomata;vaginitis,includingvaginalcandidiasis; change in amount of cervical secretion; changes incervical ectropion; pre-menstrual-like syndrome; cystitis-likesyndrome; ovarian cancer; endometrial hyperplasia; endometrialcancer.

BreastTenderness, enlargement, pain, nipple discharge, galactorrhea;fibrocysticbreastchanges;breastcancer.

CardiovascularDeep and superficial venous thrombosis; pulmonary embolism;thrombophlebitis;myocardial infarction,stroke; increase inbloodpressure.

GastrointestinalNausea, vomiting; changes in appetite; cholestatic jaundice;abdominalpain/cramps,flatulence,bloating;increasedincidenceofgallbladderdiseaseandpancreatitis.

SkinChloasmaormelasmathatmaypersistwhendrugisdiscontinued;erythema multiforme; erythema nodosum; hemorrhagic eruption;lossofscalphair;seborrhea;hirsutism;itching;skinrash;pruritus.

EyesRetinalvascularthrombosis,intolerancetocontactlenses.

Central Nervous SystemHeadache; migraine; dizziness; mental depression; chorea;insomnia;nervousness;mooddisturbances; irritability;exacerba-tionofepilepsy;dementia.MiscellaneousIncrease or decrease in weight; edema; leg cramps; changes inlibido; fatigue; exacerbation of asthma; increased triglycerides;hypersensitivity;anaphylactoid/anaphylacticreactions.

7 DRUG INTERACTIONSCoadministration of estradiol with norethindrone acetate did notelicit any apparent influence on the pharmacokinetics of noreth-indroneacetate.Similarly,norelevantinteractionofnorethindroneacetateonthepharmacokineticsofestradiolwasfoundwithintheNETAdoserangeinvestigatedinasingledosestudy.

7.1 Metabolic InteractionsEstradiolIn-vitro and in-vivo studies have shown that estrogens aremetabolized partially by cytochrome P450 3A4 (CYP3A4).Therefore, inducers or inhibitors of CYP3A4 may affect estrogendrug metabolism. Inducers of CYP3A4 such as St. Johns wort(Hypericum perforatum) preparations, phenobarbital, carbamaze-pine,andrifampinmayreduceplasmaconcentrationsofestrogens,possibly resulting in a decrease in therapeutic effects and/orchanges in the uterine bleeding profile. Inhibitors of CYP3A4such as erythromycin, clarithromycin, ketoconazole, itraconazole,ritonavirandgrapefruit juicemay increaseplasmaconcentrationsofestrogensandresultinsideeffects.

Norethindrone Acetate DrugsorherbalproductsthatinduceorinhibitcytochromeP-450enzymes,includingCYP3A4,maydecreaseorincreasetheserumconcentrationsofnorethindrone.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyActivellashouldnotbeusedduringpregnancy[seeContraindica-tions (4)].Thereappears tobe littleorno increased riskofbirthdefects inchildrenborn towomenwhohaveusedestrogensandprogestins as an oral contraceptive inadvertently during earlypregnancy.

8.3 Nursing MothersActivellashouldnotbeusedduringlactation.Estrogenadminis-trationtonursingwomenhasbeenshowntodecreasethequantityandqualityofthebreastmilk.Detectableamountsofestrogenandprogestinhavebeenidentifiedinthebreastmilkofwomenreceivingestrogenplusprogestintherapy.CautionshouldbeexercisedwhenActivellaisadministeredtoanursingwoman.

8.4 Pediatric UseActivella is not indicated in children. Clinical studies have notbeenconductedinthepediatricpopulation.

8.5 Geriatric UseTherehavenotbeensufficientnumbersofgeriatricwomeninvolvedinclinical studiesutilizingActivella todeterminewhether thoseover65yearsofagedifferfromyoungersubjectsintheirresponsetoActivella.The Womens Health Initiative StudiesIntheWHIestrogenplusprogestinsubstudy(dailyCE[0.625mg]plusMPA[2.5mg]versusplacebo),therewasahigherrelativeriskofnonfatalstrokeandinvasivebreastcancerinwomengreaterthan65yearsofage[seeClinicalStudies(14.5)].In the WHI estrogen-alone substudy (daily CE [0.625 mg]-aloneversusplacebo),therewasahigherrelativeriskofstrokeinwomengreaterthan65yearsofage[seeClinicalStudies(14.5)].The Womens Health Initiative Memory StudyIn theWHIMSancillary studiesofpostmenopausalwomen65 to79yearsofage,therewasanincreasedriskofdevelopingprobabledementiainwomenreceivingestrogenplusprogestinorestrogen-alonewhencomparedtoplacebo.Itisunknownwhetherthisfindingapplies to younger postmenopausal women [see Warnings andPrecautions(5.3),andClinicalStudies(14.6)].Since both ancillary studies were conducted in women 65 to 79yearsofage,itisunknownwhetherthesefindingsapplytoyoungerpostmenopausalwomen8[seeWarningsandPrecautions(5.3),andClinicalStudies(14.6)].

8.6 Renal ImpairmentTheeffectofrenalimpairmentonthepharmacokineticsofActivellahasnotbeenstudied.

AdversereactionsreportedwithActivella1mg/0.5mgbyinvestigatorsinthePhase3studiesregardlessofcausalityassessmentareshowninTable1.

