Summary Basis of Decision for Duavive

Clinical Pharmacology

The clinical pharmacology studies characterized the absorption, distribution, metabolism, and excretion of conjugated estrogens (CE)/bazedoxifene (BZA). The clinical pharmacology labelling has been thoroughly discussed with the sponsor, and appropriate labelling has been agreed upon by both Health Canada and the sponsor.

Conjugated estrogens are metabolized by cytochrome P450 (CYP) enzymes (e.g. CYP3A4), while BZA is metabolized by uridine diphosphate glucuronosyltransferase (UGT). Therefore, medications (CYP3A4 inhibitors and UGT inducers) that decrease the metabolism of CE and/or increase the metabolism of BZA may result in an increased risk for endometrial hyperplasia. Appropriate warnings concerning endometrial hyperplasia are found in the Duavive Product Monograph.

The exposure of BZA is increased up to 4.3-fold in women with hepatic impairment. Therefore use in patients with liver dysfunction or disease is contraindicated. The major route of excretion of radiolabelled BZA is the faeces (>90%), and <1% of the dose is eliminated in the urine. The pharmacokinetics of BZA have not been adequately evaluated in women with renal impairment; therefore, use in this population is not recommended.

The exposure of BZA was increased up to 2.3-fold in women >75 years of age [number of patients (n) = 8]. Bazedoxifene has not been adequately evaluated in women >75 years of age; therefore, use in this population is not recommended.

Overall, the clinical pharmacological data support the use of Duavive for the specified indication. Appropriate warnings and precautions are in place in the approved Duavive Product Monograph to address the identified safety concerns. For further details, please refer to the Duavive Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy and safety of Duavive were evaluated primarily in five Phase III studies. The New Drug Submission (NDS) for Duavive was originally filed with two strengths of Duavive (0.45 mg) CE/20 mg BZA and 0.625 mg CE/20 mg BZA) for the following proposed indications:

• Treatment of moderate to severe vasomotor symptoms associated with menopause.
• Treatment of moderate to severe vulvar and vaginal atrophy, associated with menopause.
• Prevention of postmenopausal osteoporosis.

Following the clinical review, both the indication and the recommended dosage strength were revised. The results of the clinical studies were not sufficient to support the approval of the two strengths of Duavive for the three proposed indications.

Based on the data provided, the recommended strength and indication for Duavive was the lower dose, 0.45 mg CE/20 mg BZA, for the indication of treatment of moderate to severe vasomotor symptoms associated with menopause, as this was the only dose of Duavive to demonstrate a positive benefit-risk profile.

For the treatment of moderate to severe vulvar and vaginal atrophy, only the 0.625 mg CE/20 mg BZA strength met all four of the primary efficacy endpoints; however, the benefit relative to placebo for the sole clinically important endpoint, most bothersome symptom, was borderline, at p = 0.048. Treatment with the 0.45 mg CE/20 mg BZA dose failed to meet 2 of the 4 co-primary efficacy endpoints. Based on this data, Duavive is not considered to have an acceptable risk/benefit profile for the treatment of vulvar/vaginal atrophy.

For the prevention of osteoporosis, the studies used bone mineral density (BMD) as a surrogate endpoint, but without data to show a correlation between BMD and fracture risk/events. As a result, the prevention of postmenopausal osteoporosis indication could not be appropriately assessed for Duavive.

Treatment of Moderate to Severe Vasomotor Symptoms

The safety and efficacy of Duavive in treating moderate to severe vasomotor symptoms (hot flushes) were assessed in two Phase III, Selective Estrogens, Menopause, and Response to Therapy (SMART) studies, SMART 2 and SMART 1.

SMART 2 was a Phase III, 12-week, double-blind, randomized, placebo-controlled study designed to assess the safety and efficacy of 0.45 mg CE/20 mg BZA and 0.625 mg CE/20 mg BZA for the treatment of moderate to severe vasomotor symptoms associated with menopause. A total of 318 women (mean age = 53 years) who were seeking treatment for hot flushes and who had 7 moderate to severe hot flushes per day or 50 or more per week at baseline were enrolled. Women were randomly assigned to 1 of 3 treatment groups, receiving either 0.45 mg CE/20 mg BZA (n = 127), 0.625 mg CE/20 mg BZA (n = 128), or placebo (n = 63). The co-primary endpoints were the change from baseline in the average daily number of moderate to severe hot flushes at Week 4 and Week 12, and the change from baseline in the average daily severity score of hot flushes at Week 4 and Week 12.

SMART 1 was a 24-month, double-blind, randomized, placebo- and active-controlled dose-ranging study evaluating the safety and efficacy of 6 combinations of CE/BZA (CE doses of 0.45 mg or 0.625 mg in combination with BZA doses of 10 mg, 20 mg, or 40 mg) compared with raloxifene 60 mg and placebo. A total of 3,397 women (mean age = 56) were enrolled of which 433 women received 0.45 mg CE/20 mg BZA. The primary endpoint was the incidence of endometrial hyperplasia. The SMART 1 study also evaluated the safety and efficacy of Duavive for the treatment of vasomotor symptoms.

