ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:oCardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.2)] oMalignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.3)] oCardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.2)] oMalignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.3)] In prospective, randomized, placebo-controlled, double-blind study the most common adverse reactions (incidence >=5 percent) were back pain, vulvovaginal pruritus, vulvovaginal mycotic infection and diarrhea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-888-824-4336 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In 12-month randomized, double-blind, parallel group, placebo-controlled study, total of 309 postmenopausal women were randomized to receive either placebo or Vagifem 10 mcg inserts. Adverse reactions with an incidence of >=5 percent in the Vagifem 10 mcg group and greater than those reported in the placebo group are listed in Table 1.Table 1: Treatment-Emergent Adverse Reactions Reported at Frequency of >= Percent in Women Receiving Vagifem 10 mcgBody System Adverse ReactionTreatmentNumber (%) of WomenPlaceboN 103n (%)VagifemN 205n (%)Body As Whole Back Pain2 (2)14 (7)Digestive System Diarrhea011 (5)Urogenital System Vulvovaginal Mycotic Infection3 (3)17 (8) Vulvovaginal Pruritus (2)16 (8)N Total number of women in study.n Number of women who experienced adverse reactions.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Vagifem 10 mcg. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Gastrointestinal disordersDiarrheaGeneral disorders and administration site conditionsDrug ineffectiveImmune system disordersHypersensitivityInvestigationsBlood estrogen increasedWeight increasedMetabolism and nutrition disordersFluid retentionNeoplasms benign and malignantBreast cancerEndometrial cancerPsychiatric disordersDepressionInsomniaCentral Nervous SystemAggravated migraineReproductive system and breast disordersEndometrial hyperplasia Vulvovaginal burning sensationVulvovaginal painGenital pruritusVulvovaginal rash Vulvovaginal swellingVaginismusVaginal ulcerationSkin and subcutaneous tissue disordersRashRash erythematousRash pruriticUrticariaVascular disordersDeep vein thrombosisAdditional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

BOXED WARNING SECTION.