Table 1: All Treatment-Emergent Adverse Reactions Regardless of Relationship Reported at a Frequency of 5 percent with Activella 1 mg/0.5 mg

EndometrialHyperplasiaStudy

(12-Months)

VasomotorSymptomsStudy

(3-Months)

OsteoporosisStudy

(2-Years)

Activella1mg/0.5mg

(n=295)1mgE2(n=296)

Activella1mg/0.5mg

(n=29)Placebo(n=34)

Activella1mg/0.5mg

(n=47)Placebo(n=48)

Body as a Whole

BackPain 6% 5% 3% 3% 6% 4%

Headache 16% 16% 17% 18% 11% 6%

Digestive System

Nausea 3% 5% 10% 0% 11% 0%

Gastroenteritis 2% 2% 0% 0% 6% 4%

Nervous System

Insomnia 6% 4% 3% 3% 0% 8%

EmotionalLability 1% 1% 0% 0% 6% 0%

Respiratory System

UpperRespiratoryTractInfection 18% 15% 10% 6% 15% 19%

Sinusitis 7% 11% 7% 0% 15% 10%

Metabolic and Nutritional

WeightIncrease 0% 0% 0% 0% 9% 6%

Urogenital System

BreastPain 24% 10% 21% 0% 17% 8%

Post-MenopausalBleeding 5% 15% 10% 3% 11% 0%

UterineFibroid 5% 4% 0% 0% 4% 8%

OvarianCyst 3% 2% 7% 0% 0% 8%

Resistance Mechanism

InfectionViral 4% 6% 0% 3% 6% 6%

MoniliasisGenital 4% 7% 0% 0% 6% 0%

Secondary Terms

InjuryAccidental 4% 3% 3% 0% 17%* 4%*

OtherEvents 2% 3% 3% 0% 6% 4%

*includingoneupperextremityfractureineachgroup


8.7 Hepatic ImpairmentThe effect of hepatic impairment on the pharmacokinetics ofActivellahasnotbeenstudied.

10 OVERDOSAGEOverdosageofestrogenplusprogestinmaycausenausea,vomiting,breast tenderness, abdominal pain, drowsiness and fatigue, andwithdrawalbleedingmayoccur inwomen.TreatmentofoverdoseconsistsofdiscontinuationofActivellatherapywithinstitutionofappropriatesymptomaticcare.

11 DESCRIPTIONActivella 1 mg/0.5 mg is a single tablet for oral administrationcontaining1mgofestradioland0.5mgofnorethindroneacetateand the following excipients: lactosemonohydrate, starch (corn),copovidone,talc,magnesiumstearate,hypromelloseandtriacetin.Activella0.5mg/0.1mgisasingletabletfororaladministrationcontaining0.5mgofestradioland0.1mgofnorethindroneacetateand the following excipients: lactosemonohydrate, starch (corn),hydroxypropylcellulose, talc, magnesium stearate, hypromelloseandtriacetin.Estradiol (E2), an estrogen, is awhiteor almostwhite crystallinepowder.Itschemicalnameisestra-1,3,5(10)-triene-3,17-diolhemihydratewiththeempiricalformulaofC18H24O2,H2Oandamolecularweightof281.4.ThestructuralformulaofE2isasfollows:

Estradiol

Norethindroneacetate(NETA),aprogestin,isawhiteoryellowish-white crystalline powder. Its chemical name is 17-acetoxy-19-nor-17-pregn-4-en-20-yn-3-one with the empirical formula ofC22H28O3 and molecular weight of 340.5. The structural formulaofNETAisasfollows:

Norethindrone Acetate

12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionEndogenousestrogensarelargelyresponsibleforthedevelopmentandmaintenanceofthefemalereproductivesystemandsecondarysexual characteristics. Although circulating estrogens exist in adynamicequilibriumofmetabolicinterconversions,estradiolistheprincipal intracellular human estrogen and is substantially morepotentthanitsmetabolites,estroneandestriol,atthereceptorlevel.Theprimarysourceofestrogen innormallycyclingadultwomenis theovarian follicle,whichsecretes70 to500mcgof estradioldaily, depending on the phase of the menstrual cycle. Aftermenopause,mostendogenousestrogenisproducedbyconversionof androstenedione, secreted by the adrenal cortex, to estrone inthe peripheral tissues. Thus, estrone and the sulfate-conjugatedform,estronesulfate,arethemostabundantcirculatingestrogensinpostmenopausalwomen.Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have beenidentified.Thesevaryinproportionfromtissuetotissue.Circulatingestrogensmodulatethepituitarysecretionofthegonad-otropins, luteinizing hormone (LH), and FSH through a negativefeedbackmechanism.Estrogensacttoreducetheelevatedlevelsofthesehormonesseeninpostmenopausalwomen.Progestincompoundsenhancecellulardifferentiationandgenerallyoppose the actionsof estrogensbydecreasing estrogen receptor

levels, increasing local metabolism of estrogens to less activemetabolites,orinducinggeneproductsthatbluntcellularresponsestoestrogen.Progestinsexerttheireffectsintargetcellsbybindingto specificprogesterone receptors that interactwithprogesteroneresponse elements in target genes. Progesterone receptors havebeen identified in the female reproductive tract, breast, pituitary,hypothalamus,andcentralnervoussystem.

12.2 PharmacodynamicsTherearenopharmacodynamicdataknownforActivellatablets.

12.3 PharmacokineticsAbsorptionEstradiolEstradiol isabsorbedthroughthegastrointestinal tract.Followingoral administration of Activella tablets, peak plasma estradiolconcentrationsarereachedwithin5to8hours.Theoralbioavail-abilityofestradiolfollowingadministrationofActivella1mg/0.5mgwhencomparedtoacombinationoralsolutionis53%.Admin-istrationofActivella1mg/0.5mgwith fooddidnotmodify thebioavailabilityofestradiol.

Norethindrone AcetateAfter oral administration, norethindrone acetate is absorbed andtransformed to norethindrone. Norethindrone reaches a peakplasmaconcentrationwithin0.5to1.5hoursaftertheadministra-tionofActivellatablets.TheoralbioavailabilityofnorethindronefollowingadministrationofActivella1mg/0.5mgwhencomparedtoacombinationoralsolutionis100%.AdministrationofActivella1mg/0.5mgwithfoodincreasesnorethindroneAUC0-72by19%anddecreasesCmaxby36%.Thepharmacokineticparametersofestradiol(E2),estrone(E1),andnorethindrone (NET) followingoraladministrationof1Activella1 mg/0.5 mg or 2 Activella 0.5 mg/0.1 mg tablet(s) to healthypostmenopausalwomenaresummarizedinTable3.

