Summary Basis of Decision for Tibella

 

Clinical Pharmacology

Tibolone (the medicinal ingredient in Tibella) is a synthetic pro-hormone and is structurally related to the steroidal progestin norethynodrel. As a parent compound, tibolone has no pharmacologic activity. However, in the body, it is converted into three active metabolites: 3α-hydroxy-tibolone, 3β-hydroxy-tibolone, and a Δ4-isomer. The three metabolites display differential effects. Two of these metabolites (3α-OH-tibolone and 3β-OH-tibolone) have predominantly estrogenic activity, whereas the third metabolite (Δ4-isomer of tibolone) has predominantly progestogenic and androgenic activities.

Following oral administration, tibolone is rapidly and extensively absorbed and has various tissue-specific effects. Tibolone has estrogenic effects on the vagina, on bone, and on the thermoregulatory centres in the brain (hot flushes). In the breast, tibolone inhibits the sulfatase enzyme thereby prevents the conversion to the 3-OH-tibolone metabolites produced in this tissue. Tibolone has an effect on endorphin levels and acts centrally to affect the thermoregulatory system. These two actions may account for the beneficial effects reported on mood and reduction in hot flushes/night sweats. In vitro studies suggest that tibolone is subject to tissue-selective local metabolism, with the Δ4-isomer mainly formed in endometrial tissue. Progestogenic effects predominate in the endometrium.

An in vivo study showed that simultaneous treatment of tibolone affects pharmacokinetics of the cytochrome P450 (CYP) 3A4 substrate midazolam to a moderate extent. CYP3A4 inducing compounds such as barbiturates, carbamazepine, hydantoins, and rifampicin may enhance the metabolism of tibolone and thus decrease its therapeutic effect. Herbal preparations containing St. John`s wort (hypericum perforatum) may induce the metabolism of estrogens and progestogens via CYP3A4. Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile. Since tibolone may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants, such as warfarin. Therefore, the simultaneous use of tibolone and anticoagulant/warfarin should be monitored, especially when starting or stopping concurrent tibolone treatment, and the anticoagulant/warfarin dose should be appropriately adjusted.

For further details, please refer to the Tibella Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The New Drug Submission (NDS) for Tibella was filed at Health Canada as a Submission Relying on Third-Party Data (SRTD) for which evidence of efficacy is based on published literature and post-market market experience. Review of the Tibella NDS consisted of a comprehensive examination of published literature based on the approved European reference product Liviella. The Tibella NDS also contained data from a bioequivalence study Mi0001-C103 which bridged the proposed Tibella 2.5 mg tablet to the reference Liviella 2.5 mg tablet.

Published literature submitted in the Tibella NDS included 22 placebo-controlled randomized clinical studies evaluating tibolone (the medicinal ingredient in Tibella) in postmenopausal women. Of these, two studies lasted 3 years (LIFT Study; number of patients [n] = 4,538) or longer (LIBERATE Study; n = 3,148), eight were 2 years, seven were 1 year, and two were 6 months in duration. Treatment allocation was double-blind in 11, single-blind in one and open-label, or unspecified in five placebo-controlled randomized clinical studies. Study populations ranged from 25 to 4,538 patients. The total number of participants in the 22 placebo-controlled studies was approximately 10,471; of these, 5,116 received Tibella at doses of 2.5 mg/day or 1.25 mg/day.

The review also included 44 active-controlled randomized clinical studies evaluating tibolone in postmenopausal or perimenopausal women. Of these, two studies lasted 3 years (OPAL Study; n = 866 and a small study by Thiebaud and colleagues; n = 40), six were 2 years, 14 were 1 year and 20 were 6 months in duration. Treatment allocation was double-blind in 12, single-blind in eight, and open-label, or unspecified in 22 active-controlled randomized studies. Study populations ranged from 22 to 866 patients. The total number of participants in the 44 active-controlled studies was approximately 6,972; of these, 2,723 received Tibella at doses of 2.5 mg/day or 1.25 mg/day.

Based on the literature data submitted, two studies were considered as pivotal in demonstrating the management of vasomotor symptoms associated with menopause. One of these studies was a placebo-controlled study that assessed the effects on hot flushes and sweats in groups of about 150 patients after a 12-week treatment with various doses of Tibella and placebo. Results of this study showed the 2.5 mg dose appeared to be the optimal dose for relieving hot flushes, sweats, and other climacteric complaints. The other study was an active-controlled study that compared the effects of a 48-week treatment of 2.5 mg Tibella with that of a continuous combined estradiol/norethisterone acetate combination in groups of about 220 post-menopausal patients. Results of this study showed Tibella relieved the climacteric symptoms (hot flushes, sweats, vaginal dryness, and rating scores on well-being); and the effects appeared to be comparable to that of the continuous combined hormone therapy-preparation.

