DIVIGEL

AbsorptionEstradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor. In a 14-day, Phase 1, multiple-dose study, Divigel demonstrated linear and approximately dose- proportional estradiol pharmacokinetics at steady state for both AUC 0-24 and C max following once daily dosing to the skin of either the right or left upper thigh (Table 2). Steady-state serum concentration of estr...

14.1 Effects on Vasomotor Symptoms in Postmenopausal Women A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of Divigel for vasomotor symptoms in 495 postmenopausal women (86.5 percent White; 10.1 percent Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2-week period prior to treatment). Women applied placebo, Divigel 0.25 grams (0.25 mg estradiol), Divigel 0.5 grams (0.5 mg estradiol) or Divigel 1.0 gram (1.0 mg estradiol) once daily to ...

The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Malignant Neoplasms [see Boxed Warning, Warnings and Precautions ( 5.2 )] . The most common adverse reactions (incidence >5 percent and greater than placebo) in any Divigel treatment group are metrorrhagia, breast tenderness, vaginal mycosis, nasopharyngitis, and upper respiratory tract infection ( 6.1 ). To report SUSPECTED ADVERSE REA...

Divigel is contraindicated in women with any of the following conditions: Abnormal genital bleeding of unknown etiology [see Warning and Precautions ( 5.2 )] Current or history of breast cancer [see Warning and Precautions ( 5.2 )] Estrogen-dependent neoplasia [see Warning and Precautions ( 5.2 )] Active DVT, PE, or history of these conditions [see Warning and Precautions ( 5.1 )] Active arterial ...

Cardiovascular Disorders: Increased risk of PE, DVT, and stroke with estrogen-alone therapy. Discontinue if an arterial or venous thrombotic or thromboembolic event occurs. ( 5.1 ) 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 , 5.8 , 5.9 ) Monitor thyroid function in women on thyroid replacement therapy ( 5.10 , 5.21 ) 5.1 Cardiovascular Disorders Div...

7 DRUG 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 reduce plasma concentrations of estrogens, possibly re...