ESTROGENUS ® 0.625 MG

" עעבקנהזןולעטמרופ " קדבנונכותותואירבהדרשמי רשואו ." רשואמןולע : לירפא 2012

“This leaflet format has beendeterminedbytheMinistryof Health and the content thereof has

been checked and approved.” Date of approval: April 2012.

PHYSICIANS’ PRESCRIBING INFORMATION

ESTROGENUS

(synthetic conjugated estrogens, B) Tablets

TABLETS

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER

Close clinical surveillance of all women takingestrogens is important. Adequate diagnostic

measures, including endometrial sampling when indicated, should be undertaken to rule out

malignancy in all cases of undiagnosed persistent or recurringabnormal vaginal bleeding. There

is no evidence that the use of “natural” estrogens results in a different endometrial risk profile

than synthetic estrogens atequivalent estrogen doses. (SeeWARNINGS, Malignant

neoplasms,Endometrialcancer.)

CARDIOVASCULAR AND OTHER RISKS

Estrogens with or without progestins should not be used for the prevention of cardiovascular

disease or dementia. (SeeCLINICAL STUDIESandWARNINGS, Cardiovascular disorders

andDementia.)

The estrogen alone substudy of the Women’s HealthInitiative (WHI) reported increased risks of

stroke and deep vein thrombosis (DVT) inpostmenopausal women (50 to 79 years of age)

during 6.8 years and 7.1 years, respectively, oftreatment with oral conjugated estrogens (CE

0.625 mg) alone per day, relative to placebo. (SeeCLINICAL STUDIESandWARNINGS,

Cardiovascular disorders.)

The estrogen-plus-progestin substudy of the WHI reported increased risks of myocardial

infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in

postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with oral

conjugated estrogens (CE 0.625 mg) combinedwith medroxyprogesterone acetate (MPA 2.5

mg) per day, relative to placebo. (SeeCLINICAL STUDIES,andWARNINGS,

Cardiovascular disordersandMalignant neoplasms,Breast cancer).

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI study, reported

increased risk of developing probable dementiain postmenopausal women 65 years of age or

older during 5.2 years of treatment with CE 0.625mgalone and during 4 years of treatment with

CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this

finding applies to younger postmenopausal women. (SeeCLINICALSTUDIES,WARNINGS,

DementiaandPRECAUTIONS, Geriatric Use.)

Other doses of conjugatedestrogens and medroxyprogesteroneacetate,and other combinations

and dosage forms of estrogens and progestins, werenot studied in the WHI clinical trials, and in

the absence of comparable data, these risks should be assumed to be similar.Because of these

risks, estrogens with or withoutprogestins should be prescribed atthe lowest effective doses and

for the shortest duration consistent with treatment goals and risks for the individual woman.

DESCRIPTION

ESTROGENUS (synthetic conjugated estrogens,B) tabletscontainablend of ten (10)

synthetic estrogenic substances.The estrogenic substances are: sodiumestrone sulfate,

sodiumequilin sulfate,sodium17α-dihydroequilin sulfate, sodium17α-estradiol sulfate,

sodium17β-dihydroequilinsulfate,sodium17α-dihydroequilenin sulfate, sodium 17β-

dihydroequilenin sulfate, sodiumequilenin sulfate, sodium17β-estradiol sulfate, and

sodiumΔ 8,9 -dehydroestrone sulfate.

The structural formulae for these estrogens are:

ESTROGENUS tablets for oral administration are available in 0.3 mg, 0.45 mg, 0.625

mg, 0.9 mgand 1.25 mg strengths of syntheticconjugated estrogens, B. These tablets

contain the following inactiveingredients: ascorbyl palmitate, butylated hydroxyanisole,

colloidal silicon dioxide, edetate disodium dehydrate, plasticized ethylcellulose,

hypromellose, lactose monohydrate*, magnesium stearate, purified water, iron oxide red,

titaniumdioxide, polyethylene glycol, polysorbate80,triacetate andtriacetin/glycerol. In

addition, the 0.45 mg tablets contain iron oxideblack and iron oxide yellow; the 0.9 mg

tablets also contain D&C yellow no. 10 aluminumlake, FD&C blue no. 1 aluminum lake

and FD&C yellow no. 6 aluminum lake; and the 1.25 mgtablets contain iron oxide

yellow.

* Amountof lactose

Estrogenus 0.3 mg: 46.7 mg/tablet.

Estrogenus 0.45 mg: 38.4mg/tablet.

Estrogenus 0.625 mg:106.4 mg/tablet.

Estrogenus 0.9 mg: 99 mg/tablet.

Estrogenus 1.25 mg: 89.4mg/tablet.

CLINICALPHARMACOLOGY

Endogenous estrogens are largely responsiblefor the development and maintenance of

the female reproductive system and secondary sexual characteristics. Although

circulating estrogens exist in a dynamicequilibriumof metabolic interconversions,

estradiol is the principal intracellular humanestrogen andis substantially more potent

than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle,

which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual

cycle. After menopause, most endogenousestrogen is produced by conversion of

androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus,

estrone and the sulfate-conjugated form, estronesulfate, are the most abundant circulating

estrogens in postmenopausal women.

Estrogens act through binding tonuclear receptors in estrogen-responsive tissues. To

date, two estrogen receptors have been identified. These varyin proportion fromtissue to

tissue.

Circulating estrogens modulate the pituitarysecretion of the gonadotropins, luteinizing

hormone (LH) and follicle-stimulating hormone (FSH), through a negative feedback

mechanism. Estrogens act to reduce theelevated levels of these hormones in

postmenopausal women.

A. Absorption

Synthetic conjugated estrogens, B are solubleinwater and are well absorbed from the

gastrointestinal tractafter release fromthe drug formulation. ESTROGENUS tablets

release synthetic conjugatedestrogens, B slowly over a period of several hours. Table 1

and Table 2 summarize the mean pharmacokinetic parameters for unconjugated (free) and

conjugated (total) estrogens following singleadministration of two 0.625 mg tablets to 21

healthy postmenopausal women under fastingconditions. The effect of food on the

bioavailability of synthetic conjugatedestrogens, B following administration of

ESTROGENUS tablets has not been studied.However, the presence of food did not

significantlyaffect the pharmacokinetics of asimilar formulation of synthetic conjugated

estrogens, B.

