Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mercury Pharmaceuticals Limited, Capital House, 85 King William Street, London, EC4N 7BL
Pharmacotherapeutic group: other estrogens
ATC code: G03CX01
Following oral administration, tibolone is rapidly metabolised into three compounds, which all contribute to the pharmacodynamic profile of Tibolone. Two of the metabolites (3α-OH-tibolone and 3β-OH-tibolone) have oestrogenic-like activities, whereas the third metabolite (4Δ-isomer of tibolone) has progestogenic and androgenic-like activities.
Tibolone substitutes for the loss of oestrogen production in postmenopausal women and alleviates menopausal symptoms. Tibolone prevents bone loss following menopause or ovariectomy.
Relief of oestrogen-deficiency symptoms.
Relief of menopausal symptoms generally occurs during the first few weeks of treatment.
Effects on the endometrium and bleeding patterns.
There have been reports of endometrial hyperplasia and endometrial cancer in patients treated with Tibolone (see section 4.4 and 4.8).
Amenorrhea has been reported in 88% of women using Tibolone 2.5 mg after 12 months of treatment. 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 11-12 months of use.
Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.
In the LIFT study, Tibolone reduced the number of women (mean age 68 years) with new vertebral fractures compared to placebo during the 3 years of treatment (ITT: Tibolone to placebo odds ratio 0.57; 95% CI [0.42, 0.78]).
After 2 years of treatment with Tibolone (2.5 mg), the increase in lumbar spine bone mineral density (BMD) was 2.6 ± 3.8%. The percentage of women who maintained or gained BMD in lumbar zone during treatment was 76%. A second study confirmed these results.
Tibolone (2.5 mg) also had an effect on hip BMD. In one study, the increase after 2 years was 0.7 ± 3.9% at the femoral neck and 1.7 ± 3.0% at the total hip. The percentage of women who maintained or gained BMD in the hip region during treatment was 72.5%. A second study showed that the increase after 2 years was 1.3 ± 5.1% at the femoral neck and 2.9 ± 3.4% at the total hip. The percentage of women who maintained or gained BMD in the hip region during treatment was 84.7%.
In clinical studies mammographic density is not increased in women treated with Tibolone compared to placebo.
Following oral administration, tibolone is rapidly and extensively absorbed. Due to rapid metabolism, the plasma levels of tibolone are very low. The plasma levels of the Δ4-isomer of tibolone are also very low. Therefore some of the pharmacokinetic parameters could not be determined. Peak plasma levels of the 3α-OH and the 3β-OH metabolites are higher but accumulation does not occur.
Table 5. Pharmacokinetic parameters of Tibolone (2.5 mg):
| Tibolone | 3α-OH metaboline | 3β-OH metabolite | Δ4 Isomer | |||||
|---|---|---|---|---|---|---|---|---|
| SD | MD | SD | MD | SD | MD | SD | MD | |
| Cmax (ng/ml) | 1,37 | 1,72 | 14,23 | 14,15 | 3,43 | 3,75 | 0,47 | 0,43 |
| Caverage | - | - | - | 1 ,88 | - | - | - | - |
| Tmax (h) | 1,08 | 1,19 | 1,21 | 1,15 | 1,37 | 1,35 | 1,64 | 1,65 |
| T1/2 (h) | - | - | 5,78 | 7,71 | 5,87 | - | - | - |
| Cmin (ng/ml) | - | - | - | 0,23 | - | - | - | - |
| AUC0-24 (ng/ml.h) | - | - | 52,23 | 44,73 | 16,23 | 9,20 | - | - |
SD = single dose ; MD = multiple dose
Excretion of tibolone is mainly in the form of conjugated (mostly sulfated) metabolites. Part of the administered compound is excreted in the urine, but most is eliminated via the faeces.
The consumption of food has no significant effects on the extent of absorption.
The pharmacokinetic parameters for tibolone and its metabolites were found to be independent of renal function.
In animal studies, tibolone had anti-fertility and embryotoxic activities by virtue of its hormonal properties. Tibolone was not teratogenic in mice and rats. It displayed teratogenic potential in the rabbit at near-abortive dosages (see section 4.6). Tibolone is not genotoxic under in vivo conditions. Although a carcinogenic effect was seen in certain strains of rat (hepatic tumours) and mouse (bladder tumours), the clinical relevance of this is uncertain.
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