In SMART 2, both the 0.45 mg CE/20 mg BZA and 0.625 mg CE/20 mg BZA treatment groups demonstrated statistically significant improvement over placebo in the average daily number of moderate and severe hot flushes at Weeks 4 and 12. However, when the two treatment groups (0.45 mg CE/20 mg BZA and 0.625 mg CE/20 mg BZA) were compared to each other, the higher strength did not appear to provide significant improvement over the 0.45 mg CE/20 mg BZA product. The adjusted mean change from baseline in the number of moderate and severe flushes for 0.45 mg CE/20 mg BZA were -5.9 and -7.63 at Week 4 and Week 12, respectively; and -2.84 and -4.92 for placebo at Week 4 and Week 12, respectively. For the 0.625 mg CE/20 mg BZA treatment group, the adjusted mean change from baseline in the number of moderate and severe flushes were -6.60 and -8.05 at Week 4 and Week 12, respectively.

The reduction in the average daily severity score of hot flushes was statistically significant for both treatment groups; the 0.45 mg CE/20 mg BZA and the 0.625 mg CE/20 mg BZA treatment groups when compared to placebo, at Week 4 and Week 12. However, when both treatment groups were compared to each other, the higher strength of 0.625 mg CE/20 mg BZA did not appear to provide significant change in the average daily severity score of hot flushes compared to the 0.45 mg CE/20 mg BZA product at Week 4. The adjusted mean change from baseline in the average daily severity of hot flushes for 0.45 mg CE/20 mg BZA were -0.58 and -0.87 at Week 4 and Week 12, respectively; and -0.09 and -0.26 for placebo at Week 4 and Week 12, respectively. For the 0.625 mg CE/20 mg BZA treatment group, the adjusted mean change from baseline in the average daily severity of hot flushes were -0.64 and -1.21 at Week 4 and Week 12, respectively.

SMART 1 provided further evidence that the 0.45 mg CE/20 mg BZA and the 0.625 mg CE/20 mg BZA treatment groups demonstrated statistically significant benefit over placebo in the reduction of the average daily number of moderate and severe hot flushes and the reduction in the daily severity score of moderate to severe hot flushes at Week 12. This effect was demonstrated for 2 years with continuous treatment.

In SMART 1, there was an acceptable rate of endometrial hyperplasia (less than 1% following 12 months of therapy) in the 0.45 mg CE/20 mg BZA and 0.625 mg CE/20 mg BZA treatment groups, suggesting that 20 mg of BZA over one year of use was sufficient to protect the endometrium in women (with intact uteri) taking either 0.45 mg or 0.625 mg CE. However, other studies provided within this NDS showed conflicting results about the endometrial safety of the 0.625 mg CE/20 mg BZA treatment.

Overall Analysis of Efficacy

For the treatment of moderate to severe vasomotor symptoms, both proposed strengths (0.45 mg CE/20 mg BZA and 0.625 mg CE/20 mg BZA) showed statistically significant efficacy relative to placebo.. However, when compared to each other, the higher strength (0.625 mg CE/20 mg BZA) did not appear to provide significant improvement over the 0.45 mg CE/20 mg BZA product. Therefore, in combination with the safety concerns regarding endometrial hyperplasia with the higher dose, it was determined that the lowest effective dose, 0.45 mg CE/20 mg BZA, be recommended for treating moderate to severe vasomotor symptoms associated with menopause. Estrogens in the context of hormone replacement therapy should be used for the shortest period possible, at the lowest effective dose (Guidance for Industry: Product Monographs of Non-Contraceptive Estrogen/Progestin-Containing Products).

The data submitted to support the use of Duavive for the treatment of moderate to severe vulvar/vaginal atrophy (VVA) associated with menopause, and for the prevention of postmenopausal osteoporosis, were considered not sufficient to support these indications. For the treatment of moderate to severe vulvar and vaginal atrophy, only the 0.625 mg CE/20 mg BZA strength met all four of the primary efficacy endpoints; however, the benefit relative to placebo for the sole clinically important endpoint, most bothersome symptom, was borderline, at p = 0.048. Treatment with the 0.45 mg CE/20 mg BZA dose failed to meet 2 of the 4 co-primary efficacy endpoints. For the prevention of osteoporosis, the studies used bone mineral density (BMD) as a surrogate endpoint, but without data to show a correlation between BMD and fracture risk/events. As a result, the prevention of postmenopausal osteoporosis indication could not be appropriately assessed.