Table 1. Mean Pharmacokinetic Parameters of Unconjugated (Free) Estrogens

Following a Single Dose of 2 x 0.625 mg ESTROGENUS Tablets Under Fasting

Conditions*

C

max

(pg/mL) t

max

(hr) t

1/2

(hr) AUC

0-48h

(pg hr/mL)

Baseline-corrected estrone

(% CV) 75.87

(39) 9.29

(25) 23.46

(59) 1601.59

(41)

Equilin

(% CV) 41.94

(49) 8.38

(27) 15.09

(55) 707.21

(46)

max = peakplasmaconcentration; t

max =time peak concentrationoccurs;t

1/2 =apparentterminal-phase disposition half-

life.AUC

0-48h =total area underthe concentration-time curve from time zero to time oflast quantifiable concentration

(48h); *Δ 8,9 Dehydroestrone(free)levels werebelow theassay limit of quantitation; CV= Coefficientof Variance

Table 2. Mean Pharmacokinetic Parametersof Conjugated (Total) Estrogens

Following a Single Dose of 2 x 0.625mg ESTROGENUS Tablets Under Fasting

Conditions

C

max t

max

(h) (ng/mL) t

1/2

(h) AUC

0-48h

(ng h/mL)

Baseline-corrected

estrone

(% CV) 3.74

(29) 8.00

(27) 14.26

(26) 62.03

(34)

Equilin

(% CV) 3.69

(44) 8.05

(36) 11.28

(28) 58.25

(53)

Dehydroestrone

(%CV) 0.74

(32) 7.55

(37) 14.14

(26) 12.93

(39)

C

max = peakplasmaconcentration; t

max =timepeak concentrationoccurs;t

1/2 = apparentterminal-phase disposition

half-life; AUC

0-48h = totalareaunder theconcentration-timecurvefromtimezerototime oflast quantifiable

concentration (48h); CV= Coefficient ofVariance

B. Distribution

The distribution of exogenous estrogens issimilar to that of endogenous estrogens.

Estrogens are widely distributed in the body and are generally found in higher

concentrations in the sex hormone target organs. Estrogens circulate in the blood largely

bound to sex hormone binding globulin (SHBG) and albumin.

C. Metabolism

Exogenous estrogens are metabolized in the samemanner as endogenous estrogens.

Circulating estrogens exist in a dynamic equilibriumof metabolic interconversions.

These transformations take place mainly in the liver. Estradiol is converted reversibly to

estrone, and both can be converted to estriol,which is the major urinary metabolite.

Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide

conjugation in the liver, biliary secretion ofconjugates into the intestine, and hydrolysis

in the intestine followed by reabsorption. In postmenopausal women, a significant

portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate,

which serves as a circulating reservoir for the formation of more active estrogens.

D. Excretion

Estradiol, estrone, and estriolare excreted in the urine alongwith glucuronide and sulfate

conjugates. The mean (SD) apparentterminal elimination half-life (t

) of conjugated

estrone is 14 (± 6) hours and conjugated equilin is 11 (± 6) hours.

E. Special Populations

No pharmacokinetic studies were conductedin special populations, including patients

with renal or hepatic impairment.

F. Drug Interactions

In vitroandin vivostudies have shown that estrogens are metabolized partiallyby

cytochromeP450 3A4 (CYP3A4). Therefore, inducers orinhibitors of CYP3A4 may

affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s Wort

preparations(Hypericumperforatum), phenobarbital, carbamazepine, and rifampin, may

reduce plasmaconcentrations of estrogens, possibly resulting in a decrease intherapeutic

effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as

erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice,

may increase plasma concentrationsof estrogens and may result in side effects.

CLINICALSTUDIES

Effects on Vasomotor Symptoms

A randomized, double-blind, placebo-controlled, dose-ranging, multi-center clinical study

was conducted to evaluate the safety and effectiveness of ESTROGENUS tablets for the

treatment of vasomotor symptoms in281 naturally or surgicallypostmenopausal women

aged 26 to 65 years whowere experiencing aminimum of seven moderate to severe hot

flushes per day or 50 per week at randomization. The majority (81%) of patients were

Caucasian (n=228) and 17.4% were Black (n=49). Patients were randomized to receive

ESTROGENUS tablets 0.3 mg,0.625 mg, 1.25 mg, or placebo once daily for 12 weeks.

ESTROGENUS (0.3 mg, 0.625 mg and 1.25 mgtablets) was shown to be statistically

better than placeboat weeks 4and 12 for relief of both thefrequency and severity of

moderate to severe vasomotor symptoms(Table 3 and 4).

Table 3. Mean Number and Mean Change in Number of Moderate to Severe

Hot FlushesPer Week ITT Population With LOCF

0.3 mg

n=66 0.625 mg

n=71 1.25mg

n=69 Placebo

n=70

Baseline

Mean(SD) 104.3(57.7) 97.3(82.1) 86.8(42.1) 96.4(58.2)

Week 4

Mean(SD) 47.0(52.9) 23.3(26.9) 24.6(47.0) 57.8(47.5)

MeanChange from

Baseline(SE) -49.8 (5.2) -72.8 (5.0) -68.3 (5.1) -37.2 (5.0)

p-valueversusplacebo0.005 <0.001 <0.001---

Week 12

Mean(SD) 30.7(47.7) 12.2(18.7) 12.4(26.3) 47.5(49.8)

MeanChange from

Baseline(SE) -66.3 (4.6) -84.6 (4.4) -82.6 (4.5) -48.3 (4.5)

p-valueversusplacebo <0.001<0.001<0.001 ---

ITT= Intenttotreat;LOCF= LastObservation Carried Forward, SD= StandardDeviation;SE= Standard

Error

Table 4. Mean Change in Severity of Moderate to Severe Hot Flushes Per

Week, ITT Population with LOCF

0.3 mg

n=66 0.625 mg

n=71 1.25mg

n=69 Placebo

n=70

Baseline

Mean(SD) 2.5 (0.3) 2.5 (0.3) 2.5 (0.3) 2.5 (0.3)

Week 4

Mean(SD) 2.1 (0.8) 1.9 (1.0) 1.5 (1.1) 2.2 (0.8)

MeanChange from

Baseline(SE) -0.5(0.1) -0.6(0.1) -1.0(0.1) -0.3(0.1)

p-valueversusplacebo0.0360.002 <0.001---

Week 12

Mean(SD) 1.5 (1.2) 1.1 (1.2) 1.0 (1.1) 1.9 (1.1)

MeanChange from

Baseline(SE) -1.0(0.1) -1.4(0.1) -1.5(0.1) -0.6(0.1)

p-valueversusplacebo 0.023 <0.001 <0.001---

ITT= Intenttotreat;LOCF= LastObservation Carried Forward, SD= StandardDeviation;SE= Standard

Error

Effects on Vulvar and Vaginal Atrophy

A randomized, double-blind, placebo-controlled, multi-center clinical study was

conducted to evaluate the safety and effectiveness of ESTROGENUS 0.3 mg tablets for

the treatment of symptomsof vulvar and vaginal atrophy in 248 naturally or surgically

postmenopausal women between 32 to 81 yearsof age (mean 58.6 years) who at baseline

had≤5% superficial cells on a vaginal smear, a vaginal pH > 5.0, and who identified

their most bothersome moderate to severesymptomof vulvar and vaginal atrophy.

