What are the side effects, risks, and contraindications of tibolone (2.5 mg daily) for treating menopausal symptoms?

Tibolone Side Effects and Safety Profile

Tibolone at 2.5 mg daily effectively treats menopausal symptoms but carries significant risks including increased breast cancer recurrence in women with breast cancer history and elevated stroke risk in women over 60 years of age. 1, 2

Common Side Effects

• Weight gain, acne, and hirsutism occur due to tibolone's androgenic properties 3
• Mood changes are reported as a common side effect 3
• Unscheduled vaginal bleeding occurs more frequently than placebo (31-44% vs 18%), though less than combined hormone therapy 2, 4
• Breast tenderness incidence is notably low compared to conventional hormone replacement therapy 1

Major Safety Concerns and Contraindications

Breast Cancer Risk

• Absolute contraindication in women with breast cancer history - the LIBERATE trial was halted early due to increased tumor recurrence risk (OR 1.50,95% CI 1.21 to 1.85) after 3.1 years 1, 2
• In women without breast cancer history, evidence shows no clear increased risk, though data quality is limited 2
• One trial in osteoporotic women with negative mammograms showed reduced breast cancer incidence (OR 0.32), but this was not the primary outcome and event numbers were low 2, 5

Cardiovascular and Cerebrovascular Events

• Increased stroke risk in women over 60 years - a trial in osteoporotic women aged 60-85 was stopped prematurely due to elevated stroke risk (OR 2.18,95% CI 1.12 to 4.21) 2, 5
• No conclusive evidence of increased cardiovascular events overall (OR 1.38,95% CI 0.84 to 2.27), though evidence quality is low 2
• Venous thromboembolic events show no clear increased risk (OR 0.85,95% CI 0.37 to 1.97) 2

Endometrial Safety

• Endometrial cancer risk remains uncertain with low event numbers (OR 2.04,95% CI 0.79 to 5.24) 2
• Tibolone rarely causes endometrial proliferation and does not increase endometrial thickness, eliminating the need for additional progestogen 4, 6

Absolute Contraindications

• Known or suspected breast cancer or history of breast cancer 1, 3
• Estrogen-dependent malignant tumors (known or suspected) 3
• Undiagnosed vaginal bleeding 3
• Untreated endometrial hyperplasia 3
• Active or recent venous thromboembolic disorders 3
• Known thrombophilic disorders 3
• Active or recent arterial thromboembolic disease 3
• Acute liver disease or history of liver disease with abnormal liver function tests 3
• Porphyria 3

Clinical Efficacy Context

• Tibolone 2.5 mg daily effectively reduces vasomotor symptoms (OR 0.33,95% CI 0.27 to 0.41 compared to placebo), though less effectively than combined hormone therapy 2, 4
• Improves vaginal dryness, sexual function, and mood more effectively than standard hormone therapy 1, 6
• Does not increase mammographic breast density, unlike combined hormone therapy 1, 6

Dosing Considerations

• Standard dose is 2.5 mg daily administered continuously 3, 4
• Alternative 1.25 mg daily dose may provide similar efficacy with potentially better tolerability, though symptom relief occurs more gradually 3, 4
• Both doses are bioequivalent regarding extent of absorption and show similar safety profiles 7, 4

Critical Clinical Pitfalls

• Age matters significantly - avoid in women over 60 years due to stroke risk, particularly in those selected for osteoporosis rather than menopausal symptoms 2, 5
• Breast cancer history is an absolute contraindication - the increased recurrence risk is well-established and clinically significant 1, 2
• Duration of follow-up in safety studies was typically only 2-3 years, limiting long-term safety conclusions 2
• Mortality from any cause shows no difference (OR 1.06,95% CI 0.79 to 1.41), though follow-up periods were limited 2