Table 3: Pharmacokinetic Parameters After Administration of 1 Tablet of Activella 1 mg/0.5 mg or 2 Tablets of Activella 0.5 mg/0.1 mg to Healthy Postmenopausal Women

1xActivella1mg/0.5mg

(n=24)Meana(%CV)b

2xActivella0.5mg/0.1mg

(n=24)Meana(%CV)b

Estradiolc (E2)

AUC0-t(pg/mL*h) 766.5(48) 697.3(53)

Cmax(pg/mL) 26.8(36) 26.5(37)

tmax(h):median(range) 6.0(0.5-16.0) 6.5(0.5-16.0)

t1/2(h)d 14.0e(29) 14.5f(27)

Estronec (E1)

AUC0-t(pg/mL*h) 4469.1(48) 4506.4(44)

Cmax(pg/mL) 195.5(37) 199.5(30)


t1/2(h)d 10.7(44)g 11.8(25)g

Norethindrone (NET)

AUC0-t(pg/mL*h) 21043(41) 8407.2(43)

Cmax(pg/mL) 5249.5(47) 2375.4(41)


t1/2(h) 9.8(32)h 11.4(36)i

AUC=areaunderthecurve,0lastquantifiablesampleCmax=maximumplasmaconcentration,tmax=timeatmaximumplasmaconcentration,t1/2=half-life,ageometricmean;bgeometric%coefficientofvariation;cbaselineunadjusteddata;dbaselineunadjusteddata;en=18;fn=16;gn=13;hn=22;in=21Following continuous dosing with once-daily administration ofActivella1mg/0.5mg,serumconcentrationsofestradiol,estrone,andnorethindronereachedsteady-statewithin twoweekswithanaccumulationof33to47%aboveconcentrationsfollowingsingledose administration.Unadjusted circulating concentrationsof E2,

E1,andNETduringActivella1mg/0.5mgtreatmentatsteadystate(dosingattime0)areprovidedinFigures1aand1b.

Figure 1a: Mean Baseline-Uncorrected Estradiol and Estrone Serum Concentration-Time Profiles Following Multiple Doses of Activella 1 mg/0.5 mg (N=24)

Time (h)

(pg/ml)

0 4 8 12 16 20 24

500

400

300

200

100

Estradiol

Estrone

Figure 1b: Mean Baseline-Uncorrected Norethindrone Serum Concentration-Time Profile Following Multiple Doses of Activella 1 mg/0.5 mg (N=24)

Time (h)0 4 8 12 16 20 24

(ng/ml) 7.5

6

4.5

3

1.5

DistributionEstradiolThe distribution of exogenous estrogens is similar to that ofendogenous estrogens. Estrogens are widely distributed in thebodyandaregenerally found inhigherconcentrations in thesexhormonetargetorgans.

Estradiol circulates in the blood bound to SHBG (37%) and toalbumin(61%),whileonlyapproximately1to2%isunbound.

Norethindrone AcetateNorethindronealsobindstoasimilarextenttoSHBG(36%)andtoalbumin(61%).

MetabolismEstradiolExogenous estrogens are metabolized in the same manner asendogenous estrogens. Circulating estrogens exist in a dynamicequilibrium of metabolic interconversions. These transformationstakeplacemainly in the liver.Estradiol is converted reversibly toestrone, and both can be converted to estriol, which is a majorurinarymetabolite.Estrogensalsoundergoenterohepaticrecircu-lationvia sulfate andglucuronideconjugation in the liver,biliarysecretion of conjugates into the intestine, and hydrolysis in theintestinefollowedbyreabsorption.

In postmenopausal women, a significant proportion of thecirculatingestrogensexistassulfateconjugates,especiallyestronesulfate,whichservesasacirculatingreservoirfortheformationofmoreactiveestrogens.

Norethindrone AcetateThemostimportantmetabolitesofnorethindroneareisomersof5-dihydro-norethindroneandtetrahydro-norethindrone,whichareexcretedmainlyintheurineassulfateorglucuronideconjugates.

ExcretionEstradiolEstradiol, estrone, and estriol are excreted in the urine alongwithglucuronideandsulfateconjugates.Thehalf-lifeofestradiolfollowingsingledoseadministrationofActivella1mg/0.5mgis12to14hours.

Norethindrone Acetate Theterminalhalf-lifeofnorethindroneisabout8to11hours.

Use in Specific PopulationsNopharmacokineticstudieswereconductedinspecificpopulations,includingwomenwithrenalorhepaticimpairment.


13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of

FertilityLong-term continuous administration of natural and syntheticestrogens in certain animal species increases the frequency ofcarcinomasofthebreast,uterus,cervix,vagina,testis,andliver.

14 CLINICAL STUDIES14.1 Effects on Vasomotor SymptomsIn a 12-week randomized clinical trial involving 92 subjects,Activella 1 mg/0.5 mg was compared to 1 mg of estradiol andto placebo. The mean number and intensity of hot flushes weresignificantly reduced frombaseline toweek4and12 inboth theActivella1mg/0.5mgandthe1mgestradiolgroupcomparedtoplacebo(seeFigure2).

Figure 2:Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study

01020304050607080

0 1 2 3 4 5 6 7 8 9 10 11 12Week

Placebo1 mg EstradiolActivella 1.0 mg/0.5 mg

# m

oder

ate -

seve

reho

t flu

shes

/wee

k

In a study conducted in Europe a total of 577 postmenopausalwomenwererandomlyassignedtoeitherActivella0.5mg/0.1mg,0.5mgE2/0.25mgNETA,orplacebofor24weeksoftreatment.Themeannumberandseverityofhotflushesweresignificantlyreducedatweek4andweek12intheActivella0.5mg/0.1mg(seeFigure3)and0.5mgE2/0.25mgNETAgroupscomparedtoplacebo.

