ENJUVIA (Page 6 of 8)

F. Pregnancy

ENJUVIA 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 ENJUVIA is administered to a nursing woman.

H. Pediatric Use

The safety and efficacy of ENJUVIA tablets in pediatric patients has not been established.

I. Geriatric Use

Clinical studies of ENJUVIA 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-alone substudy 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 versus placebo) 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 79 years, was randomized to CE (0.625 per day) or placebo. After an average follow-up of 5.2 years, the relative risk (CE vs. placebo) of probable dementia was 1.49 (95% CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 vs. 25 cases per 10,000 women-years with placebo.

Of the total number of subjects in the estrogen-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 and invasive 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, a population 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 relative risk (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 cases per 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 probable dementia in both the treatment groups and placebo groups was Alzheimer’s disease.

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% 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 WARNINGS, Dementia.)

ADVERSE REACTIONS

See BOXED WARNINGS, WARNINGS and PRECAUTIONS.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

In a 12-week clinical trial, 209 postmenopausal women with vasomotor symptoms were treated with ENJUVIA. Adverse events that occurred in the study at a rate greater than or equal to 5% and greater than placebo, regardless of relationship to study drug, are summarized in Table 8.

Table 8. ENJUVIA Tablets – Number (%) of Patients Reporting Aderse Events* with ≥ 5% Occurrence Rate by Body System
*Treatment-emergent adverse events, regardless of relationship to study drug
Body System/Adverse Event*

0.3 mg

n=68

0.625 mg

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)
Accidental Injury 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)
Vaginitis 1 (2) 5 (7) 2 (3) 3 (4)

In a second 12-week clinical trial, 310 women with symptoms of vulvar and vaginal atrophy were treated (154 women with ENJUVIA 0.3 mg tablets and 156 women with placebo). The only adverse event that occurred at a rate of >5% was headache; seven patients (4.55%) with ENJUVIA and twelve patients (7.69%) with placebo.

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

  1. Genitourinary system

    Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; 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 venous thrombosis; 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 persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of 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; exacerbation of epilepsy, dementia.

  8. Miscellaneous

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