Product InformationRegistration Status: Active
LIVIAL TABLET 2.5mg is approved to be sold in Singapore with effective from 1991-02-18. It is marketed by MSD PHARMA (SINGAPORE) PTE LTD, with the registration number of SIN05423P.
This product contains Tibolone 2.5mg in the form of TABLET. It is approved for ORAL use.
This product is manufactured by N V ORGANON in NETHERLANDS.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Tibolone is a synthetic steroid hormone drug, which is mainly non-selective in its binding profile, acting as an agonist primarily at estrogen receptors (ER), with a preference for ER alpha [L1874]. Tibolone (Livial, Org OD 14), produced by Organon (West Orange, NJ), is a synthetic steroid that possesses estrogenic, androgenic and progestogenic properties. It has been used in Europe for almost 2 decades, primarily for the prevention of postmenopausal osteoporosis and the treatment of post-menopausal symptoms [L1720]. Tibolone is approved in 90 countries to manage menopausal symptoms and in 45 countries to prevent the development of osteoporosis [L1876]. In June 2006, Organon Pharmaceuticals announced the receipt of a Not Approvable Letter from the U.S. Food and Drug Administration (FDA), advising the company that the New Drug Application (NDA) for tibolone had not been approved [L1722]. Interestingly, the use of tibolone in the treatment cardiovascular disease has been studied with inconclusive results [A32164]. Tibolone has been to have anti-resorptive effects on bone [L1874].
For the relief of post-menopausal symptoms and for the prevention of osteoporosis [L1724].
Mechanism of Action
This drug's effects are owed to the activity of its metabolites in various tissues [L1720]. 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 [A32164]. 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 [A32150]. 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 [L1720].
- Tibolone is extensively and rapidly absorbed after oral administration [L1879]. 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 [L1879].
- Tibolone is metabolized mainly in the liver [L1720]. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone [L1879]. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form [A32150].
Elimination of tibolone is not dependent renal function [L1879].
>2000 mg/kg [MSDS] 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 [L1723]. 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 [L1727]. Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine [L1728].
17-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one | tibolona | tibolonum | Tibolone |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.