Tibolone (United States: Not available): Drug information

Concerns related to adverse effects:

• Breast cancer: [Canadian Boxed Warning]: May increase the risk of breast cancer and can be dependent on individual risk factors. Based on data from the Women's Health Initiative (WHI) trial, an increased risk of invasive breast cancer may be associated with estrogen plus progestin use. The Million Women Study (MWS) also found an increased risk of breast cancer in association with tibolone therapy; risk returned to baseline within a few (≤5) years of stopping tibolone therapy. Use with caution in patients at risk for estrogen-dependent tumors (eg, strong family history, breast conditions with increased risk). Patients should receive a mammogram prior starting therapy and at regular intervals during therapy.

• Coronary artery disease: [Canadian Boxed Warning]: Based on data from the WHI trial, an increased risk of invasive myocardial infarction (MI) may be associated with estrogen plus progestin use. Tibolone has not been shown to protect against MI in women with or without existing coronary artery disease (CAD). In general, use of combined estrogen-progestogen menopausal hormone therapy (MHT) is associated with slight increase of CAD in patients >60 years of age; use caution with tibolone in this population.

• Dementia: MHT does not improve cognitive function; risk of dementia may increase with some MHT when initiated in patients >65 years of age; use caution with tibolone in this population.

• Endometrial carcinoma/hyperplasia: [ Canadian Boxed Warning]: May increase the risk of endometrial cancer in patients with an intact uterus and can be dependent on individual risk factors. Tibolone increases endometrial wall thickness. Breakthrough bleeding/spotting that occurs ≥6 months after initiation of therapy warrants referral for gynecologic evaluation. Investigate any irregular/unscheduled vaginal bleeding to rule out malignancy prior to tibolone initiation. Use caution in patients with a history of endometrial hyperplasia; may exacerbate condition.

• Ischemic stroke: [Canadian Boxed Warning]: May increase the risk of stroke and can be dependent on individual risk factors. Based on data from the WHI trial, an increased risk of stroke may be associated with estrogen use or estrogen plus progestin use. Effect may be greater in older (>60 years of age) patients. Discontinue therapy in patients who develop classical migraine, loss of consciousness, paralysis, transient aphasia, or visual disturbances.

• Lipid abnormalities: Cases of hypertriglyceridemia resulting in pancreatitis have been (rarely) reported with estrogen replacement therapy; use caution in women with preexisting hypertriglyceridemia. Other changes in lipid profiles, including dose-dependent reductions in high-density lipoprotein cholesterol, were observed with tibolone use.

• Ovarian cancer: Postmenopausal estrogen therapy and combined estrogen/progesterone therapy may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. In the MWS, the relative risk for ovarian cancer with tibolone use was similar to other types of MHT.

• Thromboembolic events: [Canadian Boxed Warning]: Based on data from the WHI trial, an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) may be associated with estrogen use or estrogen plus progestin use. Risk is increased during the first year of therapy. Discontinue therapy promptly if venous thromboembolism (VTE) occurs. Use caution in patients with thromboembolic risk factors. Screening for thrombophilic defects may be offered to patients with family history (eg, first-degree relative) of early thrombosis. Before and during treatment, assess individual patient risk factors for VTE (age, obesity, immobilization/surgery, systemic lupus erythematosus [SLE], cancer). Use tibolone with caution in patients on anticoagulation therapy for any reason.

Disease-related concerns:

• Asthma: Use caution in patients with asthma; may exacerbate disease.

• Carbohydrate intolerance: Use caution in patients with diabetes, with or without vascular involvement; may exacerbate condition.

• Cardiovascular disease: [Canadian Boxed Warning]: Estrogens with or without progestins should not be prescribed for primary or secondary prevention of cardiovascular disease. Use caution in hypertensive patients; may exacerbate disease. Discontinue therapy if significant increase in BP occurs.

• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.

• Epilepsy: Use caution in patients with epilepsy; may exacerbate disease.

• Gallstones: Use caution in patients with gallstones; may exacerbate condition.

• Hepatic disease: Use caution in patients with hepatic disorders (eg, adenoma); may exacerbate disease. Discontinue therapy if jaundice or abnormal hepatic function occurs.

• Hereditary angioedema: Estrogens may induce or exacerbate symptoms in women with hereditary angioedema. Discontinuation of therapy may be necessary.

• Metabolic/endocrine diseases: Careful evaluation is recommended prior to starting therapy in patients with metabolic or endocrine diseases and when metabolism of calcium and phosphorus is abnormal; monitor regularly as indicated.

• Migraine: Use caution in patients with migraines or severe headaches; may exacerbate condition. Discontinue if new-onset migraine-type headache occurs.

• Otosclerosis: Use caution in patients with otosclerosis; may exacerbate disease.

• Systemic lupus erythematous: Use caution in patients with SLE; may exacerbate disease.

• Uterine abnormalities: Use caution in patients with leiomyoma (uterine fibroids) or endometriosis; may exacerbate these conditions.

Dosage form specific issues:

• Lactose: May contain lactose; do not use with galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption syndromes.

Other warnings/precautions:

• Appropriate use: Administer only to patients with an intact uterus. [Canadian Boxed Warning]: A complete personal and family medical history should be taken before starting treatment. Periodic check-ups are recommended while on treatment. Not intended for combined hormone therapy; a separate progestogen should not be added to tibolone therapy. Treatment should be reserved for symptoms that adversely affect quality of life. Not intended for contraceptive use.

• Risks vs benefits: [Canadian boxed warning]: The WHI trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen-alone therapy (n=10,739) in postmenopausal women 50 to 79 years of age. The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of MI, stroke, invasive breast cancer, PE, and DVT in postmenopausal women receiving treatment with combined conjugated equine estrogens (CEE) (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day) for 5.2 years compared to those receiving placebo. The estrogen-alone arm of the WHI trial (mean age 63.6 years) indicated an increased risk of stroke and DVT in hysterectomized women treated with CEE alone (0.625 mg/day) for 6.8 years compared to those receiving placebo. Based on data from the WHI trial, estrogens with or without progestins should be prescribed at the lowest effective dose and the shortest period possible for the approved indication. Tibolone treatment should continue only as long as benefits outweigh the risks.

• Surgery patients: If prolonged immobilization is expected following elective surgery, interrupt tibolone therapy 4 to 6 weeks prior to surgery and restart only when patient is fully mobile.