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens. Adding progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be 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 (5.3)]. Cardiovascular Disorders and Probable DementiaEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2 5.4), and Clinical Studies (14.2, 14.3)]. The Womens Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo [see Warnings and Precautions (5.2) and Clinical Studies (14.2)]. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of 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 postmenopausal women [see Warnings and Precautions (5.4) Use in Specific Populations (8.5), and Clinical Studies (14.3)]. 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 goals and risks for the individual woman.Estrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2, 5.4), and Clinical Studies (14.2, 14.3)]. The WHI estrogen plus progestin substudy reported increased risks of 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 CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.2), and Clinical Studies (14.2)]. The 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 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 (5.4), Use in Specific Populations (8.5), and Clinical Studies (14.3)]. Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.3), and Clinical Studies (14.2)]. 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.. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA See full prescribing information for complete boxed warningEstrogen-Alone TherapyoThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.3) oEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.4) oThe Womens Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) (5.2)oThe WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4) Estrogen Plus Progestin TherapyoEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.4)oThe WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI) (5.2) oThe WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.3 )oThe WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4). oThere is an increased risk of endometrial cancer in woman with uterus who uses unopposed estrogens (5.3) oEstrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.4) oThe Womens Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) (5.2). oThe WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4). oEstrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.4). oThe WHI estrogen plus progestin substudy reported increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (MI) (5.2) oThe WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer (5.3 ). oThe WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is 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 endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH, through negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.. 12.2 Pharmacodynamics. Currently, there are no pharmacodynamic data known for Vagifem.. 12.3 Pharmacokinetics. AbsorptionEstrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism.In single-center, randomized, open-label, multiple-dose study conducted in 29 patients, Vagifem 10 mcg demonstrated mean estradiol (E2) Cave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2).Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple DosesPatients received vaginal inserts as once daily intravaginal treatment for the first weeks and twice weekly intravaginal maintenance for the following 10 weeks. of Vagifem 10 mcgUncorrected for baseline, N=29E2E1E1SAUC0-24 (h.pg/mL)Cave (0-24) (pg/mL)%CV CV: Coefficient of Variance for both AUC0-24 and Cave(0-24) AUC0-24 (h.pg/mL)Cave (0-24) (pg/mL)%CV AUC0-24 (h.pg/mL)Cave (0-24) (pg/mL)%CV Day 1242.0810.0933.02485.2120.2244.865158.32214.9353.57Day 14176.497.3543.69496.1420.6730.886323.41263.4850.07Day 83132.045.5059.69411.0817.1339.583804.65158.5349.76DistributionThe distribution of exogenous estrogens is similar 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 SHBG and albumin.MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of 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 of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens.ExcretionEstradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Effects on Atrophic Vaginitis. 12-month double-blind, randomized, parallel group, placebo-controlled multicenter study was conducted in the U.S. and Canada to evaluate the efficacy and safety of Vagifem 10 mcg in the treatment of atrophic vaginitis in 309 postmenopausal women between 46 and 81 years of age (mean 57.6 years of age) who at baseline identified their most bothersome symptom of atrophic vaginitis from among six symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, dyspareunia and vaginal bleeding associated with intercourse). Women inserted one insert intravaginally each day for 14 days, then one insert twice weekly for the remaining 50 weeks. The majority (92.9 percent) of the women were Caucasian (n=287), 3.2 percent were Black (n=10), 1.6 percent were Asian (n=5) and 2.2 percent were Other (n=7). All subjects were assessed for improvement in the mean change from baseline to Week 12 for co-primary efficacy variables of: composite of most bothersome symptoms of atrophic vaginitis; percentage of vaginal superficial cells and percentage of vaginal parabasal cells on vaginal smear; and vaginal pH.Relief of Vaginal SymptomsVagifem 10 mcg was statistically superior to placebo in reducing the severity of composite score of most bothersome symptoms associated with atrophic vaginitis at Week 12 (see Table 3).Table 3: Mean Change from Baseline to Week 12 in Composite Score of Most Bothersome Symptoms Compared to Placebo ITT PopulationAll randomized subjects who received at least one dose of study drug and had at least one post-baseline evaluation. PlaceboVagifem 10 mcgITT PopulationN93190Baseline meancomposite score2.292.35Change from baseline at Week 12 (LOCF)-0.84-1.20p-value versus Placebo---0.002Also demonstrated for Vagifem 10 mcg compared to placebo was statistically significant increase in the percentage of superficial cells at Week 12 (13.2 percent compared to 3.8 percent for matching placebo, p<0.001), statistically significant decrease in parabasal cells at Week 12 (-37.0 percent compared to -9.3 percent for matching placebo, p<0.001), and statistically significant mean reduction between baseline and Week 12 in vaginal pH score (-1.3 compared to -0.4 for matching placebo, p<0.001).Endometrial safety was assessed by endometrial biopsy at the screening and final study visit. Of the 172 subjects in the Vagifem 10 mcg group who had biopsy performed at end of study, 92 subjects had endometrial tissue that was atrophic or inactive and 73 subjects had no tissue or tissue insufficient for diagnosis. There was one case of adenocarcinoma grade and one case of complex hyperplasia without atypia. Three subjects exhibited polyps (two atrophic polyps and one adenomyomatus type polyp) and two others had adenomyosis and an atypical epithelial proliferation.Endometrial safety of Vagifem 10 mcg was additionally evaluated in second, 12 month, open-label, multicenter safety study. Of the 297 subjects who had biopsy performed at end of study, 183 subjects had endometrial tissue that was atrophic or inactive and 111 subjects had no tissue or tissue insufficient for diagnosis. There was one case of complex hyperplasia without atypia. Two subjects exhibited polyps.. 