Tibolone

Tibolone is a Synthetic Steroid Hormone.

Tibolone can be used in the treatment of Vasomotor symptoms associated with menopause.

Tibolone is rapidly and extensively absorbed. Time to peak plasma concentration: 1-2 hours (tibolone and active metabolites) and rapidly converted in the gastrointestinal tract and liver into 3 active metabolites, with 2 (3α-OH-tibolone, 3β-OH-tibolone) having predominantly estrogenic property and 1 (delta-4-isomer of tibolone) with progestogenic and androgenic property and get excreted Mainly via faeces (as metabolites); partly via urine (as metabolites). Elimination half-life: 6-8 hours (3α-OH-tibolone, 3β-OH-tibolone).

The common side effects of Tibolone includes: Increased risk of endometrial, breast, or ovarian cancer; endometrial hyperplasia, breakthrough bleeding and spotting; increased risk of venous thromboembolism (e.g. DVT, pulmonary embolism), ischemic stroke, dementia.

Tibolone is available in the form of Tablets.

The molecule is available in India, Japan, Germany, China.

Tibolone is a steroid that is rapidly converted into 3 active metabolites following administration which possess estrogenic, progestogenic, and androgenic properties. It substitutes for estrogen loss in postmenopausal women, reduces vasomotor symptoms of menopause, and prevents bone loss after menopause or ovariectomy.

Tibolone is available in Tablets.

Tibolone is quickly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects.

Tibolone is approved for use in the following clinical indications:

Vasomotor symptoms associated with menopause: Short-term treatment of vasomotor symptoms due to estrogen deficiency in postmenopausal women, >1 year after menopause.

Vasomotor symptoms associated with menopause: Females: Oral: 2.5 mg once daily; maximum dose: 2.5 mg/day. Initiate ≥1 year after naturally occurring menopause, or immediately in women with surgical menopause or those being treated with gonadotropin releasing hormone (GnRH) analogues.

Switching from other hormone replacement therapy: If on sequential hormone replacement therapy (HRT), initiate tibolone 1 day after the completion of the current treatment cycle. If on continuous-combined HRT, may initiate tibolone therapy at any time. Note: A separate progestogen should not be added to tibolone.

Missed dose: If >12 hours has elapsed, skip dose and resume at next regularly scheduled time.

• Tablets: 2.5 mg

Tablets

Tibolone may be contraindicated in the following conditions:

Hypersensitivity to tibolone or any component of the formulation; liver dysfunction or disease; known or suspected estrogen-dependent or progestin-dependent malignant neoplasia (e.g, endometrial cancer); endometrial hyperplasia (including untreated); known, suspected, or past history of breast cancer; undiagnosed abnormal genital bleeding; known or suspected pregnancy and lactation; active or past history of arterial thromboembolic disease (e.g, angina, stroke, myocardial infarction, coronary heart disease, transient ischemic attack); active or past history of confirmed venous thromboembolism (such as deep venous thrombosis or pulmonary embolism) or active thrombophlebitis; known thrombophilic disorders (e.g, protein C, protein S, antithrombin deficiency); partial or complete loss of vision due to ophthalmic vascular diseases; porphyria.

Concerns related to adverse effects:

• Breast cancer: 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 hormone replacement therapy (HRT) is associated with slight increase of CAD in patients >60 years of age; use caution with tibolone in this population.

• Dementia: HRT does not improve cognitive function; risk of dementia may increase with some HRT 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 HRT.

• 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.

There is no sufficient scientific evidence traceable regarding use and safety of Tibolone in concurrent use with alcohol.

The adverse reactions related to Tibolone can be categorized as

Common Adverse effects:

Increased risk of endometrial, breast, or ovarian cancer; endometrial hyperplasia, breakthrough bleeding and spotting; increased risk of venous thromboembolism (e.g. DVT, pulmonary embolism), ischaemic stroke, dementia

Less Common Adverse effects:

Fluid retention; decreased HDL cholesterol, total triglyceride, lipoprotein, total cholesterol and VLDL-C; decreased (very minor) thyroid-binding globulin, total thyroxine, sex hormone-binding globulin (SHBG).

Rare Adverse effects:

Hypertriglyceridemia resulting in pancreatitis. Eye disorders: Visual disturbances (e.g. blurred vision). Gastrointestinal disorders: Lower abdominal pain, abdominal discomfort. General disorders and administration site conditions: Oedema.

The clinically relevant drug interactions of Tibolone is briefly summarized here:

Enhanced effect of anticoagulants (e.g. warfarin).

May increase metabolism with CYP3A4 inducers (e.g. barbiturates, carbamazepine, hydantoins, rifampicin).

The most common side effects of Tibolone includes: Increased risk of endometrial, breast, or ovarian cancer; endometrial hyperplasia, breakthrough bleeding and spotting; increased risk of venous thromboembolism (e.g. DVT, pulmonary embolism), ischaemic stroke, dementia.

Symptoms: Nausea, vomiting, vaginal bleeding.

Management: Symptomatic treatment.

Pharmacodynamics:

Tibolone is a steroid that is rapidly converted into 3 active metabolites following administration which possess estrogenic, progestogenic, and androgenic properties. It substitutes for estrogen loss in postmenopausal women, reduces vasomotor symptoms of menopause, and prevents bone loss after menopause or ovariectomy.

Pharmacokinetics:

Absorption: Rapidly and extensively absorbed. Time to peak plasma concentration: 1-2 hours (tibolone and active metabolites).

Metabolism: Rapidly converted in the gastrointestinal tract and liver into 3 active metabolites, with 2 (3α-OH-tibolone, 3β-OH-tibolone) having predominantly estrogenic property and 1 (delta-4-isomer of tibolone) with progestogenic and androgenic property.

Excretion: Mainly via faeces (as metabolites); partly via urine (as metabolites). Elimination half-life: 6-8 hours (3α-OH-tibolone, 3β-OH-tibolone).

1. https://www.uptodate.com/contents/ Tibolone -drug-information?search= Tibolone &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Tibolone _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Tibolone ?type=full&mtype=generic#mechanism-of-action