During review of the Tibella NDS, it was noted that the clinical package submitted did lack sufficient pivotal clinical Phase III information to support efficacy for vulvar and vaginal atrophy associated with the menopause as the primary endpoint (e.g., vaginal dryness, vulvar irritation, itching, dysuria, etc...). In addition, data for the subgroup of women over age 65 was also noted to be limited in the submission. Knowing that the baseline risks of cancer, stroke, myocardial infarction, are likely to be higher in the elderly population, Health Canada did express concerns in regard to these important safety risks. Consequently, Health Canada issued on July 19, 2018 a Notice of Non-Compliance (NON) to the sponsor. In response to the NON, the sponsor submitted approximately 84 literature references to address the identified safety concerns. Prior to the issuance of the NON, Health Canada's Bureau of Medical Sciences was consulted on the risk of endometrial and breast cancers. A follow-up consult with Health Canada's Bureau of Medical Sciences was therefore requested based on the additional information provided by the sponsor in the NON response. Following evaluation of the additional literature submitted to Health Canada, it was concluded that based on the information provided in the NON response, in conjunction with the clinical experience and active pharmacovigilance activities observed in other jurisdictions over several decades, the available evidence supports a positive benefit-risk balance for Tibella with respect to these concerns, in appropriately-chosen patients.

Data from a bioequivalence study Mi0001-C103 were also included in the original NDS to bridge the proposed Tibella tablet to the reference Liviella tablet, as per Health Canada SRTD Guidance. Bioequivalence data were reviewed by Health Canada's Division of Biopharmaceutics Evaluation 2. Their conclusions were that Study Mi0001-C103 included with this NDS, for the proposed Tibella 2.5 mg tablets, met the requirements of the Food and Drug Regulations as far as the comparative bioavailability information is concerned.

Indication

The New Drug Submission for Tibella was filed by the sponsor with the following proposed indications:

• Treatment of estrogen deficiency symptoms in postmenopausal women, more than one year after menopause; and
• Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

Note, on June 22, 2018, the sponsor withdrew, without prejudice, the indication of prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

To ensure safe and effective use of the product, Health Canada approved the following indication:

Tibella (tibolone) is indicated for:

• Short-term treatment of vasomotor symptoms due to estrogen deficiency in postmenopausal women, more than one year after menopause.

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

Clinical Safety

The clinical data which established the overall safety of Tibella consisted of a comprehensive examination of published literature based on the approved European reference product Liviella, like that described in the Clinical Efficacy section. In 21 placebo-controlled studies (including the LIFT study), a total of 4,079 women received therapeutic doses (1.25 or 2.5 mg) of Tibella and 3,476 women received a placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years. In general, undesirable effects were observed to occur statistically more frequently during treatment with Tibella than with a placebo. Some of these undesirable effects included, lower abdominal pain, abnormal hair growth, vaginal discharge, endometrial thickening, breast tenderness, genital pruritus, vaginal candidiasis, vaginal hemorrhage, pelvic pain, cervical dysplasia, genital discharge, vulvovaginitis, weight increase, and abnormal cervical smear.

Important identified safety risks

During review of the Tibella NDS, Health Canada identified several important safety risks which included endometrial cancer, breast cancer, and stroke.

Endometrial cancer

In regard to endometrial cancer, the available data from randomized controlled studies are conflicting. However, observational studies have consistently shown that post-menopausal women who are prescribed Tibella in normal clinical practice are at an increased risk of endometrial cancer when taking Tibella, compared to either hormone non-users or sequential estrogen and progesterone therapy. In addition, it was noted that the risk of developing cancer increased with increasing duration of use. However, the possibility exists that these results may have been affected by limitations common to observational studies.

The endometrial cancer risk is about 5 in every 1,000 post-menopausal women with a uterus not using hormone replacement therapy or Tibella. The randomized placebo-controlled trial that included women who had not been screened for endometrial abnormalities at baseline, and therefore reflected clinical practice, identified the highest risk of endometrial cancer (LIFT study, mean age 68 years). In this study, no cases of endometrial cancer were diagnosed in the placebo group (n = 1,773) after 2.9 years compared with 4 cases of endometrial cancer in the Tibella group (n = 1,746). This corresponds to a diagnosis of 0.8 additional case of endometrial cancer in every 1,000 women who used Tibella for one year in this study.