14.2 Womens Health Initiative Studies. The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. global index included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.WHI Estrogen-Alone SubstudyThe WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 4.Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. EventRelative RiskCE vs. Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons. )CEn=5,310Placebon=5,429Absolute Risk per 10,000 Women-YearsCHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years. Non-fatal MI CHD death0.95 (0.78-1.16)0.91 (0.73-1.14)1.01 (0.71-1.43)544016574316All Strokes 1.33 (1.05-1.68)4533 Ischemic stroke1.55 (1.19-2.01)3825Deep vein thrombosis Not included in global index. 1.47 (1.06-2.06)2315Pulmonary embolism 1.37 (0.90-2.07)1410Invasive breast cancer 0.80 (0.62-1.04)2834Colorectal cancerResults are based on an average follow-up of 6.8 years. 1.08 (0.75-1.55)1716Hip fracture 0.65 (0.45-0.94)1219Vertebral fractures 0.64 (0.44-0.93)1118Lower arm/wrist fractures, 0.58 (0.47-0.72)3559Total fractures 0.71 (0.64-0.80)144197Death due to other causes, All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.08 (0.88-1.32)5350Overall mortality 1.04 (0.88-1.22)7975Global Index subset of the events was combined in global index, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.02 (0.92-1.13)206201For those outcomes included in the WHI global index that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was fewer hip fractures.9 The absolute excess risk of events included in the global index was non-significant events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years.Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10 Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50-59 years of age non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].WHI Estrogen Plus Progestin SubstudyThe WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the global index. The absolute excess risk of events included in the global index was 19 per 10,000 women-years.For those outcomes included in the WHI global index that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were more CHD events, more strokes, 10 more PEs, and more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were fewer colorectal cancers and fewer hip fractures.Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 YearsAdapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi ,Results are based on centrally adjudicated data. EventRelative RiskCE/MPA vs Placebo(95% nCINominal confidence intervals unadjusted for multiple looks and multiple comparisons.)CE/MPAn=8,506Placebon=8,102Absolute Risk per 10,000 Women-YearsCHD events Non-fatal MI CHD death1.23 (0.99-1.53)1.28 (1.00-1.63)1.10 (0.70-1.75)4131834258All Strokes Ischemic stroke1.31 (1.03-1.68)1.44 (1.09-1.90)33262518Deep vein thrombosisNot included in global index. 1.95 (1.43-2.67)2613Pulmonary embolism2.13 (1.45-3.11)188Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ cancer. 1.24 (1.01-1.54)4133Colorectal cancer0.61 (0.42-0.87)1016Endometrial cancer 0.81 (0.48-1.36)67Cervical cancer 1.44 (0.47-4.42)21Hip fracture0.67 (0.47-0.96)1116Vertebral fractures 0.65 (0.46-0.92)1117Lower arm/wrist fractures 0.71 (0.59-0.85)4462Total fractures 0.76 (0.69-0.83)152199Overall Mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. 1.00 (0.83-1.19)5252Global IndexA subset of the events was combined in global index, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes. 1.13 (1.02-1.25)184165Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50-59 years of age, non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)]. 14.3 Womens Health Initiative Memory Study. The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominately healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66).The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimers disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4), and Use in Specific Populations (8.5)].The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.After an average follow-up of years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4), and Use in Specific Populations (8.5)].When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4), and Use in Specific Populations (8.5)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Vagifem should not be used in women with any of the following conditions:oUndiagnosed abnormal genital bleedingoKnown, suspected, or history of breast canceroKnown or suspected estrogen-dependent neoplasiaoActive DVT, PE, or history of these conditionsoActive arterial thromboembolic disease (for example, stroke, and myocardial infarction), or history of these conditionsoKnown anaphylactic reaction or angioedema to VagifemoKnown liver impairment or diseaseoKnown protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersoKnown or suspected pregnancy. oUndiagnosed abnormal genital bleeding. oKnown, suspected, or history of breast cancer. oKnown or suspected estrogen-dependent neoplasia. oActive DVT, PE, or history of these conditions. oActive arterial thromboembolic disease (for example, stroke, and myocardial infarction), or history of these conditions. oKnown anaphylactic reaction or angioedema to Vagifem. oKnown liver impairment or disease. oKnown protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. oKnown or suspected pregnancy. oUndiagnosed abnormal genital bleeding (4)oKnown, suspected, or history of breast cancer (4, 5.3)oKnown or suspected estrogen-dependent neoplasia (4, 5.3)oActive DVT, PE, or history of these conditions (4, 5.2)oActive arterial thromboembolic disease (for example, stroke and MI), or history of these conditions (4, 5.2) oKnown anaphylactic reaction or angioedema to Vagifem oKnown liver impairment or disease (4, 5.11)oKnown protein C, protein S, or antithrombin deficient, or other known thrombophilic disorders (4)oKnown or suspected pregnancy (4, 8.1). oUndiagnosed abnormal genital bleeding (4). oKnown, suspected, or history of breast cancer (4, 5.3). oKnown or suspected estrogen-dependent neoplasia (4, 5.3). oActive DVT, PE, or history of these conditions (4, 5.2). oActive arterial thromboembolic disease (for example, stroke and MI), or history of these conditions (4, 5.2) oKnown anaphylactic reaction or angioedema to Vagifem oKnown liver impairment or disease (4, 5.11). oKnown protein C, protein S, or antithrombin deficient, or other known thrombophilic disorders (4). oKnown or suspected pregnancy (4, 8.1).

