Amena

Each tablet contains tibolone 2.5 mg.

Pharmacology: Pharmacodynamic: Tibolone is a synthetic steroid compound characterized as a selective tissue estrogenic activity regulator (STEAR). Tibolone itself has no biological activity; its effects are the result of the activity of its metabolites on various tissues. The 3αOH and 3βOH metabolites of tibolone act like estrogen in the thermoregulatory centers in the brain (preventing hot flushes), bone (preventing bone loss) and vaginal tissue (preventing dryness and soreness). In endometrial tissue, the △4-isomer acts like progesterone in the womb to prevent overgrowth of the endometrium and subsequent bleeding.
In breast tissue, the main action of progestogenic △4-isomer of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17α-hydroxysteroid dehydrogenase activity which result in clocking the conversion of estrone sulfate to the active hormone estrone and 17β-estradiol. Tibolone inhibits human breast cell proliferation and stimulate apoptosis. Unlike classical hormone replacement, therapy, the incidence of breast tenderness is low and mammographic density dose not increase with tibolone.
Tibolone has androgenic effects on certain metabolic and hematologic parameters such as decrease in plasma high density lipoprotein cholesterol, triglycerides and lipoprotein(a), and may increase blood fibrinolytic activity.
Tibolone improves vaginal dryness and vaginal atrophy. Tibolone has testoterone-like activity that appears to play a role in enhancing women's mood and libido, although response is variable.
Pharmacokinetic: Tibolone is rapidly and extensively absorbed after oral administration. It is rapidly metabolized by the liver into two estrogenic metabolites (3α- and 3β-OH-tibolone), which bind to the estrogen receptor, and a third metabolite, the △4-isomer, which binds to the progesterone and androgen receptors. Some of the pharmacokinetic parameters of tibolone cannot be determined due to its very low plasma levels. There is no significant effect on the extent of absorption when taken with food.
Peak concentrations of tibolone and its metabolites occur about 1 to 1.5 hours after oral administration; two mainmetabolites have an elimination half-life of about 7 hours. Metabolites are excreted in the bile and eliminated in the feces. About 30% of a dose is excreted in the urine.
The pharmacokinetic parameters for tibolone and its metabolites were found to independent of renal function.

Used as menopausal therapy in the treatment of menopausal vasomotor symptoms and the prevention of post menopausal osteoporosis.

Tibolone is a steroid derived from noretynodrel that has oestrogenic, progestogenic, and weak androgenic properties. The usual dose is 2.5 mg daily by mouth. Tibolone reduces vasomotor symptoms associated with the use of gonadorelin analogues for endometriosis or fibroids.
Starting Tibolone: Women experiencing a natural menopause should commence treatment with tibolone at least 12 months after their last menstrual bleed. In case of surgical menopause, treatment with Tibolone, may commence immediately.
Switching from a sequential or continuous combined HRT preparation: If changing from a sequential HRT preparation, treatment with Tibolone should start the day following completion of the prior regimen. If changing from a continuous-combined HRT preparation, treatment can start at any time.
Missed dose: A missed dose should be taken as soon as remembered, unless it is more than 12 hours overdue. In the latter case, the missed dose should be skipped and the next dose should be taken at the normal time. Missing a dose may increase the likelihood of breakthrough bleeding and spotting.

Acute toxicity with tibolone is very low in animals and therefore toxic symptoms with simultaneous ingestion of several tablets are not expected. Symptoms sucj as nausea, vomiting and withdrawal bleeding in females may develop in acute overdose. Give symptomatic treatment if such case occurs. There is no specific antidote for tibolone intoxication.

Hypersensitivity to tibolone or to any ingredient in the product.
Known, past or suspected breast cancer. An increased risk of breast cancer recurrence in the patients has been identified in a placebo controlled trial.
Known or suspected estrogen-dependent malignant tumors, e.g., endometrial cancer.
Undiagnosed genital bleeding.
Untreated endometrial hyperplasia.
Previous idiopathic or recurrent venous thromboembolism (deep venous thrombosis, pulmonary embolism)
Any history of arterial thromboembolic disease, e.g., angina, myocardial infarction, stroke, or transient ischemic attack (TIA).
Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal.
Porphyria.
Pregnancy or breastfeeding.