Figure 3: Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12

01020304050607080

0 2 4 6 8 10 12Week

Activella 0.5 mg/0.1 mg (n = 194)Placebo (n = 199)

Num

ber o

f mod

erate

to se

vere

ho

t flu

shes

14.2 Effects on the EndometriumActivella1mg/0.5mgreducedtheincidenceofestrogen-inducedendometrial hyperplasia at 1 year in a randomized, controlledclinicaltrial.Thistrialenrolled1,176subjectswhowererandomizedtooneof4arms:1mgestradiolunopposed(n=296),1mgE2+0.1mgNETA(n=294),1mgE2+0.25mgNETA(n=291),andActivella1mg/0.5mg(n=295).Attheendofthestudy,endometrialbiopsyresults were available for 988 subjects. The results of the 1 mgestradiolunopposedarmcomparedtoActivella1mg/0.5mgareshowninTable4.

Table 4: Incidence of Endometrial Hyperplasia with Unopposed Estradiol and Activella 1 mg/0.5 mg in a 12-Month Study

1mgE2(n=296)

Activella1mgE2/

0.5mgNETA(n=295)

1mgE2/0.25mg

NETA(n=291)

1mgE2/0.1mgNETA

(n=294)

No.ofsubjectswithhistologicalevaluationattheendofthestudy

247 241 251 249

No.(%)ofsubjectswithendometrialhyperplasiaattheendofthestudy

36(14.6%) 1(0.4%) 1(0.4%) 2(0.8%)

14.3 Effects on Uterine Bleeding or SpottingDuringtheinitialmonthsoftherapy,irregularbleedingorspottingoccurredwithActivella1mg/0.5mgtreatment.However,bleedingtended to decrease over time, and after 12 months of treatment

with Activella 1 mg/0.5 mg, about 86 percent of women wereamenorrheic(seeFigure4).

Figure 4: Patients Treated with Activella 1 mg/0.5 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 Intent to Treat Population, LOCF

90

80

70

60

50

401 2 3 4 5 6

Cycle%

Wom

en7

52

4953 54

55 5758 58 59

62 6470

8683

73

81

60

7874

696563

58

8 9 10 11 12

1 mg E2 (n=293)Activella (n=290)

Note:thepercentageofpatientswhowereamenorrheicinagivencycleandthroughcycle13isshown.Ifdataweremissing,thebleedingvaluefromthelastreporteddaywascarriedforward(LOCF).In the clinical trial with Activella 0.5 mg/0.1 mg, 88 percent ofwomenwereamenorrheicafter6monthsoftreatment(SeeFigure5).

Figure 5: Patients Treated with Activella 0.5 mg/0.1 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent to Treat Population, LOCF

7074 77

7985 88

969593898685

40

50

60

70

80

90

100

Cycle

Activella 0.5 mg/0.1 mgPlacebo

% W

omen

1 2 3 4 5 6

14.4 Effects on Bone Mineral DensityTheresultsoftworandomized,multicenter,calcium-supplemented(500-1000 mg per day), placebo-controlled, 2 year clinical trialshaveshownthatActivella1mg/0.5mgandestradiol0.5mgareeffectiveinpreventingbonelossinpostmenopausalwomen.Atotalof462postmenopausalwomenwithintactuteriandbaselineBMDvaluesforlumbarspinewithin2standarddeviationsofthemeaninhealthyyoungwomen(T-score>-2.0)wereenrolled.InaUStrial,327postmenopausalwomen (mean time frommenopause2.5 to3.1years)withameanageof53yearswererandomizedto7groups(0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiolwith 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mgnorethindroneacetate,and2mgestradiolwith1mgnorethindroneacetate,andplacebo.)InaEuropeantrial(EUtrial),135postmeno-pausalwomen(meantimefrommenopause8.4to9.3years)witha mean age of 58 years were randomized to 1 mg estradiol with0.25mgnorethindroneacetate,1mgestradiolwith0.5mgnoreth-indrone acetate, and placebo. Approximately 58 percent and 67percentoftherandomizedsubjectsinthetwoclinicaltrials,respec-tively,completedthetwoclinicaltrials.BMDwasmeasuredusingdual-energyx-rayabsorptiometry(DXA).AsummaryoftheresultscomparingActivella1mg/0.5mgandestradiol0.5mgtoplacebofromthetwopreventiontrialsisshowninTable5.

Table 5: Percentage Change (Mean SD) in Bone Mineral Density (BMD) for Activella 1 mg/0.5 mg and 0.5 mg E2 (Intent to Treat Analysis, Last Observation Carried Forward)

US Trial EU Trial

Placebo(n=37)

0.5mgE2(n=31)

Activella1mg/0.5mg

(n=37)Placebo(n=40)

Activella1mg/0.5mg

(n=38)

Lumbarspine -2.12.9 2.32.8* 3.83.0* -0.94.0 5.44.8*

Femoralneck -2.33.4 0.32.9** 1.84.1* -1.04.6 0.76.1

Femoraltrochanter -2.04.3

1.74.1*** 3.74.3* 0.86.9 6.37.6*

US=UnitedStates,EU=EuropeanWhileActivella0.5mg/0.1mgwasnotdirectlystudiedinthesetrials,theUStrialshowedthatadditionofNETAtoestradiolenhancestheeffectonBMD;thereforetheBMDchangesexpectedfromtreatmentwithActivella0.5mg/0.1mgshouldbeatleastasgreatasobservedwithestradiol0.5mg.*Significantly(p


Table 6: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa,b

Event RelativeRiskCE/MPAversus

Placebo(95%nCIc)

