Regulatory Decision Summary for Tibella

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

tibolone

Therapeutic area:

Sex Hormones and Modulators of the Genital System

Type of submission:

New Drug Submission (New Active Substance)

Control number:

206099
What was the purpose of this submission?

 

The sponsor was seeking market authorization for Tibella (tibolone) for the indication of treatment of estrogen deficiency symptoms in postmenopausal women.

 

Why was the decision issued?

 

Tibella (tibolone) is a New Drug Submission for which the sponsor had received a Notice of Non-compliance (NON), in part as a result of safety concerns. The sponsor has now submitted a R-NON including about 84 literature references.

In Europe, Tibella (2.5 mg tablets) is currently marketed as a generic product approved through demonstration of bioequivalence against the European reference product Liviella 2.5 mg tablets. Thus, this dossier is based on literature references on the European reference product Liviella. Data from a bioequivalence study (Study #Mi0001-C103) were provided to bridge the proposed Tibella tablet to the referenced Liviella tablet as the Health Canada Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience) (SRTD Guidance). Bioequivalence data were reviewed and it was concluded that Study #Mi0001-C103, meets the requirements of the Food and Drug Act and Regulations as far as the comparative bioavailability information is concerned.

Safety concerns identified in the NON included risks of endometrial cancer, breast cancer and stroke.. Review of the information provided in the R-NON concluded that based on the information in the R-NON regarding the safety risks of breast and endometrial cancers, and supported by clinical experience and active pharmacovigilance activities in other jurisdictions for several decades, the available evidence supports a positive benefit-risk balance for tibolone with respect to these concerns, in appropriately-chosen patients.

Some results from several large observational studies have raised concerns regarding tibolone and potential associations with these risks. However, the possibility exists that these results may have been affected by limitations common to observational studies. Information has been included in the proposed Tibella Product Monograph similar to the product information for tibolone in other jurisdictions, and this is considered an appropriate risk mitigation measure."

Tibolone increases the risk of ischaemic stroke from the first year of treatment. The baseline risk of stroke is strongly age-dependent. A large randomised placebo-controlled trial/Long-Term Intervention on Fracture with Tibolone Study (LIFT study) identified a significantly (2.2-times) increased risk of stroke, mostly ischaemic, in those assigned tibolone compared with those assigned placebos. The use of oestrogen-only and oestrogen + progestogen therapy is associated with an increased relative risk of ischaemic stroke by up to 1.5 fold. Overall, regarding the stroke risk profile of tibolone, the balance of benefits and risks in younger women is broadly similar to that of conventional combined hormone replacement therapy (HRT). For older women, tibolone may increase the risk of stroke in women over 60 years of age. Information on strokes, similar to that in other jurisdictions, has been included in the Tibella Product Monograph (in the sections of Indication, Warnings and Precautions; and Adverse Reactions).

Other important potential risks of tibolone include myocardial infarction, venous thromboembolism (VTE), ovarian cancer, hepatic dysfunction and increased blood fibrinolytic activity. Since tibolone may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants, such as warfarin. In addition to the above risks, tibolone decreases plasma high density lipoprotein (HDL). The clinical implication of this finding is not known. A mild effect on glucose tolerance has also been reported. Break-through bleeding and spotting may occur during the first months of treatment. Amenorrhea has been reported in 88% of women using tibolone 2.5 mg after 12 months of treatment. Tibolone increases endometrial wall thickness, as measured by transvaginal ultrasound.

For efficacy, two pivotal, multicentre, randomized, double-blind studies assessed the effects of tibolone on climacteric complaints. One of these studies was a placebo-controlled study and assessed the effects on hot flushes and sweats in groups of about 150 subjects after a 12-week treatment with various doses of tibolone and placebo. 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 tibolone with that of a continuous combined estradiol/norethisterone acetate combination in groups of about 220 post-menopausal subjects. Tibolone relieved the climacteric symptoms (hot flushes, sweats, vaginal dryness and rating scores on well-being); the effects appeared to be comparable to that of the continuous combined hormone therapy-preparation. The efficacy of tibolone on the climacteric symptoms was also confirmed in other published studies.

Overall, based on the information in the R-NON regarding the safety risks of stroke, breast and endometrial cancers, and supported by clinical experience and active pharmacovigilance activities in other jurisdictions for several decades, the available evidence supports a positive benefit-risk balance for tibolone in appropriately-chosen patients when it is prescribed under the conditions of use recommended in the Product Monograph (PM).

For more information on Health Canadas decision, please view the Summary Basis of Decision.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.