DESCRIPTION SECTION.

11 DESCRIPTION. Vagifem 10 mcg (estradiol vaginal inserts) are small, white, film-coated inserts containing 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. Each insert of Vagifem 10 mcg contains the following excipients: hypromellose, lactose monohydrate, maize starch and magnesium stearate. The film coating contains hypromellose and polyethylene glycol. Each Vagifem insert is mm in diameter and is placed in disposable applicator. Each insert-filled applicator is packaged separately in blister pack. Vagifem inserts are used intravaginally. When the insert comes in contact with the vaginal mucosa, estradiol is released into the vagina.Estradiol hemihydrate is white, almost white or colorless crystalline solid, chemically described as estra-1,3,5 (10)-triene-3,17-diol. The chemical formula is C18H24O2 1/2 H2O with molecular weight of 281.4.The structural formula is:. Structural Formula for Vagifem.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Generally, when estrogen is prescribed for postmenopausal woman with uterus, progestin should also be considered to reduce the risk of endometrial cancer. woman without uterus does not need progestin. In some cases, however, hysterectomized women with history of endometriosis may need progestin [see Warnings and Precautions (5.3, 5.15)].Use of estrogen-alone, or in combination with progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.. Vagifem should be administered intravaginally: o1 insert daily for weeks, followed by insert twice weekly (for example, Tuesday and Friday) (2.1). o1 insert daily for weeks, followed by insert twice weekly (for example, Tuesday and Friday) (2.1). 2.1 Treatment of Atrophic Vaginitis due to Menopause Vagifem should be administered intravaginally using the supplied applicator: insert daily for weeks, followed by insert twice weekly (for example, Tuesday and Friday).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Vagifem is small, white, round, film-coated, bi-convex vaginal insert containing 10 mcg of estradiol. Each vaginal insert is mm in diameter and is administered in disposable applicator.. oVagifem 10 mcg insert: One vaginal insert contains 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol (3) oVagifem 10 mcg insert: One vaginal insert contains 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No drug-drug interaction studies have been conducted for Vagifem.. oInducers and inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1) oInducers and inhibitors of CYP3A4 may affect estrogen drug metabolism (7.1) 7.1 Metabolic Interactions. In-vitro and in-vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. Johns wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in decrease in therapeutic 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 concentrations of estrogens and may result in side effects.

GERIATRIC USE SECTION.

8.5 Geriatric Use. There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Vagifem to determine whether those over 65 years of age differ from younger subjects in their response to Vagifem.The Womens Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.2)].In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.2)].The Womens Health Initiative Memory StudyIn the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.4), and Clinical Studies (14.3)]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Warnings and Precautions (5.4), and Clinical Studies (14.3) ].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Each Vagifem (estradiol vaginal inserts), 10 mcg, is contained in disposable, single-use applicator, packaged in blister pack. Cartons contain or 18 applicators with inset inserts.Vagifem 10 mcg applicators: NDC 0169-5176-0318 applicators: NDC 0169-5176-04Keep out of reach of children.. 16.2 Storage and Handling. Store at 25oC (77oF), excursions permitted to 15oC to 30oC (59oF to 86oF). Do not refrigerate.[See USP Controlled Room Temperature.].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. oVagifem is an estrogen (estradiol) indicated for the treatment of atrophic vaginitis due to menopause (1.1). oVagifem is an estrogen (estradiol) indicated for the treatment of atrophic vaginitis due to menopause (1.1). 1.1 Treatment of Atrophic Vaginitis due to Menopause.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling.. 17.1 Vaginal Bleeding. Inform postmenopausal women of the importance of reporting vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.3)].. 17.2 Possible Serious Adverse Reactions with Estrogen-Alone Therapy. Inform postmenopausal women of possible serious adverse reactions of estrogen-alone therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.2, 5.3, 5.4)].. 17.3 Possible Less Serious but Common Adverse Reactions with Estrogen-Alone Therapy. Inform postmenopausal women of possible less serious but common adverse reactions of estrogen-alone therapy such as headache, breast pain and tenderness, nausea and vomiting.. 17.4 Instructions for Use of Applicator. Step 1: Tear off single applicator.Step 2: Separate the plastic wrap and remove the applicator from the plastic wrap as shown in Figure A.If after opening the package you see that the insert has come out of the applicator but has not fallen out of the package, carefully put it back into the applicator for insertion. Please keep your hands clean and dry while handling the insert. Figure Step 3: Hold the applicator so that the finger of one hand can press the applicator plunger as shown in Figure B.Figure Step 4: Next select the best position for vaginal insertion of Vagifem (estradiol vaginal inserts) that is most comfortable for you. See suggested reclining Figure or standing Figure position illustrated below:Figure Figure Step 5: Using the other hand, guide the applicator gently and comfortably through the vaginal opening (see Figures and above). If prior to insertion the insert falls out of the applicator, throw the insert and applicator away and use new insert-filled applicator. Step 6: The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less.Step 7: Once the insert-filled applicator has been inserted, gently press the plunger until the plunger is fully depressed. This will eject the insert inside your vagina where it will dissolve slowly over several hours.Step 8: After depressing the plunger, gently remove the applicator and dispose of it the same way you would plastic tampon applicator. The applicator is of no further use and should be discarded properly. Insertion may be done at any time of the day. It is advisable to use the same time daily for all applications of Vagifem (estradiol vaginal inserts). If you have any questions, please consult your healthcare provider or pharmacist.. Removing applicator from packaging. Pressing the applicator plunger. Figure C. Application via standing position.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is 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 endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH, through negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Vagifem should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when Vagifem is administered to nursing woman.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Vagifem therapy with institution of appropriate symptomatic care.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel VAGIFEM 10 MCG 18 Inserts. NDC 0169-5176-04Vagifem(R) (estradiol vaginal inserts)10mcg18 vaginal insertsnovo nordisk(R) 18 Vaginal Inserts.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Vagifem is not indicated in children. Clinical studies have not been conducted in the pediatric population.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Currently, there are no pharmacodynamic data known for Vagifem.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionEstrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism.In single-center, randomized, open-label, multiple-dose study conducted in 29 patients, Vagifem 10 mcg demonstrated mean estradiol (E2) Cave at Day 83 of 5.5 pg/mL after 12 weeks of treatment (see Table 2).Table 2: Arithmetic Means of Estradiol (E2), Estrone (E1), and Estrone Sulfate (E1S) PK Parameters Following Multiple DosesPatients received vaginal inserts as once daily intravaginal treatment for the first weeks and twice weekly intravaginal maintenance for the following 10 weeks. of Vagifem 10 mcgUncorrected for baseline, N=29E2E1E1SAUC0-24 (h.pg/mL)Cave (0-24) (pg/mL)%CV CV: Coefficient of Variance for both AUC0-24 and Cave(0-24) AUC0-24 (h.pg/mL)Cave (0-24) (pg/mL)%CV AUC0-24 (h.pg/mL)Cave (0-24) (pg/mL)%CV Day 1242.0810.0933.02485.2120.2244.865158.32214.9353.57Day 14176.497.3543.69496.1420.6730.886323.41263.4850.07Day 83132.045.5059.69411.0817.1339.583804.65158.5349.76DistributionThe distribution of exogenous estrogens is similar 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 SHBG and albumin.MetabolismExogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of 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 of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as circulating reservoir for the formation of more active estrogens.ExcretionEstradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.Use in Specific PopulationsNo pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.