CE/MPAn=8,506

Placebon=8,102

AbsoluteRiskper10,000Women-Years

CHDevents 1.23(0.99-1.53) 41 34

Non-fatalMI 1.28(1.00-1.63) 31 25

CHDdeath 1.10(0.70-1.75) 8 8

Allstrokes 1.31(1.031.68) 33 25

Ischemicstroke 1.44(1.091.90) 26 18

Deepveinthrombosisd 1.95(1.432.67) 26 13

Pulmonaryembolism 2.13(1.453.11) 18 8

Invasivebreastcancere 1.24(1.011.54) 41 33

Colorectalcancer 0.61(0.420.87) 10 16

Endometrialcancerd 0.81(0.481.36) 6 7

Cervicalcancerd 1.44(0.474.42) 2 1

Hipfracture 0.67(0.470.96) 11 16

Vertebralfracturesd 0.65(0.460.92) 11 17

Lowerarm/wristfracturesd 0.71(0.590.85) 44 62

Totalfracturesd 0.76(0.690.83) 152 199

OverallMortalityf 1.00(0.83-1.19) 52 52

GlobalIndexg 1.13(1.02-1.25) 184 165

aAdaptedfromnumerousWHIpublications.WHIpublicationscanbeviewedatwww.nhlbi.nih.gov/whi.bResultsarebasedoncentrallyadjudicateddata.cNominalconfidenceintervalsunadjustedformultiplelooksandmultiplecomparisons.dNotincludedinglobalindex.eIncludesmetastaticandnon-metastaticbreastcancer,withtheexceptionofinsitubreastcancer.fAlldeaths,exceptfrombreastorcolorectalcancer,definiteorprobableCHD,PEorcerebrovasculardisease.gAsubsetoftheeventswascombinedinaglobalindexdefinedastheearliestoccurrenceofCHDevents,invasivebreastcancer,stroke,pulmonaryembolism,colorectalcancer,hipfracture,ordeathduetoothercauses.Timingoftheinitiationofestrogenplusprogestintherapyrelativetothestartofmenopausemayaffecttheoverallriskbenefitprofile.TheWHIestrogenplusprogestinsubstudy,stratifiedbyage,showedinwomen50to59yearsofageanon-significanttrendtowardreducedrisk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI,0.44-1.07)].WHI Estrogen-Alone SubstudyTheWHI estrogen-alone substudywas stopped early because anincreased risk of stroke was observed, and it was deemed thatno further informationwouldbeobtained regarding the risksandbenefitsofestrogen-aloneinpredeterminedprimaryendpoints.Results of the estrogen-alone substudy, which included 10,739women (average 63 years of age, range 50 to 79; 75.3 percentWhite,15.1percentBlack,6.1percentHispanic,3.6percentOther),afteranaveragefollow-upof7.1years,arepresentedinTable7.

Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa

EventRelativeRisk

CEversusPlacebo(95%nCIb)

CEn=5,310

Placebon=5,429

AbsoluteRiskper10,000Women-Years

CHDeventsc 0.95(0.781.16) 54 57

Non-fatalMI c 0.91(0.731.14) 40 43

CHDdeath c 1.01(0.711.43) 16 16

Allstrokesc 1.33(1.05-1.68) 45 33

Ischemicstrokeb 1.55(1.192.01) 38 25

Deepveinthrombosisc,d 1.47(1.062.06) 23 15

Pulmonaryembolismc 1.37(0.902.07) 14 10

Invasivebreastcancerc 0.80(0.621.04) 28 34

Colorectalcancere 1.08(0.751.55) 17 16

Hipfracturec 0.65(0.450.94) 12 19

Vertebralfracturesc,d 0.64(0.44-0.93) 11 18

Lowerarm/wristfracturesc,d 0.58(0.47-0.72) 35 59

Totalfracturesc,d 0.71(0.64-0.80) 144 197

Deathduetoothercausese,f 1.08(0.881.32) 53 50

Overallmortalityc,d 1.04(0.881.22) 79 75

GlobalIndexg 1.02(0.921.13) 206 201

aAdaptedfromnumerousWHIpublications.WHIpublicationscanbeviewedatwww.nhlbi.nih.gov/whi.bNominalconfidenceintervalsunadjustedformultiplelooksandmultiplecomparisons.cResultsarebasedoncentrallyadjudicateddataforanaveragefollow-upof7.1years.dNotincludedinglobalindex.eResultsarebasedonanaveragefollow-upof6.8years.fAlldeaths,exceptfrombreastorcolorectalcancer,definiteorprobableCHD,PEorcerebrovasculardisease.gAsubsetoftheeventswascombinedinaglobalindex,definedastheearliestoccurrenceofCHDevents,invasivebreastcancer,stroke,pulmonaryembolism,colorectalcancer,hipfracture,ordeathduetoothercauses.

For those outcomes included in the WHI global index thatreachedstatisticalsignificance,theabsoluteexcessriskper10,000women-years in the group treated with CE-alone was 12 morestrokes,whiletheabsoluteriskreductionper10,000women-yearswas 7 fewer hip fractures.9 The absolute excess risk of eventsincluded in theglobal indexwasanon-significant5eventsper10,000women-years.Therewasnodifferencebetweenthegroupsintermsofall-causemortality.Nooveralldifference forprimaryCHDevents (nonfatalMI, silentMIandCHDdeath)andinvasivebreastcancerincidenceinwomenreceiving CE-alone compared with placebo was reported in finalcentrallyadjudicatedresultsfromtheestrogen-alonesubstudy,afteranaveragefollowupof7.1years.Centrallyadjudicated results forstrokeevents from theestrogen-alonesubstudy,afteranaveragefollow-upof7.1years,reportednosignificantdifference indistributionofstrokesubtypeorseverity,includingfatalstrokes,inwomenreceivingCE-alonecomparedtoplacebo.Estrogen-aloneincreasedtheriskforischemicstroke,andthisexcessriskwaspresentinallsubgroupsofwomenexamined.10

Timingoftheinitiationofestrogen-alonetherapyrelativetothestartofmenopausemayaffect theoverall riskbenefitprofile.TheWHIestrogen-alonesubstudy,stratifiedbyage,showedinwomen50to59yearsofageanon-significanttrendtowardreducedriskforCHD[HR0.63(95percentCI,0.36-1.09)]andoverallmortality[HR0.71(95percentCI,0.46-1.11)].