The majority (82%) of the women wereCaucasian(n=203),11%wereHispanic

(n=26), 4%were Black (n=9) and3%were Asian (n=6). All patients were assessedfor

improvement in the mean change from baseline to Week 12 for three co-primary efficacy

variables: most bothersomesymptomof vulvar and vaginal atrophy (defined as the

moderate tosevere symptomthat had beenidentified bythe patient as most bothersome

to her at baseline); percentage of vaginalsuperficial cells and percentage of vaginal

parabasal cells; and vaginal pH.

In this study, a statistically significant meanchange between baseline and week 12 for the

group treated with ESTROGENUS 0.3 mg tablets comparedto placebowas observed for

the symptoms, vaginal dryness and pain withintercourse. See Table 5. ESTROGENUS

0.3 mg tablets increased superficial cells bya mean of 17.1% ascompared to 2.0% for

placebo (statistically significant). A corresponding statistically significant mean

reduction frombaseline in parabasal cells(41.7% for ESTROGENUS0.3 mg tablets and

6.8% for placebo) was observed at week 12.The mean reduction between baseline and

week 12 in the pH was 1.69 in the ESTROGENUS 0.3 mg tabletsgroup and 0.45 in the

placebo group (statistically significant).

Table 5. Change from Baseline to Week 12in the Severity of Vaginal Dryness and

Pain with Intercourse,SymptomsThat Were Identified by the Menopausal Study

Patient as Her Most Bothersome Symptom of Vulvar and Vaginal Atrophy at

Baseline

Most Bothersome Symptom at

Baseline* ESTROGENUS

0.3 mg Placebo

Vaginal Dryness

n56 54

Baseline Severity 2.52 2.54

Mean Severity at Week 12 0.80 1.81

Mean Change in Severity from

Baseline (s.d.) -1.71 (0.85)

-0.72 (0.66)

p-value vs. placebo <0.001 ---

Pain With Intercourse

n35 40

Baseline Severity 2.74 2.70

Mean Severity at Week 12 0.94 1.95

Mean Change in Severity from

Baseline (s.d.) -1.80 (1.02) -0.75 (0.95)

p-value vs. placebo <0.001

---

* Treatment differences assessedby ANCOVA orrank ANCOVA (% cell data)

with baseline as covariate for the modified intent-to-treat population, last-

observation-carried-forward data set.

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women

in two substudiesto assess the risks and benefits of eitherthe use of oral conjugated

estrogens (CE 0.625 mg) alone per day orin combination with medroxyprogesterone

acetate (CE 0.625 mg/MPA 2.5 mg) per daycompared toplacebointhe prevention of

certain chronic diseases. The primary endpoint was the incidence of coronary heart

disease (CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death), with

invasive breast cancer as the primary adverse outcomestudied. A “global index”

includedthe earliest occurrence ofCHD, invasive breast cancer, stroke, pulmonary

embolism(PE), endometrial cancer (only inthe estrogen plusprogestin substudy),

colorectal cancer, hip fracture, or death duetoother causes. Thestudy did not evaluate

the effects of CE or CE/MPA on menopausal symptoms.

The estrogen-alone substudy was stopped earlybecause anincreased risk of stroke was

observed and it was deemed that no further information would be obtained regarding the

risks and benefits of estrogenalone in predetermined primary endpoints. Results of the

estrogen-alone substudy, which included 10,739women (average age of 63 years, range

50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average

follow-up of 6.8 years are presented in Table 6.

Table 6:Relative And Absolute Risk Seen InThe Estrogen-Alone Substudy Of WHI a

Placebo

n = 5,429 CE

n = 5,310 Event Relative Risk

CE vs. Placebo

(95% nCI a ) Absolute Risk per 10,000

Women-Years

CHD events b 0.95 (0.79- 1.16) 56 53

Nonfatal MI b

0.91 (0.73-1.14) 43 40

CHD death b

1.01(0.71- 1.43) 16 16

Stroke c 1.39 (1.10-1.77) 32 44

Deep vein thrombosis b,d 1.47 (1.06-2.06) 15 23

Pulmonary embolism b 1.37 (0.90-2.07) 10 14

Invasive breast cancer b 0.80 (0.62-1.04) 34 28

Colorectal cancer c 1.08 (0.75-1.55) 16 17

Hip fracture c 0.61 (0.41-0.91) 17 11

Vertebral fractures c,d 0.62 (0.42-0.93) 17 11

Total fractures c,d 0.70 (0.63-0.79) 195 139

Death due to other causes c,e 1.08 (0.88-1.32) 50 53

Overall mortality c,d 1.04 (0.88-1.32) 7881

Global index c,f 1.01 (0.91-1.12) 190 192

Nominal confidence intervals unadjusted for multiple looks andmultiple comparisons

Results arebasedon centrally adjudicateddata for an averagefollow-upof7.1 years

Resultsare basedonanaverage follow-upof6.8years

d Not includedinGlobalIndex

e All deaths, except frombreast or colorectalcancer,definite/probable CHD, PE orcerebrovascular disease

f A subsetof the eventswas combinedin a “global index”,defined as theearliest occurrenceofCHD events,

invasivebreastcancer, stroke,pulmonaryembolism, colorectal cancer, hip fracture,ordeath due toother

causes

For those outcomes included in the WHI“global index” that reached statistical

significance, the absolute excess risk per10,000 women-years in the group treated with

estrogen-alone was 12 more strokes, whilethe absolute risk reduction per 10,000 women-

years was6fewer hip fractures. The absoluteexcess riskof eventsincluded in the

“global index” was a nonsignificant 2 events per 10,000 women-years. There was no

difference between the groups in termsof all-cause mortality. (See BOXED

WARNINGS, WARNINGS, and PRECAUTIONS.)