PREGNANCY SECTION.

8.1 Pregnancy. Vagifem should not be used during pregnancy [see Contraindications (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

RECENT MAJOR CHANGES SECTION.

oWarnings and Precautions, Malignant Neoplasms (5.3) 11/2017. oWarnings and Precautions, Malignant Neoplasms (5.3) 11/2017.

REFERENCES SECTION.

15 REFERENCES. 1.Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007; 297:1465-1477.2.Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006; 166:357-365.3.Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without Uterus. Arch Int Med. 2006; 166:772-780.4.Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004; 292:1573-1580.5.Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006; 295:1647-1657.6.Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003; 289:3234-3253.7.Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic cancers and Associated Diagnostic Procedures. JAMA. 2003; 290:1739-1748.8.Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004; 291:2947-2958.9.Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Womens Health Initiative Randomized Trial. Bone Miner Res. 2006; 21:817-828.10.Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Womens Health Initiative. Circulation. 2006; 113:2425-2434.. 1.Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007; 297:1465-1477.. 2.Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006; 166:357-365.. 3.Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without Uterus. Arch Int Med. 2006; 166:772-780.. 4.Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004; 292:1573-1580.. 5.Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006; 295:1647-1657.. 6.Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003; 289:3234-3253.. 7.Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic cancers and Associated Diagnostic Procedures. JAMA. 2003; 290:1739-1748.. 8.Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004; 291:2947-2958.. 9.Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Womens Health Initiative Randomized Trial. Bone Miner Res. 2006; 21:817-828.. 10.Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Womens Health Initiative. Circulation. 2006; 113:2425-2434.

SPL PATIENT PACKAGE INSERT SECTION.