In conclusion, Duavive (0.45 mg CE/20 mg BZA) was considered acceptable for demonstrating efficacy in the treatment of moderate to severe vasomotor symptoms associated with menopause, in women with a uterus. In the SMART 2 study, Duavive significantly reduced the number and severity of hot flushes compared with placebo at Weeks 4 and 12. In the SMART 1 study, Duavive also significantly reduced the number and severity of hot flushes compared with placebo beginning at Week 4 and this effect was demonstrated for 2 years with continued treatment. The effects of Duavive on endometrial hyperplasia and endometrial malignancy were assessed in SMART 1 and SMART 5, and the incidence of endometrial hyperplasia for Duavive (0.45 mg CE/20 mg BZA) in the 12 month and 24 month studies was less than 1%.

For more information, refer to the Duavive Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of CE/BZA was evaluated in 4,158 postmenopausal women who participated in multiple-dose studies. Among these, 1,224 were treated with Duavive (0.45 mg CE/20 mg BZA) and 1,069 received placebo. Long-term exposure to Duavive over 2 years was evaluated. There were a total of 699 women exposed to Duavive for at least one year and 297 women exposed to Duavive for 2 years.

Duavive (0.45 mg CE/20 mg BZA) was well-tolerated. No unexpected safety concerns were identified when postmenopausal women received doses for up to 24 months (SMART 1). Side effects observed during treatment with Duavive included those generally seen with estrogen-containing products. The Duavive Product Monograph, including the Warnings and Precautions section, outlines possible side effects of concern which users of Duavive may experience. Some of the more rare side effects that may occur with the use of Duavive, such as venous thromboembolic events and superficial thrombotic events; cardiovascular events, including myocardial infarction and coronary artery disorder; cerebrovascular events; and certain breast disorders were not observed during the course of the clinical studies but will be tracked in the post-market setting. Results for clinical laboratory values, vital signs, and electrocardiograms showed no clinically important differences among the treatment groups. Overall, the incidence of treatment emergent adverse events, serious adverse events, and withdrawals due to adverse events was similar among the active treatment groups and placebo.

Endometrial safety is a concern in postmenopausal women with uteri using estrogens. The role of bazedoxifene in Duavive is to protect the endometrium. In the results of SMART 1, there was an acceptable rate of endometrial hyperplasia in the 0.45 mg CE/ 20 mg BZA and 0.625 mg CE/20 mg BZA treatment groups [that is (i.e.) less than 1%], suggesting that 20 mg of BZA over one year of use was sufficient to protect the endometrium in women (with intact uteri) taking either 0.45 mg or 0.625 mg CE. However, other studies provided with this drug submission showed conflicting results about the safety of the 0.625 mg CE/20 mg BZA treatment, with results demonstrating an acceptable level of endometrial hyperplasia over 2 years in those women who were treated with 0.45 mg CE/20 mg BZA but with rates of endometrial hyperplasia in the 0.625 mg CE/20 mg BZA treatment group that were unacceptably high. Based on the data provided, the lower dose (0.45 mg CE/20 mg BZA) was the only dose of Duavive to demonstrate a positive benefit-risk profile.

The Duavive Product Monograph has a list of the adverse events (regardless of causality) with an incidence exceeding the placebo rate and reported by ≥1% of patients from the double-blind placebo-controlled Phase III studies of Duavive. The most common adverse reactions that occurred in the CE/BZA group include abdominal pain, muscle spasms and pain, vulvo-vaginal mycotic infection, diarrhea, dyspepsia and nausea, nasopharyngitis, and oropharyngeal pain.

In the randomized clinical studies, 7.5% of the 1,224 women treated with Duavive discontinued treatment due to an adverse event, compared with 10.0% of the 1,069 women who received placebo. The most common adverse event leading to discontinuation as the primary reason in the four studies for up to 2 years was hot flush in 0.7% in women treated with Duavive and 1.8% of women who received placebo.

A Serious Warnings and Precautions box is included in the Duavive Product Monograph stating the increased risk of stroke and deep vein thrombosis found in the WHI study, for hysterectomized women treated with estrogen alone (0.625 mg/day) for 6.8 years compared to those receiving placebo. The text states that estrogens should not be prescribed for the prevention of cardiovascular disease and should be prescribed at the lowest effective dose for the shortest period possible for the approved indication. Appropriate warnings and precautions are in place in the approved Duavive Product Monograph to address the identified safety concerns obtained from the WHI study, as well as other known safety issues with estrogen replacement products.

Overall, treatment with the lowest dose of Duavive (0.45 mg CE/20 mg BZA) was generally safe and well tolerated. The clinical data from the Phase III placebo controlled studies only support the lower dose of Duavive (0.45 mg CE/20 mg BZA) for the treatment of moderate to severe vasomotor symptoms associated with menopause, in women with a uterus.

For more information, refer to the Duavive Product Monograph, approved by Health Canada and available through the Drug Product Database.