14.6 WomensHealthInitiativeMemoryStudyTheWHIMSestrogenplusprogestinancillarystudyofWHIenrolled4,532predominantlyhealthypostmenopausalwomen65yearsofageandolder(47percentwere65to69yearsofage,35percentwere70 to74yearsofage,18percentwere75yearsofageandolder)toevaluatetheeffectsofdailyCE(0.625mg)plusMPA(2.5mg) on the incidence of probable dementia (primary outcome)comparedtoplacebo.Afteranaveragefollow-upof4years,therelativeriskofprobabledementiaforCEplusMPAversusplacebowas2.05(95percentCI,1.21-3.48).TheabsoluteriskofprobabledementiaforCEplusMPAversusplacebowas45versus22casesper10,000women-years.Probable dementia as defined in this study included Alzheimersdisease (AD), vascular dementia (VaD) and mixed types (havingfeaturesofbothADandVaD).Themostcommonclassificationofprobabledementia in the treatmentgroupand theplacebogroupwasAD.Sincetheancillarystudywasconductedinwomen65to79yearsofage,itisunknownwhetherthesefindingsapplytoyoungerpostmenopausalwomen[seeWarningsandPrecautions(5.3),andUseinSpecificPopulations(8.5)].TheWHIMSestrogen-aloneancillarystudyofWHIstudyenrolled2,947 predominantly healthy hysterectomized postmenopausalwomen65to79yearsofage(45percentwere65to69yearsofage,

36percentwere70to74yearsofage,19percentwere75yearsofageandolder)toevaluatetheeffectsofdailyCE(0.625mg)-aloneontheincidenceofprobabledementia(primaryoutcome)comparedtoplacebo.Afteranaveragefollow-upof5.2years,therelativeriskofprobabledementia for CE-alone versus placebo was 1.49 (95 percent CI,0.83-2.66). The absolute risk of probable dementia for CE-aloneversus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD,VaDandmixed types (having featuresofbothADandVaD).ThemostcommonclassificationofprobabledementiainthetreatmentgroupandtheplacebogroupwasAD.Sincetheancillarystudywasconductedinwomen65to79yearsofage,itisunknownwhetherthese findings apply to younger postmenopausal women [seeWarningsandPrecautions(5.3),andUse inSpecificPopulations(8.5)].When data from the two populations were pooled as planned intheWHIMSprotocol,thereportedoverallrelativeriskforprobabledementia was 1.76 (95 percent CI, 1.19-2.60). Differencesbetweengroupsbecameapparentinthefirstyearoftreatment.Itisunknownwhetherthesefindingsapplytoyoungerpostmenopausalwomen[seeWarningsandPrecautions(5.3),andUseinSpecificPopulations(8.5)].

15 REFERENCES1.RossouwJE,etal.PostmenopausalHormoneTherapyandRiskofCardiovascularDiseasebyAgeandYearsSinceMenopause.JAMA.2007;297:1465-1477.2.HsiaJ,etal.ConjugatedEquineEstrogensandCoronaryHeartDisease.ArchIntMed.2006;166:357-365.3.CushmanM,etal.EstrogenPlusProgestinandRiskofVenousThrombosis.JAMA.2004;292:1573-1580.4.CurbJD,etal.VenousThrombosisandConjugatedEquineEstrogeninWomenWithoutaUterus.ArchIntMed.2006;166:772-780.5.ChlebowskiRT,etal.InfluenceofEstrogenPlusProgestinonBreastCancerandMammographyinHealthyPostmenopausalWomen.JAMA.2003;289:3234-3253.6.StefanickML,etal.EffectsofConjugatedEquineEstrogensonBreastCancerandMammographyScreeninginPostmenopausalWomenWithHysterectomy.JAMA.2006;295:1647-1657.7.AndersonGL,etal.EffectsofEstrogenPlusProgestinonGynecologicCancersandAssociatedDiagnosticProcedures.JAMA.2003;290:1739-1748.8.ShumakerSA,etal.ConjugatedEquineEstrogensandIncidenceofProbableDementiaandMildCognitiveImpairmentinPostmenopausalWomen.JAMA.2004;291:2947-2958.9.JacksonRD,etal.EffectsofConjugatedEquineEstrogenonRiskofFracturesandBMDinPostmenopausalWomenWithHysterectomy:ResultsFromtheWomensHealthInitiativeRandomizedTrial.JBoneMinerRes.2006;21:817-828.10.HendrixSL,etal.EffectsofConjugatedEquineEstrogenonStrokeintheWomensHealthInitiative.Circulation.2006;113:2425-2434.

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedActivella 1 mg/0.5 mgisawhite,film-coatedtablet,engravedwithNOVO288ononesideand theAPISbullon theother. It isround,6mmindiameterandbi-convex.(NDC0169-5174-02).Itissuppliedas28tabletsinacalendardialpackdispenser.Activella 0.5 mg/0.1 mg is a white, film-coated tablet,engraved with NOVO 291 on one side and the APIS bull on theother.Itisround,6mmindiameterandbi-convex.(NDC0169-5175-10).Itissuppliedas28tabletsinacalendardialpackdispenser.

16.2 Storage and HandlingStore in a dry placeprotected from light.Store at 20C to 25C(68F to 77F), excursions permitted to 15C to 30C (59F to86F).

17 PATIENT COUNSELING INFORMATIONSeeFDA-approvedpatientlabeling(PatientInformation)

17.1 Abnormal Vaginal BleedingInform postmenopausal women of the importance of reportingabnormalvaginalbleedingtotheirhealthcareproviderassoonaspossible[seeWarningsandPrecautions(5.2)].