Breast cancer

Concerning the risk of breast cancer, Tibella has been shown to increase the risk of breast cancer compared to no treatment in women with a previous history of breast cancer. Therefore, use of Tibella in women with known, past or suspected breast cancer is contraindicated in the Tibella Product Monograph. For women with no prior history of breast cancer, evidence with respect to breast cancer risk in association with Tibella is inconclusive. The Million Women Study has identified a significant increase in the risk of breast cancer in association with use of the 2.5 mg dose. This risk became apparent within a few years of use and increased with duration of intake, returning to baseline within a few (at most five) years after stopping treatment. The increase in the risk of breast cancer could not be confirmed in a study using the General Practice Research Database. An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years. Any increased risk in users of oestrogen-only and Tibella therapies is lower than seen in users of oestrogen-progestogen combinations. The level of risk is dependent on the duration of use. Hormone replacement therapy, especially oestrogen-progestogen combined treatment, increases the density of mammographic images that may adversely affect the radiological detection of breast cancer.

Stroke

Tibella has been shown to increase the risk of stroke. In the double-blind, randomized LIFT Study (N = 4,538) in women between 60 and 85 years of age (mean age 68.3 ± 5.2 years), 3-year treatment with Tibella 1.25 mg/day compared to placebo was associated with an increase in the absolute risk of stroke of 2.3 (95% confidence interval, 0.4 to 4.2) per 1000 person-years and an increase in the relative hazard of 2.19 (95% confidence interval, 1.14 to 4.23; p = 0.02). Baseline incidence over a 5-year period is estimated to be 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. For women who use used tibolone for 5 years, the number of additional cases would be expected to be about 4 per 1000 users aged 50-59 years and 13 per 1000 users aged 60-69 years. The LIFT study identified a significantly increased risk of stroke, mostly ischaemic, in tibolone users; risk increased from the first year of treatment. Randomised controlled trials have identified an approximate 1 to 3 times increase in stroke risk for combined HRT. In younger women, the risk profile of tibolone is broadly similar to that for conventional combined hormone-replacement therapy (HRT). For women older than about 60 years, the risks associated with tibolone start to outweigh the benefits because of the increased risk of stroke.

The important safety risks of endometrial cancer, breast cancer, and stroke have been included in the Tibella Product Monograph in a Serious Warnings and Precautions box.

Other important potential safety risks

Other important safety risks associated with use of Tibella include myocardial infarction, venous thromboembolism, and ovarian cancer.

Myocardial infarction

There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without existing coronary artery disease who received combined estrogen-progestogen or estrogen-only hormone replacement therapy. In an epidemiological study using the General Practice Research Database (GPRD) no evidence was found of protection against myocardial infarction in postmenopausal women who received Tibella.

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women's Health Initiative (WHI) trial indicate that the use of estrogen plus progestin is associated with an increased risk of coronary heart disease in postmenopausal women. Findings from the WHI trial demonstrated that in the combined estrogen plus progestin arm, among 10,000 women over a one-year period, there were 7 more cases of coronary heart disease (37 on combined hormone replacement therapy versus 30 on placebo).

In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10,000 women over a one-year period, there was no statistically significant difference in the rate of coronary heart disease.

In the Heart and Estrogen/progestin Replacement Study (HERS) of postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), a randomized placebo-controlled clinical trial of secondary prevention of coronary heart disease, treatment with 0.625 mg/day oral conjugated equine estrogen plus 2.5 mg oral medroxyprogesterone acetate demonstrated no cardiovascular benefit. Specifically, during an average follow-up of 4.1 years, treatment with conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of coronary heart disease events in postmenopausal women with established coronary heart disease. There were more coronary heart disease events in the hormone treated group than in the placebo group in year 1, but not during the subsequent years.

From the original HERS trial, 2,321 women consented to participate in an open label extension of HERS known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with coronary heart disease.

The risk of coronary artery disease is slightly increased in users of combined estrogen-progestogen hormone replacement therapy over the age of 60. There is no evidence to suggest that the risk of myocardial infarction with Tibella is different to the risk with other hormone replacement therapy.