FDA-Approved Patient Labeling. Vagifem(R) (estradiol vaginal inserts)Read this PATIENT INFORMATION before you start using Vagifem and read what you get each time you refill your Vagifem prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.. What is the most important information should know about VAGIFEM(an estrogen hormone)oUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb) Report any unusual vaginal bleeding right away while you are using Vagifem. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.oDo not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline of brain function)oUsing estrogen-alone may increase your chances of getting strokes or blood clotsoUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age or olderoDo not use estrogens with progestins to prevent heart disease, heart attack, strokes or dementiaoUsing estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clotsoUsing estrogens with progestin may increase your chance of getting dementia, based on study of women 65 years of age or olderoYou and your healthcare provider should talk regularly about whether you still need treatment with Vagifem. oUsing estrogen-alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using Vagifem. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.. oDo not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia (decline of brain function). oUsing estrogen-alone may increase your chances of getting strokes or blood clots. oUsing estrogen-alone may increase your chance of getting dementia, based on study of women 65 years of age or older. oDo not use estrogens with progestins to prevent heart disease, heart attack, strokes or dementia. oUsing estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots. oUsing estrogens with progestin may increase your chance of getting dementia, based on study of women 65 years of age or older. oYou and your healthcare provider should talk regularly about whether you still need treatment with Vagifem. What is VagifemVagifem is medicine that contains estradiol (an estrogen hormone) in vaginal insert.What is Vagifem used forVagifem is used after menopause to:oTreat menopausal changes in and around the vagina You and your healthcare provider should talk regularly about whether you still need treatment with Vagifem to control these problems.Who should not use VagifemDo not start using Vagifem if you:oHave unusual vaginal bleedingoCurrently have or have had certain cancers Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use Vagifem.oHad stroke or heart attackoCurrently have or have had blood clotsoCurrently have or have had liver problemsoHave been diagnosed with bleeding disorderoAre allergic to Vagifem or any of its ingredients See the list of ingredients in Vagifem at the end of this leaflet.oThink you may be pregnantTell your healthcare provider:oIf you have any unusual vaginal bleeding Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. oAbout all of your medical problems Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.oAbout all the medicines you take This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Vagifem works. Vagifem may also affect how your other medicines work.oIf you are going to have surgery or will be on bed rest You may need to stop using Vagifem.oIf you are breast feeding The hormone in Vagifem can pass into your breast milk.How should use VagifemVagifem is an insert that you place in your vagina with an applicator.oTake the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for youoEstrogens should be used at the lowest dose possible for your treatment only as long as needed You and your healthcare provider should talk regularly (for example, every to months) about the dose you are using and whether you still need treatment with Vagifem.Step 1: Tear off single applicator.Step 2: Separate the plastic wrap and remove the applicator from the plastic wrap as shown in Figure A. If after opening the package you see that the insert has come out of the applicator but has not fallen out of the package, carefully put it back into the applicator for insertion. Please keep your hands clean and dry while handling the insert. Figure Step 3: Hold the applicator so that the finger of one hand can press the applicator plunger as shown in Figure B.Figure Step 4: Next select the best position for vaginal insertion of Vagifem (estradiol vaginal inserts) that is most comfortable for you. See suggested reclining Figure or standing Figure position illustrated below:Figure Figure Step 5: Using the other hand, guide the applicator gently and comfortably through the vaginal opening (see Figures and above). If prior to insertion the insert falls out of the applicator, throw the insert and applicator away and use new insert-filled applicator. Step 6: The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less.Step 7: Once the insert-filled applicator has been inserted, gently press the plunger until the plunger is fully depressed. This will eject the insert inside your vagina where it will dissolve slowly over several hours.Step 8: After depressing the plunger, gently remove the applicator and dispose of it the same way you would plastic tampon applicator. The applicator is of no further use and should be discarded properly. Insertion may be done at any time of the day. It is advisable to use the same time daily for all applications of Vagifem (estradiol vaginal inserts). If you have any questions, please consult your healthcare provider or pharmacist.DosageVagifem therapy consists of the following dosing regimen:One (1) Vagifem insert intravaginally once daily for the first two (2) weeks, then one (1) insert twice weekly (for example Tuesday and Friday) for as long as you use Vagifem.What are the possible side effects of VagifemVagifem is only used in the vagina; however, the risks associated with oral estrogens should be taken into account.