Final centrally adjudicated results for CHD events and centrally adjudicated resultsfor

invasive breast cancer incidence fromtheestrogen-alone substudy, after an average

follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal

MI, silentMI andCHD death)and invasive breast cancer incidence in women receiving

CE alone compared with placebo (see Table 6).

The estrogen-plus-progestin substudy wasalso stopped early because,according tothe

predefined stopping rule, after an averagefollow-up of 5.2 years of treatment, the

increased riskof breast cancer and cardiovascular events exceeded the specified benefits

included in the “global index.” The absolute excess risk ofevents included in the “global

index” was 19 per 10,000 women-years (RR 1.15, 95% nCI 1.03-1.28).

For those outcomes included in the WHI“global index” that reached statistical

significance after 5.6 yearsof follow-up, the absoluteexcess risks per 10,000 women-

years in the group treated with CE/MPA were6 more CHD events, 7 more strokes, 10

more PEs, and 8 more invasive breast cancers, while the absolute riskreductionsper

10,000 women-years were 7 fewer colorectalcancers and 5 fewerhip fractures. (See

BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Results of the estrogen-plus-progestin substudy, which included 16,608 women (average

age of 63 years, range 50 to 79; 83.9%White, 6.8% Black, 5.4% Hispanic, 3.9% Other)

are presented in Table 7 below.

Table 7. Relative And Absolute Risk Seen inthe Estrogen-Plus Progestin Substudy of WHI

at an Average of 5.6 Years a

Placebo

n = 8102 CE/MPA

n = 8506 Event Relative Risk

CE/MPA vs. Placebo

(95% nCI b )

Absolute Risk per 10,000

Women-Years

CHD events 1.24 (1.00-1.54) 33 39

Non-fatal MI 1.28 (1.00-1.63) 25 31

CHD death 1.10 (0.70-1.75) 8 8

All strokes 1.31 (1.02-1.68) 24 31

Ischemic stroke 1.44 (1.09 -1.90) 18 26

Deep vein thrombosis 1.95 (1.43 – 2.67) 13 26

Pulmonary embolism 2.13 (1.45-3.11) 8 18

Invasive breast cancer c 1.24 (1.01-1.54)33 41

Invasive colorectalcancer0.56 (0.38-0.81) 16 9

Endometrial cancer 0.81 (0.48-1.36) 7 6

Cervical cancer 1.44 (0.47-4.42) 1 2

Hip fracture 0.67 (0.47-0.96) 16 11

Vertebral fractures 0.65 (0.46-0.92) 17 11

Lower arm/wrist fractures 0.71 (0.59-0.85) 62 44

Total fractures 0.76 (0.69-0.83) 199 152

a Results arebasedoncentrally adjudicateddata. Mortality data wasnotpart of the adjudicateddata;

however,dataat5.2 yearsoffollow-upshowednodifference betweenthegroups in terms ofall-cause

mortality(RR0.98, 95% nCI 0.82-1.18)

Nominal confidence intervals unadjusted for multiple looks andmultiple comparisons

c Includes metastatic andnon-metastaticbreast cancer,withtheexception ofin situbreast cancer

Women’s Health Initiative Memory Study

The estrogen-alone Women’s Health Initiative Memory Study (WHIMS), a substudy of

WHI study, enrolled 2,947 predominantly healthy postmenopausal women 65 years of

age and older (45% were age 65 to 69 years,36% were 70 to 74 years, and 19% were 75

years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg)on

the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 5.2 years, 28women in the estrogen-alone group (37 per

10,000 women-years) and 19 in the placebogroup (25 per 10,000 women-years) were

diagnosed with probable dementia. The relative risk of probable dementia in the

estrogen-alone group was 1.49 (95% CI 0.83-2.66)compared to placebo. It is unknown

whether these findingsapply to younger postmenopausal women. (See BOXED

WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

The estrogen-plus-progestin WHIMS substudy enrolled 4,532 predominantly healthy

postmenopausal women 65 years ofage and older (47% were aged65 to 69 years, 35%

were 70 to 74 years, and 18% were 75 years of age andolder)to evaluate the effects of

CE 0.625 mg plus MPA 2.5 mg onthe incidence of probable dementia (primary outcome)

compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen plus progestin group (45

per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were

diagnosed with probable dementia. The relative risk of probable dementia in the

hormone therapy group was 2.05 (95% CI 1.21-3.48) compared to placebo. Differences

between groups becameapparent inthe first year of treatment. It is unknown whether

these findings apply to younger postmenopausal women. (See BOXED WARNING,

WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)

When data fromthe two populations were pooled as planned in the WHIMS protocol, the

reported overall relative risk for probabledementia was 1.76 (95% CI 1.19-2.60). It is

unknown whether these findings apply toyounger postmenopausal women. (See

BOXED WARNING, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)

INDICATIONS AND USAGE

ESTROGENUS 0.3 mgtablets are indicated in the:

1.Treatment of moderate to severe vasomotor symptoms associated with

menopause.

2.Treatment of moderate to severe vaginal dryness and pain with intercourse,

symptomsof vulvar and vaginal atrophy,associated withmenopause. When

prescribing solely for the treatment ofmoderate to severe vaginal dryness and

pain with intercourse, topical vaginal products should be considered.

ESTROGENUS 0.45 mg, 0.625 mg, 0.9 mg and 1.25 mgtablets are indicated in the

treatment ofmoderate to severe vasomotor symptoms associated with menopause.

CONTRAINDICATIONS

ESTROGENUS tablets should not be usedin women with any of the following

conditions:

1.Undiagnosed abnormal genital bleeding.

2.Known, suspected, or historyof cancer of the breast.

3.Known or suspected estrogen-dependent neoplasia.

4.Active deep vein thrombosis, pulmonary embolism or a history of these conditions.

5.Active orrecent (e.g.,within the past year) arterial thromboembolic disease (e.g.,

stroke, myocardial infarction).

6.Liver dysfunction or disease.

7.Known hypersensitivity tothe ingredients of ESTROGENUS Tablets.

8.Known or suspected pregnancy. Thereis no indication for ESTROGENUS in

pregnancy. There appears to be little or noincreased risk ofbirth defects in children

born to women who have used estrogens and progestins fromoral contraceptives

inadvertently during early pregnancy. (See PRECAUTIONS.)

