Tibolone
Pronunciation
(TYE boe lone)
Index Terms
- Tibella
Pharmacologic Category
- Steroid, Synthetic
Pharmacology
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]).
Excretion
Feces (major route; as metabolites); urine (minor route; as metabolites).
Time to Peak
Tibolone and active metabolites: 1 to 2 hours.
Half-Life Elimination
3α/3β -OH-tibolone: 6 to 8 hours.
Use: Labeled Indications
Vasomotor symptoms associated with menopause: Short-term treatment of vasomotor symptoms due to estrogen deficiency in postmenopausal women, >1 year after menopause.
Contraindications
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; known, suspected, or past history of breast cancer; undiagnosed abnormal genital bleeding; untreated endometrial hyperplasia; 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.
Dosing: Adult
Vasomotor symptoms associated with menopause: Females: Oral: 2.5 mg once daily. 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.
Dosing: Geriatric
Refer to adult dosing.
Administration
Oral: Administer at the same time each day without regard to meals. Swallow tablet whole with water/fluid.
Storage
Store at 15°C to 30°C. Store blister cards in original outer container. Protect from light and moisture.
Drug Interactions
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Monitor therapy
Anticoagulants: Tibolone may enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). 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. Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Estrogen Derivatives. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Avoid combination
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. 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. Consider therapy modification
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Avoid combination
Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Monitor therapy
Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Monitor therapy
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Monitor therapy
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. 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. Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination
Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Monitor therapy
Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Consider alternative, non-hormonal forms of contraception. If used as hormone replacement therapy, monitor for estrogen deficiency. Monitor all patients using tipranavir/ritonavir and ethinyl estradiol/norethindrone for dermatologic adverse effects. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy
Test Interactions
Coagulation, corticoid binding globulin, glucose tolerance, lipid, sex hormone-binding globulin, and thyroid function tests may be altered.
Adverse Reactions
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
Warnings/Precautions
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.
Monitoring Parameters
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.
Pregnancy Considerations
Tibolone is approved for use in postmenopausal women; use is contraindicated during pregnancy. Discontinue immediately if pregnancy occurs.
Patient Education
What is this drug used for?
• It is used to treat symptoms of low estrogen levels in women who have been through menopause (change of life).
• It may be given to you for other reasons. Talk with the doctor.
• Do not use this drug as birth control to prevent pregnancy.
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
• Upset stomach or throwing up
• Stomach pain or cramps
• Feeling dizzy, tired, or weak
• Headache
• Feeling more or less hungry
• A change in weight without trying
• Change in sex interest
• Muscle or joint pain
• Feeling nervous and excitable
• Pimples (acne)
• Hair growth
• Hair loss
WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
• High blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit
• Liver problems like dark urine, feeling tired, not hungry, upset stomach, stomach pain, light-colored stools, throwing up, or yellow skin or eyes
• Gallbladder problems like pain in the upper right belly area, right shoulder area, or between the shoulder blades; change in stools; dark urine or yellow skin or eyes; or fever with chills
• Pancreatitis like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up
• High blood pressure like very bad headache or dizziness, passing out, or change in eyesight
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight
• Vaginal bleeding that does not stop or go back to normal
• Lump in the breast, breast pain or soreness, or nipple discharge
• Vaginal itching or discharge
• Pelvic pain
• Pain when passing urine
• Trouble passing urine
• Eyesight changes or loss, bulging eyes, or change in how contact lenses feel
• A heartbeat that does not feel normal
• A burning, numbness, or tingling feeling that is not normal
• Depression or other mood changes
• Memory problems or loss
• Swelling
• Blood clots like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing
• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.
Further information
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