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:oHeart attackoStrokeoBlood clotsoDementiaoBreast canceroCancer of the lining of the uterus (womb) oCancer of the ovaryoHigh blood pressureoHigh blood sugaroGallbladder diseaseoLiver problemsoEnlargement of benign tumors of the uterus (fibroids)Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:oNew breast lumpsoUnusual vaginal bleedingoChanges in vision or speechoSudden new severe headachesoSevere pains in your chest or legs with or without shortness of breath, weakness and fatigueLess serious, but common, side effects include:oHeadacheoBreast painoIrregular vaginal bleeding or spottingoStomach or abdominal cramps, bloatingoNausea and vomitingoHair lossoFluid retentionoVaginal yeast infectionThese are not all the possible side effects of Vagifem. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.What can do to lower my chances of serious side effect with VagifemoTalk with your healthcare provider regularly about whether you should continue using VagifemoIf you have uterus, talk with your healthcare provider about whether the addition of progestin is right for you The addition of progestin is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while using Vagifem.oHave pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.oIf you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease Ask your healthcare provider for ways to lower your chances for getting heart disease.General information about the safe and effective use of Vagifem.Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Vagifem for conditions for which it was not prescribed. Do not give Vagifem to other people, even if they have the same symptoms you have. It may harm them. Keep Vagifem out of the reach of children.This leaflet provides summary of the most important information about Vagifem. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Vagifem that is written for health professionals. You can get more information by calling the toll free number 1-888-824-4336.What are the ingredients in VagifemVagifem (estradiol vaginal inserts) are small, white, film-coated inserts containing estradiol. Each insert also contains hypromellose, lactose monohydrate, maize starch and magnesium stearate. The film coating contains hypromellose and polyethylene glycol.Each Vagifem insert is contained in disposable applicator, packaged in blister pack. Cartons contain or 18 applicators with inset inserts.Store at 25oC (77oF); excursions permitted to 15oC to 30oC (59oF to 86oF). Do not refrigerate. [see USP Controlled Room Temperature].Vagifem(R) is registered trademark owned by Novo Nordisk Health Care AG.(C) 2003-2019 Novo Nordisk Date of Issue: 04/19For information contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, NJ 08536, USA1-888-824-4336Manufactured by:Novo Nordisk A/S2880 Bagsvaerd, Denmark. oTreat menopausal changes in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Vagifem to control these problems.. oHave unusual vaginal bleeding. oCurrently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use Vagifem.. oHad stroke or heart attack. oCurrently have or have had blood clots. oCurrently have or have had liver problems. oHave been diagnosed with bleeding disorder. oAre allergic to Vagifem or any of its ingredients See the list of ingredients in Vagifem at the end of this leaflet.. oThink you may be pregnant. oIf you have any unusual vaginal bleeding. Vaginal bleeding after menopause may be warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. oAbout all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.. oAbout all the medicines you take. This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Vagifem works. Vagifem may also affect how your other medicines work.. oIf you are going to have surgery or will be on bed rest. You may need to stop using Vagifem.. oIf you are breast feeding The hormone in Vagifem can pass into your breast milk.. oTake the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for you. oEstrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every to months) about the dose you are using and whether you still need treatment with Vagifem.. oHeart attack. oStroke. oBlood clots. oDementia. oBreast cancer. oCancer of the lining of the uterus (womb) oCancer of the ovary. oHigh blood pressure. oHigh blood sugar. oGallbladder disease. oLiver problems. oEnlargement of benign tumors of the uterus (fibroids). oNew breast lumps. oUnusual vaginal bleeding. oChanges in vision or speech. oSudden new severe headaches. oSevere pains in your chest or legs with or without shortness of breath, weakness and fatigue. oHeadache. oBreast pain. oIrregular vaginal bleeding or spotting. oStomach or abdominal cramps, bloating. oNausea and vomiting. oHair loss. oFluid retention. oVaginal yeast infection. oTalk with your healthcare provider regularly about whether you should continue using Vagifem. oIf you have uterus, talk with your healthcare provider about whether the addition of progestin is right for you. The addition of progestin is generally recommended for woman with uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while using Vagifem.. oHave pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.. oIf you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.. Removing applicator from packaging. Pressing the applicator plunger. Application via reclining position. Application via standing position.

