Regulatory Decision Summary for Bijuva

The clinical safety and efficacy of Bijuva was evaluated in a double-blind, placebo-controlled, randomized, multi-center study in postmenopausal women with an intact uterus. The general safety of Bijuva was evaluated for up to 52 weeks of treatment in 1,835 postmenopausal women; endometrial safety was evaluated after 52 weeks of treatment in 1,255 post-menopausal women. The efficacy subgroup was evaluated after 4 and 12 weeks of treatment in 726 postmenopausal women with at least 50 moderate to severe vasomotor symptoms per week at baseline.

Bijuva at both to-be-marketed doses (1.0 mg estradiol hemihydrate (E2)/100 mg progesterone (P) and 0.5 mg E2/100 mg P) was significantly better than placebo in reducing the number and severity of moderate to severe vasomotor symptoms (VMS) at Week 4 and Week 12. Secondary outcomes, including those evaluating patient reporting outcomes (Clinical Global Impression/Menopause-Specific Quality of Life Questionnaire), also showed significant improvement over placebo at the 1.0 mg E2/100 mg P and 0.5 mg E2/100 mg P doses.

Although a greater drug response was observed in the 1.0 mg E2/100 mg P dose group at Week 4, the 0.5 mg E2/100 mg P dose group catches up by Week 12. Health Canada considers it important to provide women with both therapeutic dosing options. Patients should be treated with the lowest effective dose for their symptoms to minimize unwanted side effects. Titration of dose to relieve VMS should be undertaken based on treatment goals and risks for the individual woman.

Subgroup analysis identified a race effect. While the mean change in frequency of moderate to severe VMS at the 1.0 mg E2/100 mg P and 0.5 mg E2/100 mg P doses was signifcantly greater than placebo in the white population, no significant change in frequency was observed in Black or African Americans at either dose compared to placebo. This is in part due to the large placebo response observed in Black or African Americans. The effectiveness of Bijuva in Black/African American women to reduce moderate to severe VMS has not been established.

The dose of progesterone offered in Bijuva is sufficient to protect against endometrial hyperplasia in women with an intact uterus. Incidence of endometrial hyperplasia after 12 months of treatment was ≤ 1%, with an upper bound of the one-sided 95% Confidence Interval (CI) that did not exceed 4% for that rate in any of the active treatment arms.

Overall, Bijuva was considered safe and well-tolerated over 12 months of evaluation. Treatment emergent adverse events (TEAEs) were more common in the active treatment groups than placebo, but were generally consistent with those expected for women in this demography and undergoing estradiol and progesterone treatment. Expected side effects, like bleeding/spotting, breast abnormalities (e.g. breast tenderness), proliferative endometrium, and increased triglyceride levels were observed in a dose-dependent manner. Serious risks associated with use of estrogen and progesterone in combination, including Bijuva, are well-defined with increases in the risk of stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, invasive breast cancer, and probable dementia. However, the overall risk of these serious outcomes remains low as defined by the Women’s Health Initiative (WHI) estrogen plus progestin substudy (2002). The toxicology of 17β-estradiol and progesterone in animals has been well characterized in the literature. Non-mutagenic carcinogenicity was established for estrogens and progestogens in non-clinical studies and is considered to be a class-effect.

The safety and efficacy of 17β-estradiol to treat VMS in postmenopausal women had previously been established. The safety and efficacy of micronized progesterone to prevent endometrial hyperplasia in postmenopausal women with an intact uterus undergoing estrogen therapy had also been previously established. Bijuva provides a fixed-dose combination product containing 17β-estradiol and micronized progesterone for the treatment of moderate to severe VMS in menopausal women with an intact uterus.

A single Bijuva capsule is taken once per day, orally in the evening with food. Clinical data support that the benefits of Bijuva in the form of providing relief from VMS outweigh the risks in postmenopausal women. Rare but serious risks associated with estrogen plus progestogen use are addressed in the Product Monograph as class effects; appropriate risk mitigation strategies and monitory recommendations are provided. As such, A notice of compliance was issued for Bijuva.