Tibolone
Tibolone Uses, Dosage, Side Effects, Food Interaction and all others data.
Tibolone is a synthetic steroid that has estrogenic, androgenic and progestagenic properties. After oral administration, Tibolone is rapidly metabolized into three compounds which contribute to the pharmacological effects of Tibolone. Two of these metabolites (the 3α−OH and 3β−OH metabolite) have predominantly estrogenic activity; a third metabolite (δ4-isomer of Tibolone) and the parent compound have predominantly progestagenic and androgenic activities. Tibolone substitutes for the loss of estrogen production in postmenopausal women and alleviates menopausal symptoms. It prevents bone loss following menopause or ovariectomy. It has estrogenic effects on the vagina, on bone and on the thermoregulatory centers in the brain (hot flushes). It improves vaginal dryness and vaginal atrophy. Tibolone has also effects on mood and libido.
Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma . The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator .
Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety .
| Trade Name | Tibolone |
| Generic | Tibolone |
| Tibolone Other Names | tibolona, Tibolone, tibolonum |
| Type | |
| Formula | C21H28O2 |
| Weight | Average: 312.453 Monoisotopic: 312.208930142 |
| Groups | Approved, Investigational |
| Therapeutic Class | Drugs for menopausal symptoms: Hormone replacement therapy |
| Manufacturer | ADVANZ Pharma |
| Available Country | United Kingdom |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Treatment of symptoms resulting from the natural or surgical menopause in post menopausal women. Prevention of osteoporosis in women who have gone through the menopause and are at high risk of fractures, but cannot take other medicines used to prevent osteoporosis.
Tibolone is also used to associated treatment for these conditions: Vasomotor Symptoms Associated With Menopause
How Tibolone works
This drug's effects are owed to the activity of its metabolites in various tissues .
Upon ingestion, 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. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body.
The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II. The combined effects of this process prevent the conversion to active estrogens.
In the uterus, the progestogenic activity of the Delta(4)-metabolite and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner .
Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences.
The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process.
In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway .
The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the Δ4-isomer functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2 .
Dosage
Tibolone dosage
Treatment of symptoms resulting from the natural or surgical menopause: The recommended dose is 2.50 mg once daily.
Prevention of post-menopausal bone mineral density loss: The recommended dose is 2.50 mg once daily.
Improvement of symptoms generally occurs within a few weeks, but optimal results are obtained when therapy is continued for at least 3 months. Review should be needed for continuation of treatment after 6 months, taking into account the risk-benefit ratio for the individual user at that moment.
Starting Tibolone: Women experiencing a natural menopause should commence treatment with Tibolone at least 12 months after their last natural bleed. In case of a surgical menopause,treatment with Tibolone may commence immediately.
Switching from combined or oestrogen only hormone replacement therapy (HRT): In women with a uterus who change from an oestrogen-only preparation, a withdrawal bleed should be induced before starting Tibolone. If changing from a sequential HRT preparation, treatment with Tibolone should be started after the progestagen phase has been completed. If changing from a continuous-combined HRT preparation, treatment can be started at any time. If abnormal vaginal bleeding is the reason for switching from combined HRT, it is advised to investigate the cause of bleeding before starting Tibolone.
Missed tablets: 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.
As for all steroids with hormonal activity, yearly medical examination particularly of the breasts and pelvic areas is advisable. A review should be needed for continuation of treatment after 6 months.
Side Effects
Gastrointestinal disorders like abdominal pain,skin and subcutaneous tissue disorders like abnormal hair growth, acne, reproductive system and breast disorders like vaginal discharge, endometrial hypertrophy, postmenopausal haemorrhage, breast tenderness, genital pruritus, vaginal candidiasis, cervical dysplasia etc.
Toxicity
>2000 mg/kg
The Million Women Study (MWS), which had a prospective observational design, studied the use of hormone replacement therapy. The results indicated that the increase in the incidence of breast cancer with estrogen and progestogen (compared to estrogen alone) was greater than the reduction in occurrence of endometrial cancer associated with adding progestogen to estrogen therapy. The MWS also reported a marked increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations .
Tibolone treatment in rodent studies showed an increased association with the development of a range of tumors in long-term oral carcinogenicity studies. These tumors included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes. Tibolone failed to show any evidence of genotoxicity in studies for gene mutations, chromosomal damage as well as DNA damage .
Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine [L1728].
Precaution
- Leiomyoma (uterine fibroids) or endometriosis
- A history of, or risk factors for,thromboembolic disorders
- Risk factors for oestrogen dependent tumors, e.g. 1st degree heredity for breast cancer
- Hypertension
- Liver disorders (e.g. liver adenoma)
- Diabetes mellitus with or without vascular involvement
- Cholelithiasis
- Migraine or (severe) headache
- Systemic lupus erythematosis
- A history of endometrial hyperplasia
- Epilepsy
- Asthma
- Osteosclerosi
Reasons for Immediate Withdrawal of Therapy
: Therapy should be discontinued 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
Interaction
Since Tibolone may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants. This effect has been demonstrated with warfarin. Therefore, the simultaneous use of Tibolone and warfarin should be monitored, especially when starting or stopping concurrent Tibolone treatment, and the warfarin dose should be appropriately adjusted.