Conditions Which Need Supervision: The patient should be If any of the following conditions are present, have occurred previously and/or have been aggravated during pregnancy or previous hormone treatment since these conditions may recur or be aggravated during Tibolone treatment: Leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders; risk factors for estrogen-dependent tumors eg, 1st degree heredity for breast cancer; hypertension; liver disorders (eg, liver adenoma); diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus (SLE); a history of endometrial hyperplasia; epilepsy; asthma; otosclerosis.
Reasons for Immediate Withdrawal of Therapy: Discontinued the tibolone treatment in case a contraindication is discovered and in the following situations: Jaundice or deterioration in liver function, significant increase in blood pressure, new onset of migraine-type headache.
Endometrial Cancer: There is conflicting data on the risk of emdometrial cancer and use of tibolone in ramdomized controlled trials. However, it has been shown in observational studies that tibolone increases the risk of endometrial cancer with increasing duration of use and increases endometrial wall thickness as measured by transvaginal ultrasound in women who are prescribed with tibolone in normal clinical practice.
Tibolone may cause breakthrough bleeding and spotting during the first months of treatment. If these symptoms are still present after 6 months of treatment, if it starts beyond that time or if it continues after treatment has been discontinued, advise patient to report to their doctor and be referred to gynecological investigation. Endometrial biopsy should be done to exclude endometrial malignancy.
When estrogens are administered alone or for prolonged periods, the risk of endometrial hyperplasia and carcinoma is increased. The addition of progesterone to estrogen-only HRT for atleast 12 days per cycle greatly reduces this risk in non-hysterectomized women.
Breast Cancer: There is no conclusive evidence on the association of tibolone with increased risk of breast cancer. However, a significant increase in the risk of breast cancer was observed in the Million Women Study (MWS) with use of the 2.5 mg tibolone dose; the risk became apparent within a few years and after an increased duration of intake, returning to baseline within a few (at most five) years after stopping treatment.
Investigations, including mammography, should be carried out in accordance with currently accepted screening guidelines, modified to the clinical needs of the individual.
Venous Thromboembolism: A higher relative risk of developing VTE (i.e., deep vein thrombosis or pulmonary embolism) is observed with the use of estrogen or estrogen-progesterone HRT. A two- to three-fold higher risk in patients using tibolone compared to non-users was found in a randomized clinical trial and epidemiological studies. It is estimated that the number of VTE cases that will occur over a 5-year period in non-users is about 3 per 1000 women whose age is 50-59 years old and 8 per 1000 women who are 60-69 years old. In healthy women who use HRT for 5 years, it is estimated that the number of additional cases of VTE over a five year period will be between 2 and 6 (best estimate=4) per 1000 women who are 60-60 years old. This is more likely to occur in the first year of HRT use than later. It is not known whether the same level of risk will occur with the use of tibolone.
Personal history or family history, severe obesity (Body mass index BMI >30 kg/m²) and SLE are the generally recognized factors for VTE. The possible role of varicose veins in VTE is not known.
Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. To exclude a thrombophilic predisposition, the patient should be investigated for personal or strong family history of thromboembolism or recurrent spontaneous abortion. The use of HRT in these patients should be viewed as contraindicated until a thorough evaluation of thrombophilic factors have been made or anticoagulant therapy is initiated. A careful consideration of the benefit-risk of use of HRT is required in patients already on anticoagulant treatment.
Prolonged immobilization, major trauma or major surgery may temporarily increase the risk of VTE. As with all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE after surgery. HRT should be temporarily stopped 4 to 6 weeks earlier (if possible) in instances where prolonged immobilization is likely to follow elective surgery, particularly abdominal surgery or orthopedic surgery to the lower limbs. Do not restart therapy until the patient is completely mobilized.
Tibolone should be discontinued in case VTE develops after initiation of therapy. Patients should report immediately to their doctor any potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnea).
Coronary Artery Disease (CAD): Randomized controlled trials have shown no evidence of cardiovascular benefit with the use of continuous-combined conjugated estrogens and medroxyprogesterone acetate (MPA). This was demonstrated in the Women is Health Initiative (WHI) and Heart and estrogen/progestin Replacement Study (HERS) which showed a possible increased risk of cardiovascular morbidity in the first year of use with no overall benefit.
Only limited data from randomized controlled trials examined the effects of cardiovascular morbidity and mortality of other HRT products and therefore it is uncertain whether these findings will also extend to other HRT products such as tibolone.
Stroke: The risk of ischemic stroke has been shown to be increased during the first year of treatment with tibolone (2.2-fold increase). The baseline risk of stroke is strongly age-dependent and therefore the risk is greater with older age (tibolone users for 5 years will have additional cases of about 4 per 1000 users in women 50-59 years old and 13 per 1000 in users 60-69 years old).
Ovarian Cancer: Some epidemiological studies have shown that long-term (at least 5-10 years) use of estrogen-only HRT products has been associated with an increased risk of ovarian cancer in hysterectomized women. However, it is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.
Other Conditions: A marked dose-dependent decrease in HDL cholesterol (-16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2 years) was observed with tibolone treatment. A decrease in total triglycerides and lipoprotein(a) levels were also observed. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. LDL-C levels were unchanged. The clinical implication of these findings is not yet known.
Rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy. Closely monitor women with pre-existing hypertriglyceridemia during estrogen therapy or HRT.
Patients with cardiac or renal dysfunction should be carefully observed since estrogens may cause fluid retention. A very minor decrease in thyroid binding globulin (TBG) and total T4 has been observed with tibolone therapy. Tibolone also decreases the level of sex-hormone-binding globulin (SHBG). However, levels of T3 and corticoid binding globulin (CBG) and circulating cortisol are unaffected.
The evidence for improvement of cognitive function is inconclusive. Although some evidence exist from the WHI trial of increased risk of probable dementia in women who start using continuous combined conjugated estrogen and MPA after 65 years old, it is not known whether these findings apply to younger postmenopausal women or other HRT products.
Carcinogenicity/Mutagenicity: Similar to treatment with other sex hormones, long-term carcinogenicity in rodents has shown tha tibolone was associated with the development of a range of tumors (i.e., pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and tests). No evidence of genotoxicity was shown for tibolone in gene mutation, chromosomal damage and DNA damage assays.
Effects on ability to drive and use machines: Tibolone is not known to have any effects on alertness and concentration.
Use in Children: The use in this population is not recommended.
Use in the Elderly: No dose adjustment is necessary.