SPL UNCLASSIFIED SECTION.

1.1 Treatment of Atrophic Vaginitis due to Menopause.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store at 25oC (77oF), excursions permitted to 15oC to 30oC (59oF to 86oF). Do not refrigerate.[See USP Controlled Room Temperature.].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oNursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3)oGeriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Womens Health Initiative Memory ancillary studies of the Womens Health Initiative (8.5). oNursing Mothers: Estrogen administration to nursing women has been shown to decrease the quantity and quality of breast milk (8.3). oGeriatric Use: An increased risk of probable dementia in women over 65 years of age was reported in the Womens Health Initiative Memory ancillary studies of the Womens Health Initiative (8.5). 8.1 Pregnancy. Vagifem should not be used during pregnancy [see Contraindications (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.. 8.3 Nursing Mothers. Vagifem should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen therapy. Caution should be exercised when Vagifem is administered to nursing woman.. 8.4 Pediatric Use. Vagifem is not indicated in children. Clinical studies have not been conducted in the pediatric population.. 8.5 Geriatric Use. There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Vagifem to determine whether those over 65 years of age differ from younger subjects in their response to Vagifem.The Womens Health Initiative Studies In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies (14.2)].In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies (14.2)].The Womens Health Initiative Memory StudyIn the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen-alone or estrogen plus progestin when compared to placebo [see Warnings and Precautions (5.4), and Clinical Studies (14.3)]. Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Warnings and Precautions (5.4), and Clinical Studies (14.3) ].. 8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics of Vagifem has not been studied.. 8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of Vagifem has not been studied.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oEstrogens increase the risk of gallbladder disease (5.5)oDiscontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.6, 5.7, 5.10, 5.11)oThe Vagifem applicator may cause vaginal abrasion (5.18)oMonitor thyroid function in women on thyroid replacement therapy (5.12, 5.19) oEstrogens increase the risk of gallbladder disease (5.5). oDiscontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs (5.6, 5.7, 5.10, 5.11). oThe Vagifem applicator may cause vaginal abrasion (5.18). oMonitor thyroid function in women on thyroid replacement therapy (5.12, 5.19) 5.1 Risks from Systemic Absorption. Vagifem is intended only for vaginal administration. Systemic absorption occurs with the use of Vagifem. The warnings, precautions, and adverse reactions associated with the use of systemic estrogen-alone therapy should be taken into account.. 5.2 Cardiovascular Disorders. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.StrokeIn the WHI estrogen-alone substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year and persisted [see Clinical Studies (14.2)]. Should stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies (14.2)]. The increase in risk was demonstrated after the first year and persisted.1 Should stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.Coronary Heart DiseaseIn the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo2 [see Clinical Studies (14.2)].Subgroup analysis of women 50 to 59 years of age suggests statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1 In the WHI estrogen plus progestin substudy, there was statistically non-significant increased risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and trend toward decreasing relative risk was reported in years through [see Clinical Studies (14.2)].In postmenopausal women with documented heart disease (n=2,763), average 66.7 years of age, in controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus 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 plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of the original HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.Venous Thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first years3 [see Clinical Studies (14.2)]. Should VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.In the WHI estrogen plus progestin substudy, statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted4 [see Clinical Studies (14.2)]. Should VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.If feasible, estrogens should be discontinued at least to weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.. 5.3 Malignant Neoplasms Endometrial CancerAn increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in woman with uterus. The reported endometrial cancer risk among unopposed estrogen users is about to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than year. The greatest risk appears associated with prolonged use, with an increased risk of 15- to 24-fold for to 10 years or more and this risk has been shown to persist for at least to 15 years after estrogen therapy is discontinued.Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. 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.There is no evidence that the use of natural estrogens results in different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be precursor to endometrial cancer.Breast CancerThe most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]5 [see Clinical Studies (14.2)].The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. 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 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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 groups6 see Clinical Studies (14.2) ].Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an increase in abnormal mammograms requiring further evaluation.All women should receive yearly breast examinations by healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.Ovarian CancerThe WHI estrogen plus progestin substudy reported statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus MPA versus placebo was versus cases per 10,000 women-years.7 meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than years [median of years] vs. greater than years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within years before cancer diagnosis) was 1.37 (95% CI 1.27-1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.. 5.4 Probable Dementia In the WHIMS estrogen-alone ancillary study of WHI, population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average 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 versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].In the WHIMS estrogen plus progestin ancillary study of WHI, population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies (14.3)].. 5.5 Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.. 5.6 Hypercalcemia. Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.. 5.7 Visual Abnormalities. Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.. 5.8 Addition of Progestin When Woman Has Not Had Hysterectomy. Studies of the addition of progestin for 10 or more days of cycle of estrogen administration, or daily with estrogen in continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be precursor to endometrial cancer.There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.. 5.9 Elevated Blood Pressure. In small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In large, randomized, placebo-controlled clinical trial, generalized effect of estrogens on blood pressure was not seen.. 5.10 Hypertriglyceridemia. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.. 5.11 Hepatic Impairment and/or Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with impaired liver function. For women with history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.. 5.12 Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.. 5.13 Fluid Retention. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogen-alone is prescribed.. 5.14 Hypocalcemia. Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.. 5.15 Exacerbation of Endometriosis. few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.. 5.16 Hereditary Angioedema. Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.. 5.17 Exacerbation of Other Conditions. Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.. 5.18 Local Abrasion. few cases of local abrasion induced by the Vagifem applicator have been reported, especially in women with severely atrophic vaginal mucosa.. 5.19 Laboratory Tests. Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy.. 5.20 Drug-Laboratory Test Interactions. Accelerated prothrombin 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 antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.Impaired glucose tolerance.

LACTATION SECTION.

8.2 Lactation Risk SummaryEstrogens are present in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Vagifem and any potential adverse effects on the breastfed child from Vagifem or from the underlying maternal condition.