Food Interaction
- Avoid St. John's Wort. St. John's Wort induces CYP3A4, increasing the metabolism of estrogens and progesterone and therefore reducing the efficacy of tibolone.
- Take with or without food.
Elimination Route
Tibolone is extensively and rapidly absorbed after oral administration . The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug .
Half Life
The elimination half-life is approximately 45 h .
Clearance
Elimination of tibolone is not dependent renal function .
Elimination Route
Excreted in the urine and feces in the form of sulfated metabolites , .
The predominant route of elimination of tibolone is via the feces, although some excretion occurs via the urine .
Pregnancy & Breastfeeding use
USFDA pregnancy category D. Tibolone is contraindicated in lactating women
Contraindication
- Pregnancy and lactation
- Known past or suspected breast cancer
- Known or suspected estrogen dependent malignant tumours (e.g. endometrial cancer)
- Undiagnosed genital bleeding
- Untreated endometrial hyperplasia
- Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
- Any history of arterial thromboembolic disease (e.g. angina, myocardial infarction,stroke or TIA)
- Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal.
- Known hypersensitivity to the active substance or any of the excipients
- Porphyria
Acute Overdose
The acute toxicity of Tibolone in animals is very low. Therefore, toxic symptoms are not expected to occur if several tablets are taken simultaneously. In cases of acute overdose - nausea, vomiting, and withdrawal bleeding in females may develop. Symptomatic treatment can be given if necessary
Storage Condition
Store in a dry & cool place, protected from light & moisture
Innovators Monograph
You find simplified version here Tibolone
Tibolone contains Tibolone see full prescribing information from innovator Tibolone Monograph, Tibolone MSDS, Tibolone FDA label
FAQ
What is Tibolone used for?
Tibolone helps to restore the balance of female hormones in women who have a lack of oestrogen; It helps to ease symptoms such as hot flushes and night sweats. You will only be prescribed it if these symptoms seriously interfere with your daily life.
How safe is Tibolone?
Tibolone is associated with a small increased risk of both stroke and endometrial cancer. It may also be associated with an increased risk of breast cancer.
What are the common side effect of Tibolone?
The common side effect of Tibolone are include:headache, dizziness, nausea, abdominal pain, swollen feet and itching. Breast tenderness is uncommon. Slight bleeding or spotting may commonly occur initially but tends to subside after a few months.
Is Tibolone safe during pregnancy?
Tibolone is contraindicated during pregnancy.If pregnancy occurs during medication with Tibolone, treatment should be withdrawn immediately.
What are the benefits of Tibolone?
Benefits of Tibolone has positive effects on sexual well-being and mood, and improves dyspareunia and libido.
Does Tibolone cause breast cancer?
Tibolone increases the risk of recurrent breast cancer in women with a history of breast cancer, and may increase the risk of stroke in women over 60 years of age.
What is the best time of day to take Tibolone?
You may take Tibolone at whatever time of day you find easiest to remember, but try to take your doses at the same time of day, each day. You can take the tablets before or after meals. You may find it helps to swallow the tablet with a drink of water.
How long can Tibolone be used?
Evidence shows that taking Tibolone increases the risk of breast cancer. The extra risk depends on how long you use Tibolone. but the risk may persist for 10 years or more when women have used HRT for more than 5 years.
Does Tibolone stop periods?
If a woman starts taking it at least 1 year after the periods have stopped, she should not get any monthly periods.
Can Tibolone cause high blood pressure?
Tibolone has no deleterious effect on blood pressure in women with hypertension but has contrasting effects on biochemical risk factors.
Does Tibolone affect the liver?
The severity of liver injury due to tibolone has varied from mild, transient serum enzyme elevations to moderately severe acute hepatitis. No instances of acute liver failure, death, or chronic hepatitis have been linked to Tibolone use.
What type of steroid is Tibolone?
Tibolone is a synthetic steroid with weak estrogenic.
Can Tibolone make I bleed?
A minority of women will bleed on Tibolone therapy.
When does Tibolone start working?
It usually takes start working a few weeks before you will feel the initial benefits of HRT and up to three months to feel the full effects.
How long should I take Tibolone?
Tibolone should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and Tibolone should only be continued as long as the benefit outweighs the risk.
Can I take Tibolone long term?
No evidence indicates that Tibolone increases the risk of other long-term adverse events.
Is Tibolone safe during breastfeeding?
Tibolone is contraindicated during breastfeeding?
What happen If I missed Tibolone?
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.
Can I overdose on Tibolone?
The acute toxicity of Tibolone in animals is very low. Therefore, toxic symptoms are not expected to occur, even when several tablets are taken simultaneously. In cases of acute overdose, nausea, vomiting and vaginal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary.