Pregnancy: Pregnancy Category D.
Tibolone is contraindicated in pregnant women including those in the perimenopausal period. Tibolone has been shown to cross the placenta in rabbits and was found to be teratogenic in rats and rabbits, and therefore, tibolone should be withdrawn immediately if patient becomes pregnant during the course of therapy.
Lactation: Tibolone is contraindicated in breastfeeding mothers.

Gastrointestinal: Abdominal pain (upper and lower), gastrointestinal upset, cholestatic jaundice, gall bladder disease.
Skin and Subcutaneous Tissue Disorders: Abnormal hair growth, acne, rash, pruritus, seborrheic dermatitis, itching, facial hypertrichosis, chloasma, erythema multiforme, erythema nodosum, vascular purpura.
Reproductive System and Breast Disorder: Vaginal discharge, leucorrhea, vaginal hemorrhage/bleeding, vaginal candidiasis, vaginal mycosis, endometrial wall thickening/hyperplasia, postmenopausal hemorrhage, breast tenderness, genital pruritus, pelvic pain, cervical dysplasia, genital discharge, vulvovaginitis, breast discomfort, fungal infection, nipple pain.
Estrogen-dependent neoplasms: Endometrial cancer, breast cancer.
Investigations: Weight increase, abnormal cervical smear (the majority consisted of benign changes), changes in liver function parameters.
Central Nervous System Disorders: Dizziness, headache, migraine, depression, probable dementia.
Cardiovascular System Disorders: Venous thromboembolism (i.e., deep leg or pelvic venous thrombosis and pulmonary embolism), myocardial infarction, stroke/ischemic stroke.
Musculoskeletal Disorders: Arthralgia, myalgia.
Others: Visual disturbances, (including blurred vision), edema, thromboembolism.
Adverse reactions reported in association with estrogen-progesterone treatment: Estrogen-dependent neoplasms both benign and malignant (i.e., endometrial cancer), venous thromboembolism (deep leg or pelvic venous thrombosis and pulmonary embolism) is more frequent among HRT users than among non-users (see Contraindications and Precautions), myocardial infarction, gall bladder disease, skin and subcutaneous disorders (i.e., chloasma, erythema multiforme, erthema nodosum, vascular purpura), and probable dementia.

Tibolone may enhance the blood fibrinolytic activity of anticoagulants such as warfarin. Use with caution during concomitant use especially when starting or stopping concurrent tibolone treatment.
In vivo, the pharmacokinetics of midazolam (cytochrome P450 3A4 substrate) may be affected to a moderate extent and therefore drug interactions with other CYP3A substrates may be expected. However, the clinical relevance is dependent on the pharmacological and pharmacokinetic properties of the substrate involved.
The metabolism of tibolone may be enhanced and its activity reduced by compounds that induce liver enzymes (e.g., phenytoin, carbamazepine and rifampicin).

Store at temperatures not exceeding 30°C.

Oestrogens, Progesterones & Related Synthetic Drugs

G03CX01 - tibolone ; Belongs to the class of other estrogens. Used in the treatment of menopausal symptoms.

Rx