WARNINGS

See BOXED WARNINGS.

1.Cardiovascular disorders

Estrogen and estrogen/progestintherapies havebeen associated with an increased risk

of cardiovascular eventssuch as myocardialinfarction and stroke, as well as venous

thrombosis and pulmonary embolism (venous thromboembolism(VTE)). Should any

of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension,diabetes mellitus,

tobaccouse, hypercholesterolemia, and obesity) and/or venous thromboembolism

(e.g., personal history or family history of VTE, obesity, and systemic lupus

erythematosus) should be managed appropriately.

a. Stroke

In the estrogen-alone substudy of the Women’s Health Initiative(WHI) study,

statistically significant increased riskofstroke was reported in women receiving

CE 0.625 mg daily compared to womenreceiving placebo (44 versus 32 per

10,000 women-years). The increase in riskwas demonstrated in year 1 and

persisted. (See CLINICAL STUDIES).

In the estrogen-plus-progestin substudyof WHIstudy, a statistically significant

increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5

mg daily compared to women receiving placebo (31 vs. 24per 10, 000women-

years). The increase inriskwas demonstratedafter the first yearand persisted.

(SeeCLINICAL PHARMACOLOGY, CLINICAL STUDIES.)

b.Coronary heart disease

In the estrogen-alone substudy of WHI, no overall effect on coronary heart

disease (CHD) events (defined as non-fatal MI, silent MI or death due to CHD)

was reported in women receiving estrogen alone compared to placebo. (See

CLINICAL STUDIES.)

In the estrogen-plus-progestin substudy of the WHI study, no statistically

significant increase of CHD events wasreported inwomen receivingCE/MPA

compared to women receiving placebo (39 versus 33 per 10,000 women-years).

An increasein relativeriskwas demonstratedin year 1,and a trend toward

decreasing relative risk wasreported in years 2 through 5.

In postmenopausal women with documented heart disease (n = 2,763, average age

66.7 years), a controlled clinical trial ofsecondary prevention of cardiovascular

disease (Heart and Estrogen/ProgestinReplacement Study (HERS)) treatment

with CE/MPA (0.625 mg/2.5 mgper day) demonstrated no cardiovascular benefit.

During an average follow-up of 4.1 years,treatment with CE/MPA did not reduce

the overall rate of CHD events in postmenopausal women with established

coronary heart disease. There were more CHD events in the CE/MPA-treated

group thanin the placebo group inyear 1,but not during the subsequent years.

Participationin an open label extensionof the original HERS trial (HERS II) was

agreed to by 2,321 women. Average follow-up in HERS II was an additional 2.7

years, for a total of 6.8 years overall.Rates of CHD events were comparable

among women in the CE/MPA group andthe placebo group in HERS, HERS II,

and overall.

Large doses of estrogen (5 mgconjugatedestrogens per day), comparable to those

used to treat cancerofthe prostate and breast, have been shown in a large

prospective clinical trialin men to increase the risks of nonfatal myocardial

infarction, pulmonary embolism,and thrombophlebitis.

c.Venous thromboembolism

In the estrogen-alone substudy of WHIthe risk of VTE (DVT and pulmonary

embolism[PE]), was reportedto beincreased for women taking conjugated

equine estrogens (30 vs. 22 per 10,000 women-years), althoughonly the increased

risk of DVT reached statistical significance (23 vs. 15 per 10,000 women years).

The increasein VTE riskwas demonstrated during the first year. (See CLINICAL

STUDIES.)

In the estrogen-plus-progestin substudy ofWHI, a statistically significant 2-fold

greater rate of VTE wasreported in women receiving CE/MPA compared to

women receiving placebo (35 vs. 17 per10,000 women-years). Statistically

significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years)

and PE (18 vs. 8 per 10,000 women-years)were also demonstrated. The increase

in VTE risk was demonstrated during the first yearand persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery

of the type associated with an increased risk of thromboembolism,or during

periods of prolonged immobilization.

2.Malignant neoplasms

a.Endometrialcancer

The use of unopposed estrogens in women withintact uteri has been associated with

an increased risk of endometrial cancer. The reported endometrial cancer risk among

unopposed estrogen users is about 2- to 12-times greater than in non-users, and

appears dependent on duration of treatmentand on estrogen dose. Most studies show

no significant increased risk associated withuse of estrogens for less than 1 year. The

greatest risk appears associated with prolonged use, withincreased risks of 15- to 24-

fold for 5 to 10 years or more. This risk hasbeenshown to persist for at least 8 to 15

years after estrogen therapy is discontinued.

Clinicalsurveillance ofall women taking estrogen/progestin combinations is

important. Adequate diagnostic measures, including endometrial sampling when

indicated, should be undertaken to rule outmalignancy in all cases of undiagnosed

persistent or recurring abnormal vaginal bleeding. There is no evidence that the use

of natural estrogens resultsin adifferent endometrial risk profile than synthetic

estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has

been shown to reduce the risk of endometrial hyperplasia, whichmay be a precursor

to endometrial cancer.

b.Breast cancer

In somestudies, the use of estrogensand progestins by postmenopausal women has

been reported to increase the risk of breast cancer. The most important randomized

clinical trial providing information about this issue is the Women's Health Initiative

(WHI) (seeCLINICAL STUDIES). The results fromobservational studies are

generally consistentwiththose oftheWHI clinical trial.

Observational studieshave also reportedan increased risk of breast cancer for

estrogen-plus-progestincombination therapy,and a smaller increased risk for

estrogen-alone therapy, after several years of use. For bothfindings, the excess risk

increased with duration of use, and appearedto return to baseline over about five

years after stopping treatment (only the observational studies have substantial data on

risk after stopping). In these studies,the risk of breast cancer was greater, and became

apparentearlier, withestrogen-plus-progestin combination therapy as compared to

estrogen-alone therapy. However, these studies have not found significant variation in

the risk of breast cancer among differentestrogens or among different estrogen-plus-

progestin combinations, doses, orroutes of administration.

In the estrogen-alone substudy of WHI, after an averageof 7.1 years of follow-up, CE

(0.625 mgdaily) was not associated with anincreased risk of invasive breast cancer

(RR 0.80, 95% nCI 0.62-1.04).

