Femring is used only in the vagina, however, the risks associated with oral estrogens should be taken into account.
Estrogens increase the risk of gallbladder disease ( 5.4 )
Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.9 , 5.10 )
Monitor thyroid function in women on thyroid replacement therapy ( 5.11 , 5.18 )
5.1Cardiovascular 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.
Stroke In the WHI estrogen-alone substudy, a 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 1 and persisted [see Clinical Studies (14.3) ] . Should a 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, a 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 (14.3) ] .
The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. Coronary Heart Disease In 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 placebo 2 [see Clinical Studies (14.3) ].
Subgroup analyses of women 50 to 59 years of age suggest a 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 woman-years). 1 In the WHI estrogen plus progestin substudy, there was a 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 a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies (14.3) ].
In postmenopausal women with documented heart disease (n = 2,763, average 66.7 years of age), in a 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 CHD.
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 HERS, HERS II. 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 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 2 years 3 [see Clinical Studies (14.3) ] .
Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. In the WHI estrogen plus progestin substudy, a 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 8 per 10,000 women-years) were also demonstrated.
The increase in VTE risk was demonstrated during the first year and persisted 4 [see Clinical Studies (14.3) ] . Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. 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.
5.2Malignant Neoplasms Endometrial Cancer
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. 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 treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more.
This risk has been shown to persist for at least 8 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 a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users.
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 (14.3) ] . After a 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 abso
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Interactions
No drug interaction studies have been conducted for Femring.
Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism ( 7.1 )
7.1Metabolic 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. John’s wort ( Hypericum perforatum ) preparations, phenobarbital, carbamazepine and rifampin may decrease the plasma concentration of estrogens, possibly resulting in a 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 the plasma concentration of estrogens and may result in side effects.
Grossesse et allaitement
8.1Pregnancy
Femring 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.
Effets indésirables
The following serious adverse reactions are discussed elsewhere in the labeling:
Malignant Neoplasms [see Boxed Warning , Warnings and Precautions (5.2) ]. Most common adverse reactions (incidence > 5 percent) are vaginal bleeding and breast tenderness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Millicent at 1-877-810-2101 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
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. In a 13-week clinical trial that included 225 postmenopausal women treated with Femring and 108 women treated with placebo vaginal rings, adverse reactions that occurred at a rate of ≥ 2 percent are summarized in Table 1 .
Table 1. Incidence of Adverse Reactions Occurring in ≥ 2 Percent of Subjects Presented in Descending Frequency of Preferred Term AE = adverse event; NOS = not otherwise specified Adverse Event Placebo (n = 108) Estradiol 0.05 mg/day (n = 113) Estradiol 0.10 mg/day (n = 112) n (percent) n (percent) n (percent) Headache (NOS) 10 (9.3) 8 (7.1) 11 (9.8) Intermenstrual Bleeding 2 (1.9) 9 (8.0) 11 (9.8) Vaginal Candidiasis 3 (2.8) 7 (6.2) 12 (10.7) Breast Tenderness 2 (1.9) 7 (6.2) 12 (10.7) Back Pain 4 (3.7) 7 (6.2) 4 (3.6) Abdominal Distension 3 (2.8) 8 (7.1) 3 (2.7) Sinusitis (NOS) 2 (1.9) 2 (1.8) 4 (3.6) Uterine Pain 1 (0.9) 2 (1.8) 5 (4.5) Urinary Tract Infection (NOS) 2 (1.9) 1 (0.9) 4 (3.6)
6.2Postmarketing Experience 1.
A few cases of toxic shock syndrome (TSS) have been reported in women using vaginal rings. TSS is a rare, but serious disease that may cause death. Warning signs of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-rash on face and body. 2. Cases of ring adherence to the vaginal or bladder wall, making ring removal difficult, have been reported in women using vaginal rings and may require surgical removal of the device.
Women should be carefully evaluated for vaginal or bladder wall ulceration or erosion. Cases of vaginal erosion and vaginal ulceration have been reported with other estradiol vaginal rings. If an ulceration or erosion has occurred, consideration should be given to leaving the ring out and not replacing it until healing is complete to prevent the ring from adhering to the vaginal tissue. 3. A few cases of bowel obstruction associated with vaginal ring use have been reported.
Persistent abdominal complaints consistent with obstruction should be carefully evaluated. 4. A few cases of inadvertent ring insertion into the urinary bladder, which may require surgical removal, have been reported for women using vaginal rings. Persistent unexplained urinary symptoms should be carefully evaluated. The following additional adverse reactions have been identified during post-approval use of Femring. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary system Uterine cancer, vaginal hemorrhage, ovarian cyst, irregular menstruation, metrorrhagia, menorrhagia, dysmenorrhea, uterine enlargement. Breasts Breast cancer, fibrocystic breast disease, breast disorder, breast mass, breast enlargement, breast pain, nipple pain, breast discharge. Cardiovascular Chest pain, increased blood pressure, irregular heart rate, pulmonary embolism, cerebrovascular accident (stroke), hemiparesis, transient ischemic attack, thrombosis.
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