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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; however, the pharmacokinetics of tibolone and its metabolites are not dependent upon renal function.
Use is contraindicated with liver dysfunction or disease.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Tibella: 2.5 mg
Not available in the US
Oral: Administer at the same time each day without regard to meals. Swallow tablet whole with water/fluid.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).
Vasomotor symptoms associated with menopause: Short-term treatment of vasomotor symptoms due to estrogen deficiency in postmenopausal women, >1 year after menopause.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
ALERT: [Canadian Boxed Warning]: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Dermatologic: Genital pruritus
Endocrine & metabolic: Hirsutism, weight gain
Gastrointestinal: Lower abdominal pain
Genitourinary: Abnormal cervical or vaginal Papanicolaou smear, breast tenderness, cervical dysplasia, endometrial hyperplasia, genital discharge, pelvic pain, vaginal discharge, vaginal hemorrhage, vulvovaginal candidiasis, vulvovaginitis
<1%:
Cardiovascular: Edema
Dermatologic: Acne vulgaris, pruritus
Gastrointestinal: Abdominal distress
Infection: Fungal infection, vaginal mycosis
Nervous system: Nipple pain
Frequency not defined:
Cardiovascular: Acute myocardial infarction, cerebrovascular accident, deep vein thrombosis, ischemic stroke, pulmonary embolism
Endocrine & metabolic: Decreased glucose tolerance, decreased HDL cholesterol, decreased LDL cholesterol (decrease in VLDL), decreased serum cholesterol, decreased serum triglycerides, decreased thyroxine binding globulin, decreased total T4, lipid metabolism disorder
Genitourinary: Abnormal vaginal hemorrhage
Hematologic & oncologic: Decreased sex hormone binding globulin, endometrial carcinoma, malignant neoplasm of breast
Postmarketing:
Dermatologic: Seborrheic dermatitis, skin rash
Hepatic: Abnormal hepatic function tests
Nervous system: Depression, dizziness, headache, migraine
Neuromuscular & skeletal: Musculoskeletal disease (including arthralgia and myalgia)
Ophthalmic: Blurred vision, visual disturbance
Hypersensitivity to tibolone or any component of the formulation; liver dysfunction or disease; known or suspected estrogen-dependent or progestin-dependent malignant neoplasia (eg, 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 (eg, 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 (eg, 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: [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 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.
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.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy
Anticoagulants: Tibolone may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Risk D: Consider therapy modification
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Risk X: Avoid combination
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Risk C: Monitor therapy
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Melatonin: Estrogen Derivatives may increase the serum concentration of Melatonin. Risk C: Monitor therapy
MetyraPONE: Estrogen Derivatives may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Risk X: Avoid combination
Pomalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Estrogen Derivatives. Protease Inhibitors may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy
Tacrolimus (Systemic): Estrogen Derivatives may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
Tranexamic Acid: Estrogen Derivatives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy
Tibolone is approved for use in postmenopausal women; use is contraindicated during pregnancy. Discontinue immediately if pregnancy occurs.
It is not known if tibolone or its metabolites are present in breast milk.
Use is contraindicated in women who are breastfeeding.
Routine physical examination that includes family medical history and BP; breasts and pelvic exam are recommended, including a Papanicolaou smear. Monitor for signs of endometrial cancer in female patients with uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. Baseline mammography, blood serum glucose, serum calcium, triglycerides and cholesterol levels, and LFTs. Monitor for signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy. Assess need for therapy 3 to 6 months after initiation.
Tibolone itself is pharmacologically inactive; it is converted to 3 active metabolites with estrogenic, progestogenic, and androgenic properties. It substitutes for estrogen loss in postmenopausal women and decreases vasomotor symptoms of menopause.
Absorption: Rapid and complete.
Metabolism: Rapidly converted in the GI tract and liver into 3 active metabolites (3α-OH-tibolone [estrogenic], 3β-OH-tibolone [estrogenic], and delta-4-isomer of tibolone [progestogenic/androgenic]).
Half-life elimination: 3α/3β -OH-tibolone: 6 to 8 hours.
Time to peak: Tibolone and active metabolites: 1 to 2 hours.
Excretion: Feces (major route; as metabolites); urine (minor route; as metabolites).