Inthe estrogen-plus-progestinsubstudy, after a mean follow-up of 5.6 years, the WHI

substudy reported an increasedrisk of breast cancer. Inthis substudy, prior use of

estrogen alone or estrogen-plus-progestincombination hormone therapy was reported

by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI

1.01-1.54), and the absolute risk was 41 vs. 33 cases per 10,000 women-years, for

estrogen plus progestin compared withplacebo, respectively. Among women who

reported prior use of hormone therapy, the relative risk of invasive breast cancer was

1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for estrogen

plus progestin compared with placebo.Among women who reported no prior use of

hormone therapy, the relative risk of invasive breast cancer was1.09, and the absolute

risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin

compared with placebo.In the WHI trial,invasive breast cancers were larger and

diagnosed at a more advanced stage in the estrogen-plus-progestin group compared

with the placebo group. Metastatic disease was rare, with no apparent difference

between the two groups. Other prognostic factors, such as histologic subtype, grade

and hormone receptor status did not differ between the groups.

The use of estrogen alone and estrogen plus progestin has been reported to result in an

increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and

performmonthly breast self-examinations.In addition, mammography examinations

should be scheduled based on patient age, risk factors, and prior mammogramresults.

3. Dementia

In the estrogen-alone Women's Health InitiativeMemory Study (WHIMS), a

substudy of WHI, a populationof 2,947 hysterectomized women aged 65 to 79 years

was randomized to CE (0.625 mgdaily) orplacebo. In the estrogen-plus-progestin

WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years

was randomized to CE/MPA (0.625mg/2.5 mg daily) or placebo.

In the estrogen-alone substudy, after anaverage follow-up of 5.2 years, 28 women in

the estrogen-alone group and 19 women in the placebo group were diagnosed with

probable dementia. The relative risk of probable dementia for CE alone vs. placebo

was 1.49 (95% CI 0.83-2.66). The absolute riskof probable dementia for CE alone vs.

placebo was 37 vs. 25 cases per 10,000 women-years.

In the estrogen-plus-progestin substudy, after an average follow-up of four years, 40

women in the estrogen-plus-progestin group and 21 women in the placebo group were

diagnosed with probable dementia. Therelative risk of probable dementia for

estrogen plus progestin vs. placebo was 2.05(95% CI 1.21-3.48). The absolute risk

of probable dementia for CE/MPA vs. placebo was 45 vs. 22 cases per 10,000

women-years.

When data fromthe two populations were pooled as planned in the WHIMS protocol,

the reported overall relative risk forprobable dementia was 1.76 (95% CI 1.19-2.60).

Since both substudies were conducted in women aged 65 to 79 years, it is unknown

whether these findings apply to younger postmenopausal women. (See BOXED

WARNINGS and PRECAUTIONS, and Geriatric Use.)

4. Gallbladder disease

A two- to four-fold increase in therisk ofgallbladder disease requiring surgery in

postmenopausal women receivingestrogens has been reported.

5. Hypercalcemia

Estrogen administration may lead to severehypercalcemia in patientswith breast

cancer and bone metastases. If hypercalcemia occurs, use of the drug should be

stopped and appropriate measures takento reduce the serumcalciumlevel.

6. Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens.

Discontinue medication pending examination ifthere is sudden partial or complete

loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination

reveals papilledemaor retinal vascularlesions, estrogens should be permanently

discontinued.

PRECAUTIONS

A.General

1.Addition of a progestin whena woman has not had a hysterectomy

Studies of the addition of a progestin for10 or more days of a cycle of estrogen

administration, or daily with estrogen ina continuous regimen, have reported a

lowered incidence of endometrial hyperplasia thanwould be induced by estrogen

treatment alone. Endometrial hyperplasia may bea precursor to endometrial

cancer.

There are, however, possible risks that may be associated with the use of

progestins with estrogenscompared to estrogen-alone regimens. These include: a

possible increased risk of breast cancer,adverse effects on lipoprotein metabolism

(e.g., lowering HDL, raising LDL) and impairment of glucose tolerance.

2.Elevated blood pressure

Ina small number of case reports, substantial increases in blood pressure have

been attributed to idiosyncratic reactionsto estrogens. In a large, randomized,

placebo-controlled clinical trial, a generalized effect of estrogens on blood

pressure was not seen. Blood pressure should be monitored at regular intervals

with estrogen use.

3.Hypertriglyceridemia

In patientswith pre-existinghypertriglyceridemIa, estrogen therapymay be

associated with elevations ofplasma triglycerides leadingto pancreatitis and other

complications.

4.Impaired liver function and past history ofcholestatic jaundice

Estrogens may be poorly metabolized in patients with impaired liver function.

For patients with a history of cholestatic jaundice associated with past estrogen

use or with pregnancy,cautionshould be exercised and inthe caseof recurrence,

medication should be discontinued.

5.Hypothyroidism

Estrogen administrationleads to increasedthyroid-binding globulin (TBG) levels.

Patients with normal thyroid function cancompensate for the increased TBG by

making more thyroid hormone, thus maintaining free T

andT

serum

concentrations in the normal range. Patients dependent on thyroid hormone

replacement therapy who arealso receiving estrogens may require increased doses

of their thyroid replacement therapy. These patients should have their thyroid

function monitored to maintain theirfree thyroid hormone levels in an acceptable

range.

6.Fluid retention

Estrogens may cause somedegree of fluidretention. Because of this, patients who

have conditions that might be influenced bythis factor, such as a cardiac or renal

dysfunction, warrant careful observation when estrogens are prescribed.

7.Hypocalcemia

Estrogens should be used with caution inindividuals with severe hypocalcemia.

8.Ovarian cancer

The estrogen-plus-progestin substudy ofWHIreported that after an average

follow-up of 5.6 years, therelative risk for ovarian cancer for estrogen plus

progestin vs. placebo was 1.58 (95% nCI 0.77 – 3.24), but was not statistically

significant. The absolute risk for estrogen plus progestin vs. placebo was 4.2 vs.

2.7 cases per 10,000 women-years. In someepidemiologic studies, the use of

estrogen only products, in particular for10 or more years, has been associated

with an increased risk ofovarian cancer. Other epidemiologic studies have not

found these associations.

9.Exacerbation of endometriosis

Endometriosis may be exacerbated withadministration of estrogens. Malignant

transformation of residual endometrialimplants has been reported in women

treated post-hysterectomy with estrogen-alone therapy. For patients known to

have residual endometriosis post-hysterectomy, the addition of progestin should

be considered.

10.Exacerbation of other conditions

Estrogensmay cause an exacerbation ofasthma, diabetes mellitus,epilepsy,

migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and

should be used with caution inwomen with these conditions.