17.2 Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy

Inform postmenopausal women of possible serious adversereactionsofestrogenplusprogestintherapyincludingCardiovas-cular Disorders, Malignant Neoplasms, and Probable Dementia[seeWarningsandPrecautions(5.1,5.2,5.3)].

17.3 Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy

Inform postmenopausal women of possible less serious butcommonadversereactionsofestrogenplusprogestintherapysuchasheadache,breastpainandtenderness,nauseaandvomiting.

DateofIssue:10/2013Rx OnlyActivellaisaregisteredtrademarkownedbyNovoNordiskFemCareAGForinformationcontact:NovoNordiskInc.800ScuddersMillRoadPlainsboro,NJ08536,USA1-866-668-6336www.novonordisk-us.comManufacturedby:NovoNordiskA/S2880Bagsvaerd,Denmark2000-2013NovoNordisk1013-00018509-1November2013


Patient Information

Activella (AK-ti-vel-la) (estradiol/norethindrone acetate) Tablets

ReadthisPatientInformationbeforeyoustarttakingActivellaandeachtimeyougetarefill.Theremaybenewinformation.Thisinformationdoesnottaketheplaceoftalkingtoyourhealthcareprovideraboutyourmenopausalsymptomsoryourtreatment.

What is the most important information I should know about Activella

(a combination of estrogen and progestin)?Donotuseestrogenswithprogestinstopreventheart

disease,heartattacks,strokes,ordementia(declineofbrainfunction).

Takingestrogenswithprogestinsmayincreaseyourchancesofgettingheartattacks,strokes,breastcancer,orbloodclots.

Takingestrogenswithprogestinsmayincreaseyourchanceofgettingdementia,basedonastudyofwomen65yearsofageorolder.

Donotuseestrogen-alonetopreventheartdisease,heartattacks,strokesordementia.

Takingestrogen-alonemayincreaseyourchanceofgettingcanceroftheuterus(womb).

Takingestrogen-alonemayincreaseyourchancesofgettingstrokesorbloodclots.

Takingestrogen-alonemayincreaseyourchanceofgettingdementia,basedonastudyofwomen65yearsofageorolder.

YouandyourhealthcareprovidershouldtalkregularlyaboutwhetheryoustillneedtreatmentwithActivella.

What is Activella?Activellaisaprescriptionmedicinethatcontainstwokindsofhormones,anestrogenandaprogestin.

What is Activella used for?Activellaisusedaftermenopauseto:

reducemoderatetoseverehotflushes Estrogensarehormonesmadebyawomansovaries.The

ovariesnormallystopmakingestrogenswhenawomanisbetween45and55yrsold.Thisdropinbodyestrogenlevelscausesthechangeoflifeormenopause,theendofmonthlymenstrualperiods.Sometimesbothovariesareremovedduringanoperationbeforenaturalmenopausetakesplace.Thesuddendropinestrogenlevelscausessurgicalmenopause.

Whentheestrogenlevelsbegindropping,somewomengetveryuncomfortablesymptoms,suchasfeelingsofwarmthintheface,neck,andchest,orsudden,intenseepisodesofheatandsweating(hotflashesorhotflushes).Insomewomen,thesymptomsaremild,andtheywillnotneedtotakeestrogens.Inotherwomen,symptomscanbemoresevere.YouandyourhealthcareprovidershouldtalkregularlyaboutwhetherornotyoustillneedtreatmentwithActivella.

treatmoderatetoseveremenopausalchangesinand around the vagina

YouandyourhealthcareprovidershouldtalkregularlyaboutwhetheryoustillneedtreatmentwithActivella1.0mg/0.5mgtotreattheseproblems.IfyouuseActivella1.0mg/0.5mgonlytotreatyourmenopausalchangesinandaroundyourvagina,talkwithyourhealthcareprovideraboutwhetheratopicalvaginalproductwouldbebetterforyou.

helpreduceyourchancesofgettingosteoporosis(thin weak bones)

IfyouuseActivellaonlytopreventosteoporosisfrommenopause,talktoyourhealthcareprovideraboutwhetheradifferenttreatmentormedicinewithoutestrogensmightbebetterforyou.

YouandyourhealthcareprovidershouldtalkregularlyaboutwhetheryoustillneedtreatmentwithActivella.

Who should not take Activella?Do not take Activella if you have had your uterus (womb) removed (hysterectomy).

Activellacontainsaprogestintodecreasethechanceofgettingcanceroftheuterus.Ifyoudonothaveauterus,youdonotneedaprogestinandyoushouldnottakeActivella.

Do not take Activella if you:

haveunusualvaginalbleeding Vaginalbleedingaftermenopausemaybeawarningsign

ofcanceroftheuterus(womb).Yourhealthcareprovidershouldcheckanyunusualvaginalbleedingtofindoutthecause.

currentlyhaveorhavehadcertaincancers Estrogensmayincreasethechanceofgettingcertaintypesof

cancers,includingcancerofthebreastoruterus.Ifyouhaveorhavehadcancer,talkwithyourhealthcareprovideraboutwhetheryoushouldtakeActivella.

hadastrokeorheartattackcurrentlyhaveorhavehadbloodclotscurrentlyhaveorhavehadliverproblemshavebeendiagnosedwithableedingdisorderareallergictoActivella or any of its ingredients SeethelistofingredientsinActivellaattheendofthis

leaflet.thinkyoumaybepregnant Activellaisnotforpregnantwomen.Ifyouthinkyoumay

bepregnant,youshouldhaveapregnancytestandknowtheresults.DonottakeActivellaifthetestispositiveandtalktoyourhealthcareprovider.