Venous thromboembolism

Estrogen or estrogen-progestogen hormone replacement therapy is associated with a 1.3 to 3-fold risk of developing venous thromboembolism (i.e., deep vein thrombosis or pulmonary embolism). The occurrence of such an event is more likely in the first year of hormone replacement therapy than later. In an epidemiological study using a United Kingdom database, the risk of venous thromboembolism in association with Tibella was lower than the risk associated with conventional hormone replacement therapy, but only a small proportion of women were current users of Tibella and a small increase in risk compared with non-use cannot be excluded.

In the estrogen plus progestin arm of the WHI trial, among 10,000 women on combined hormone replacement therapy over a one-year period, there were 18 more cases of venous thromboembolism, including 8 more cases of pulmonary embolism. In the estrogen-alone arm of the WHI trial, among 10,000 women on estrogen therapy over a one-year period, there were 7 more cases of venous thromboembolism, although there was no statistically significant difference in the rate of pulmonary embolism.

Patients with known thrombophilic states have an increased risk of venous thromboembolism and hormone replacement therapy or Tibella may add to this risk. Hormone replacement therapy is therefore contraindicated in these patients.

Generally recognized risk factors for venous thromboembolism include use of estrogens, older age, major surgery, prolonged immobilization, obesity (body mass index >30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in venous thromboembolism. As in all postoperative patients, prophylactic measures need to be considered to prevent venous thromboembolism following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping hormone replacement therapy or Tibella 4 to 6 weeks earlier is recommended, if possible. Treatment should not be restarted until the woman is completely mobilized.

In women with no personal history of venous thromboembolism but with a first-degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) hormone replacement therapy or Tibella is contraindicated.

Women already on anticoagulant treatment require careful consideration of the benefit-risk of use of hormone replacement therapy or Tibella.

Ovarian cancer

Epidemiological evidence from a large meta-analysis demonstrated a slight increased risk in women taking estrogen-only or combined estrogen-progestogen hormone replacement therapy, which becomes apparent within 5 years of use and diminishes over time after stopping.

Some other studies, including the WHI trial, suggest that the use of combined hormone replacement therapies may be associated with a similar, or slightly smaller risk.

In the Million Women Study it was shown that the relative risk for ovarian cancer with use of Tibella was similar to the risk associated with use of other types of hormone replacement therapies.

Other potential safety risks

Reduced high-density lipoproteins

Decreases in plasma high-density lipoprotein (HDL), as well as total triglycerides, lipoprotein (a) levels, total cholesterol, and very low-density lipoprotein cholesterol (VLDL-C) levels. Treatment with Tibella resulted in a marked dose-dependent decrease in HDL (from -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2 years). It also reduces total triglyceride, total cholesterol, and lipoprotein (a) levels (mean reductions 38%, 13%, and 36%, respectively) with no change in low-density lipoprotein cholesterol (LDL). The clinical implication of these findings is not known.

A mild effect on glucose tolerance has also been reported; however, fasting glucose levels remain within the normal range during clinical trials.

Bleeding

Break-through bleeding and spotting may occur during the first months of treatment with Tibella. Breakthrough bleeding and/or spotting has been reported in 32.6% of women during the first 3 months of treatment, and in 11.6% of women after 11 to 12 months of use. Amenorrhea has been reported in 88% of women using Tibella 2.5 mg after 12 months of treatment. Tibella increases endometrial wall thickness, as measured by transvaginal ultrasound.

Conclusion

For all women the decision to prescribe Tibella should be based on an assessment of the individual patient's overall risks and, particularly for patients aged 60 and over, this assessment should include consideration of the risk of stroke.

After careful selection of users, Tibella should be prescribed for the shortest duration consistent with treatment goals. Review the need for continuation of treatment after 6 months, taking into account the risk-benefit ratio for the individual user at that moment (including cardiovascular disease, endometrial cancer, and breast cancer). Tibella should only be continued for as long as the benefit outweighs the risks. Also note, Tibella should be prescribed only to women with intact uteri since the medication includes progestogenic activity.

Submitted data demonstrated that Tibella relieved the vasomotor symptoms (i.e., hot flushes, sweats, and vaginal dryness) and showed improved scores in overall well-being. These effects were comparable to that of the continuous combined hormone therapy-preparation. The important identified risks of Tibella include endometrial cancer, breast cancer, and stroke. Other important risks include myocardial infarction, venous thromboembolism, ovarian cancer, hepatic dysfunction, and increased blood fibrinolytic activity. This information has been included in the Tibella Product Monograph similar to the product information for tibolone in other jurisdictions, and this is considered an appropriate risk mitigation measure.

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