B. Information for Patients

Physicians are advised to discuss thePATIENT INFORMATIONleaflet with

patients for whomthey prescribe ESTROGENUS tablets.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for the

indication and then guided by clinicalresponse rather than by serumhormone

levels (e.g., estradiol, FSH).

D. Drug/Laboratory Test Interactions

1.Acceleratedprothrombin time, partial thromboplastin time, and platelet

aggregation time; increased platelet count;increased factors II, VII antigen,

VIII antigen,VIII coagulant activity,IX, X, XII, VII-X complex, II-VII-X

complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and

antithrombin III, decreased antithrombin IIIactivity; increasedlevels of

fibrinogen and fibrinogen activity;increased plasminogen antigen and

activity.

2.Increased thyroid-binding globulin (TBG) levels leading to increased

circulating total thyroid hormone levels as measured by protein-bound iodine

(PBI), T

levels (by column or by radioimmunoassay) or T

levels by

radioimmunoassay. T

resin uptake is decreased,reflecting the elevated TBG.

Free T

and free T

concentrations are unaltered. Patients on thyroid

replacement therapy may require higher doses of thyroid hormone.

3.Other binding proteins may be elevatedin serum, (i.e., corticosteroid binding

globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased

total circulating corticosteroids and sex steroids, respectively. Free hormone

concentrations may be decreased. Other plasma proteins may be increased

(angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

4.Increased plasmaHDL and HDL

cholesterol subfraction concentrations,

reduced LDL cholesterol concentration, increased triglyceride levels.

5.Impaired glucose tolerance.

6.Reduced response to metyrapone test.

E.Carcinogenesis, Mutagenesis, Impairment ofFertility

SeeBOXED WARNINGS, WARNINGSandPRECAUTIONS.

Long-termcontinuous administration of natural and synthetic estrogens in certain

animal species increases the frequency ofcarcinomas of the breast,uterus,cervix,

vagina, testis, and liver.

F. Pregnancy

ESTROGENUS tablets should not be used during pregnancy. (See

CONTRAINDICATIONS.)

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the

quantity and quality of the milk. Detectable amounts of estrogens have been

identified in the milk of mothers receiving this drug. Caution should be exercised

when ESTROGENUS is administered to a nursing woman.

H. Pediatric Use

The safetyand efficacyof ESTROGENUS tablets in pediatricpatients has not been

established.

I. Geriatric Use

Clinicalstudies ofESTROGENUS did not include sufficient numbers of subjects

aged 65 and over to determine whether they respond differently from younger

subjects.

Of the total number of subjects in the estrogen-alonesubstudy of the WHI study,

46 percent (n = 4,943) were 65 years and older, while 7.1 percent (n = 767) were

75 years and older. There was a higher relative risk (CE versusplacebo) of stroke

in women less than 75 years of age compared to women 75 years and over.

In the estrogen-alone substudy of WHIMS, a substudy of WHI, a population of

2,947 hysterectomized women, aged 65 to 79years, was randomized to CE (0.625

per day) or placebo. After an average follow-up of 5.2 years, the relativerisk (CE

vs. placebo)of probable dementia was 1.49 (95% CI 0.83-2.66). The absolute

risk of developing probable dementia withestrogen alone was 37 vs. 25casesper

10,000 women-years with placebo.

Ofthe total number of subjects intheestrogen-plus-progestin substudy of the

WHI study, 44 percent (n = 7,320) were 65-74 years of age, while 6.6 percent

(n = 1,095) were 75 years and older. There was a higher relative risk (CE/MPA

versus placebo) of non-fatal stroke andinvasive breast cancer in women 75 and

older compared to women less than 75 years of age. In women greater than 75, the

increased risk of non-fatal stroke and invasive breast cancer observed in the

estrogen-plus-progestin combination group compared to the placebo group was 75

vs. 24 per 10,000 women-years and 52 vs. 12 per 10,000 women-years,

respectively.

In the estrogen-plus-progestin substudy of WHIMS, apopulation of 4,532

postmenopausal women, aged 65 to 79 years, was randomized to CE/MPA (CE

0.625 mg/2.5 mg). In the estrogen-plus-progestin group, after an average follow-

up of 4 years, the relativerisk (CE/MPA versus placebo)of probable dementia

was 2.05 (95% CI 1.21-3.48). The absolute risk of developing probable dementia

with CE/MPA was 45 vs. 22 casesper 10,000 women-years with placebo.

Seventy-nine percent of the cases of probable dementia occurred in women that

were older than 70 for the CE group, and 82 percent of the cases of probable

dementia occurred in women who were older than 70 in the CE/MPA group. The

most common classification of probabledementia in both the treatment groups

and placebo groups was Alzheimer’s disease.

When data fromthe two populations were pooled as planned in the WHIMS

protocol, the reported overall relative risk for probable dementia was 1.76 (95%

CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79

years, it is unknown whether these findings apply to younger postmenopausal

women. (See BOXED WARNINGSand WARNINGS, Dementia.)

ADVERSEREACTIONS

SeeBOXED WARNINGS, WARNINGSandPRECAUTIONS.

Because clinical trials are conducted under widely varying conditions, adverse reaction

rates observed in the clinicaltrials of a drug cannot be directly compared to rates in the

clinical trials ofanotherdrug and may not reflect the rates observed in practice. The

adverse reaction information fromclinicaltrials does, however, provide a basis for

identifying the adverse events that appear tobe related to drug use and forapproximating

rates.

In a 12-week clinical trial, 209 postmenopausal women with vasomotor symptoms were

treated with ESTROGENUS. Adverse events that occurred in the study at a rate greater

than or equal to 5% and greater than placebo, regardless ofrelationship to study drug, are

summarized in Table 8.