What should I tell my healthcare provider before taking Activella?Before you take Activella, tell your healthcare provider if you:

haveanyunusualvaginalbleeding Vaginalbleedingaftermenopausemaybeawarningsignof

canceroftheuterus(womb).Yourhealthcareprovidershouldcheckanyunusualvaginalbleedingtofindoutthecause.

haveanyothermedicalconditions Yourhealthcareprovidermayneedtocheckyoumore

carefullyifyouhavecertainconditions,suchasasthma(wheezing),epilepsy(seizures),diabetes,migraine,endome-triosis,lupus,angioedema(swellingoffaceandtongue),orproblemswithyourheart,liver,thyroid,kidneys,orhavehighcalciumlevelsinyourblood.

aregoingtohavesurgeryorwillbeonbedrest Yourhealthcareproviderwillletyouknowifyouneedtostop

takingActivella.arebreastfeeding ThehormonesinActivellacanpassintoyourbreastmilk.

Tell your healthcare provider about all the medicines you take,includingprescriptionandnonprescriptionmedicines,vitamins,andherbalsupplements.SomemedicinesmayaffecthowActivellaworks.Activellamayalsoaffecthowyourothermedicineswork.Keepalistofyourmedicinesandshowthemtoyourhealthcareproviderandpharmacistwhenyougetanewmedicine.

How should I take Activella?TakeActivellaexactlyasyourhealthcareprovidertellsyou

totakeit.Take1Activellaatthesametimeeachday.Youandyourhealthcareprovidershouldtalkregularly(every

3to6months)aboutthedoseyouaretakingandwhetheryoustillneedtreatmentwithActivella.

Follow the instructions below to use your Activella Dispenser.

How to use the Activella Dispenser

1. Set the Day Reminder.

Turntheinnerdiscsothecurrentdayoftheweekislinedupwiththelittleplastictab.

2. How to Take the First Tablet.

Pullplastictabupandbreakoff.Tipoutthefirsttablet.

3. Every Day.

Turntheoutertransparentdialonespaceclockwiseasindicatedbythearrow.Tipoutthenexttablet.

Note: The transparent dial can only be turned after the tablet in the opening has been removed.

What are the possible side effects of Activella?Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

heartattackstrokebloodclotsdementiabreastcancercanceroftheliningoftheuterus(womb)canceroftheovaryhighbloodpressurehighbloodsugargallbladderdiseaseliverproblemschangesinyourthyroidhormonelevelsenlargementofbenigntumors(fibroids)


Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

newbreastlumpsunusualvaginalbleedingchangesinvisionorspeechsuddennewsevereheadachesseverepainsinyourchestorlegswithorwithoutshortness

ofbreath,weaknessandfatigue

Less serious, but common side effects include:

headachebreastpainirregularvaginalbleedingorspottingstomachorabdominalcramps,bloatingnauseaandvomitinghairlossfluidretentionvaginalyeastinfection

ThesearenotallthepossiblesideeffectsofActivella.Formoreinformation,askyourhealthcareproviderorpharmacist.Tellyourhealthcareproviderifyouhaveanysideeffectthatbothersyouordoesnotgoaway.YoumayreportsideeffectstoNovoNordiskat1-888-824-4336ortoFDAat1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Activella?Talkwithyourhealthcareproviderregularlyaboutwhether

youshouldcontinuetakingActivella.Ifyouhaveauterus,talkwithyourhealthcareproviderabout

whethertheadditionofaprogestinisrightforyou.Theadditionofaprogestinisgenerallyrecommendedfora

womanwithauterustoreducethechanceofgettingcanceroftheuterus(womb).

SeeyourhealthcareproviderrightawayifyougetvaginalbleedingwhiletakingActivella.

Haveapelvicexam,breastexamandmammogram(breastX-ray)everyyearunlessyourhealthcareprovidertellsyousomethingelse.

Ifmembersofyourfamilyhavehadbreastcancerorifyouhaveeverhadbreastlumpsoranabnormalmammogram(breastx-ray),youmayneedtohavebreastexamsmoreoften.

Ifyouhavehighbloodpressure,highcholesterol(fatintheblood),diabetes,areoverweight,orifyouusetobacco,youmayhavehigherchancesforgettingheartdisease.

Askyourhealthcareproviderforwaystoloweryourchancesforgettingheartdisease.

How should I store Activella?StoreActivellaatroomtemperaturebetween68Fto77F

(20Cto25C).StoreActivellainadryplaceprotectedfromlight.

KEEP ACTIVELLA and all medicines out of the reach of children.

General information about the safe and effective use of Activella.Medicinesaresometimesprescribedforconditionsthatarenotmentionedinpatientinformationleaflets.DonottakeActivellaforconditionsforwhichitwasnotprescribed.DonotgiveActivellatootherpeople,eveniftheyhavethesamesymptomsyouhave.Itmayharmthem.

ThisleafletsummarizesthemostimportantinformationaboutActivella.Ifyouwouldlikemoreinformation,talkwithyourhealthcareproviderorpharmacist.YoucanaskyourpharmacistorhealthcareproviderforinformationaboutActivellathatiswrittenforhealthprofessionals.

Formoreinformationgotowww.activella.comorcall1-866-668-6336.

ThisPatientInformationhasbeenapprovedbytheU.S.FoodandDrugAdministration.

ActivellaisaregisteredtrademarkownedbyNovoNordiskFemCareAG

Theembossed(Apis)bullsymbolonthetabletsisatrademarkofNovoNordiskA/S.

NovoNordiskInc.800ScuddersMillRoadPlainsboro,NJ08536,USA1-866-668-6336www.novonordisk-us.com

Manufacturedby:NovoNordiskA/S2880Bagsvaerd,Denmark

Revised:10/2013

2000-2013NovoNordisk1013-00018509-1November2013

What are the ingredients in Activella? Active ingredients: estradiolandnorethindroneacetate

Inactive Ingredients: lactosemonohydrate,starch(corn),copovidone,talc,magnesiumstearate,hypromellose,andtriacetin.

The0.5mg/0.1mgtabletalsocontainshydroxypropylcellulose.

activella - novo-pi.com · 1 ——— warnings and precautions ——— • estrogens increase...

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