Table 8. ESTROGENUS Tablets – Number (%) of Patients

Reporting Adverse Events* with 5%Occurrence Rate by Body System

0.3 mg 0.625 mg

Body System/Adverse Events* n=68 n=72 1.25 mg

n=69 Placebo

n=72

Number of Patients in Safety Sample(%) 68 (100) 72 (100)69 (100)72 (100)

Number of Patients with Adverse Events

(%) 49 (72) 55 (76) 56 (81) 51 (71)

Number of Patients without Adverse Events

(%) 19 (28) 17 (24) 13 (19) 21 (29)

Body as a Whole

Abdominal Pain 3 (4) 11 (15) 3 (4) 7 (10)

AccidentalInjury 6 (8) 2 (3) 3 (4) 5 (7)

Flu Syndrome 4 (6) 3 (4) 5 (7) 3 (4)

Headache 10 (15) 18 (25) 11 (16) 15 (21)

Pain 10 (15) 14 (19) 7 (10) 6 (8)

Digestive System

Flatulence 3 (4) 5 (7) 3 (4) 2 (3)

Nausea 5 (7) 7 (10) 8 (12) 6 (8)

Nervous System

Dizziness 5 (7) 3 (4) 1 (1) 3 (4)

Paresthesia 0 4 (6) 1 (1) 0

Respiratory System

Bronchitis 0 3 (4) 5 (7) 3 (4)

Rhinitis 3 (4) 4 (6) 5 (7) 4 (6)

Sinusitis 2 (3) 3 (4) 5 (7) 2 (3)

Urogenital System

Breast Pain 0 9 (12) 10 (14) 3 (4)

Dysmenorrhea 1 (2) 6 (8) 1 (1) 2 (3)

*Treatment-emergentadverse events,regardlessofrelationship tostudydrug

In a second 12-week clinical trial, 310 women with symptoms of vulvar and vaginal

atrophy were treated (154 women withESTROGENUS 0.3 mg tablets and 156 women

with placebo). The only adverse event thatoccurred at a rate of >5% was headache;

seven patients (4.55%) with ESTROGENUS and twelve patients (7.69%) with placebo. Vaginitis 1 (2) 5 (7) 2 (3) 3 (4)

The following additional adverse reactions have been reported with estrogen and/or

progestin therapy:

1.Genitourinary system

Changes in vaginal bleeding pattern andabnormal withdrawal bleeding or flow;

breakthrough bleeding; spotting;dysmenorrhea; increase in size ofuterine

leiomyomata; vaginitis, including vaginalcandidiasis; change in amount of cervical

secretion; changes in cervical ectropion;ovarian cancer; endometrial hyperplasia;

endometrial cancer.

2.Breasts

Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast

changes; breast cancer.

3.Cardiovascular

Deep and superficial venousthrombosis; pulmonary embolism;thrombophlebitis;

myocardial infarction; stroke; increase in blood pressure.

4.Gastrointestinal

Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased

incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.

5.Skin

Chloasma or melasma that may persistwhen drug is discontinued; erythema

multiforme; erythemanodosum; hemorrhagic eruption;lossof scalp hair; hirsutism;

pruritus, rash.

6.Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

7.Central Nervous System

Headache; migraine; dizziness; mental depression; chorea; nervousness; mood

disturbances; irritability; exacerbationof epilepsy,dementia.

8.Miscellaneous

Increase or decrease in weight; reducedcarbohydrate tolerance; aggravation of

porphyria; edema; arthralgias; leg cramps;changes in libido; urticaria, angioedema,

anaphylactoid/anaphylactic reactions;hypocalcemia; exacerbation of asthma;

increased triglycerides.

OVERDOSAGE

Serious ill effects have not been reportedfollowing acute ingestion of large doses of

estrogen-containing products by young children. Overdosage of estrogen may cause

nausea and vomiting, and withdrawalbleeding may occur in females.

DOSAGE AND ADMINISTRATION

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin

should also be initiated toreduce the risk of endometrial cancer. A woman without a

uterus does not need progestin. Use ofestrogen, alone or in combination with a

progestin, should be with the lowest effective dose and for the shortest duration

consistent with treatment goals and risks for the individual woman. Patients should be re-

evaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to

determine iftreatment is still necessary (seeBOXED WARNINGS and WARNINGS).

For women who have a uterus, adequate diagnostic measures, such as endometrial

sampling, when indicated, should be undertaken to rule out malignancy in cases of

undiagnosed persistent or recurring abnormal vaginal bleeding.

ESTROGENUS tablets are takenorally, once daily for:

1.The treatment ofmoderate to severe vasomotor symptoms, associated with

menopause.

ESTROGENUS 0.3 mg

ESTROGENUS 0.45 mg

ESTROGENUS 0.625 mg

ESTROGENUS 0.9 mg

ESTROGENUS 1.25 mg

2.The treatment ofmoderate to severe vaginal dryness and pain with intercourse,

symptomsof vulvar and vaginal atrophy,associated with menopause. When

prescribingsolelyfor the treatment ofmoderate to severe vaginal dryness and pain

during intercourse, topical vaginal products should be considered.

ESTROGENUS 0.3 mg

Patients should be started at the lowestapproved dose of 0.3 mg ESTROGENUS daily.

Subsequent dosage adjustment (which will differ dependingon the indication) may be

made based upon the individual patient response. This dose should be periodically

reassessed by the healthcare provider.

HOW SUPPLIED

ESTROGENUS

(synthetic conjugated estrogens, B) Tablets

0.3 mg:

The tablets are oval, white, film-coated, and debossed with “E” on one side and “1”

on the reverse and are available in bottles of: 100 Tablets

0.45 mg:

The tablets are oval, mauve, film-coated, and debossed with “E” on one side and “2”

on the reverse and are available in bottles of: 100 Tablets

0.625 mg:

The tablets are oval, pink, film-coated, and debossed with “E” on one side and “3”

on the reverse and are available in bottles of: 100 Tablets

0.9 mg:

The tablets are oval, light blue-green, film-coated, and debossed with “E” on one side

and “5” on the reverse and are available in bottles of: 100 Tablets

1.25 mg:

The tablets are oval, yellow, film-coated, and debossed with “E” on one side and “4”

on the reverse and are available in bottles of: 100 Tablets

STORAGE

Store in a dry place below 25°Cin the original package.

Keep this and all drugs out of the reach of children.

Dispense in a tightcontainer with a child-resistantclosure.

REGISTRATION NUMBERS

Estrogenus 0.3 mg: 147 96 33333 00.

Estrogenus 0.45 mg: 147 97 33341 00.

Estrogenus 0.625 mg: 147 98 33340 00.

Estrogenus 0.9 mg: 147 99 33338 00.

Estrogenus 1.25 mg: 148 01 33339 00.

MANUFACTURER

Teva Women’s Health, Inc.

425 Privet Rd.,

Horsham, PA 19044,

USA.

LICENCE HOLDER

Salomon Levin & Elstein Ltd.,

P.O.Box 3696, Petach Tikva, 49133.

Document Outline