Saidala 24: Tibolone

Generic Name: Tibolone
Brand Names: Livial®, Tibofem®, Ladybon®, Tibella® among others
Drug Class: Tissue-selective synthetic steroid; with estrogenic, progestogenic, and androgenic activity
Dosage Form: 2.5 mg oral tablets
Route of Administration: Oral, once daily
Therapeutic Use: Management of menopausal symptoms, prevention of postmenopausal osteoporosis, and treatment of endometriosis

Tibolone is a synthetic steroid prodrug that is rapidly converted into active metabolites with estrogenic, progestogenic, and androgenic activity. It is used primarily in postmenopausal women to relieve vasomotor symptoms (such as hot flushes), improve vaginal atrophy, support bone density, and enhance libido and mood. Due to its complex mechanism, tibolone exhibits tissue-selective effects and is often categorized as a "selective tissue estrogenic activity regulator" (STEAR) or "tissue-selective estrogen progestin androgen regulator" (SPEAR).

2. Indications and Therapeutic Uses

Vasomotor Symptoms of Menopause: relief of moderate to severe hot flashes and night sweats in postmenopausal women.
Vaginal Atrophy / Urogenital Symptoms: improvement of vaginal dryness, dyspareunia, and urinary urgency.
Prevention of Postmenopausal Osteoporosis: provides beneficial effects on bone mineral density and reduces fracture risk.
Endometriosis (off-label in some regions): relief of endometriotic pain and lesions through hormonal suppression.

3. Dosage and Administration

3.1 Standard Regimen

2.5 mg oral tablet taken once daily, swallowed whole with water.
Can be taken with or without food, preferably at the same time each day.

3.2 Initiation Guidelines

Natural menopause: commence therapy 12 months or more after last menstrual period.
Surgical menopause or women on GnRH analogues: therapy may begin immediately.
Switching from other HRT regimens:
- After sequential combined HRT: start medial dose the day after completing prior cycle.
- After continuous-combined HRT: may initiate at any time in treatment cycle.

3.3 Duration of Use

Common treatment duration ranges from 2 to 5 years, sometimes longer if symptoms persist and risk profile allows.
Decision to continue beyond 5 years should involve individualized risk–benefit assessment.

3.4 Missed Dose

If missed and less than 12 hours have elapsed, take immediately.
If over 12 hours late, skip dose and resume next day.
Do not double dose. Missing doses may increase risk of breakthrough bleeding or spotting.

4. Mechanism of Action and Pharmacology

4.1 Pharmacodynamics – Metabolism & Receptor Activity

Tibolone itself is pharmacologically inactive. It is converted in the liver and gastrointestinal tract into three primary active metabolites:
- 3α‑hydroxytibolone and 3β‑hydroxytibolone: potent estrogen receptor agonists, particularly selective for ERα; mediate beneficial effects on hot flashes, bone, and urogenital tissues.
- Δ⁴‑tibolone: functions as a progesterone and androgen receptor agonist, exerting progestogenic activity in the uterus and androgenic effects systemically.
These metabolites exhibit tissue-selective activity, with estrogenic action evident in bone, brain, and vagina, while progestogenic/androgenic activity counters estrogenic stimulation in endometrium and breast.
Relative receptor affinities: Δ⁴‑tibolone has strong affinity for progesterone receptors (~90% of promegestone) but exerts weak progestogenic potency (~13% of norethisterone). Androgenic activity is significant via Δ⁴‑tibolone (~35% of metribolone affinity), more than most progestins.

4.2 Pharmacokinetics

Bioavailability: ~92% following oral administration.
Protein binding: ~96.3% to plasma proteins (mainly albumin).
Time to peak levels: ~1–2 hours post-dose.
Half-life: Approximate elimination half-life of 45 hours for tibolone and its metabolites collectively.
Excretion: ~40% via urine and ~60% via feces, primarily as metabolites.

5. Clinical Efficacy

5.1 Vasomotor and Genital Symptoms

Tibolone 2.5 mg daily significantly reduces frequency and severity of hot flashes within 4 weeks, continuing through 12 weeks, compared to placebo.
Improvement in vaginal maturation index and reduction in urinary symptoms also demonstrated by week 4.
Lower dose (1.25 mg) provides similar efficacy over longer time, with possible earlier benefits in sexual function.

5.2 Bone Mineral Density and Osteoporosis Prevention

Daily tibolone 2.5 mg increases bone mineral density at spine and femoral neck, significantly reducing fracture risk in older postmenopausal women.
Also associated with reduced risk of breast and possibly colon cancer in select trials, though stroke risk may increase in older populations.

6. Contraindications

Known or suspected estrogen- or progestin-dependent malignancy, e.g., breast or endometrial cancer.
Undiagnosed abnormal vaginal bleeding or untreated endometrial hyperplasia.
Active or previous history of arterial thromboembolic events (e.g., stroke, myocardial infarction), coronary artery disease, or transient ischemic attack.
Venous thromboembolism history or known thrombophilia (e.g., protein C/S deficiency).
Severe hepatic impairment or active liver disease.
Hypersensitivity to tibolone or any excipient.
Known pregnancy or breastfeeding.

7. Warnings and Precautions

7.1 Cardiovascular and Cerebrovascular Risks

Increased risk of stroke (OR ~1.74) and other cardiovascular events (OR ~1.38), particularly in women over age 60.
Does not significantly increase venous thromboembolism risk, unlike many estrogen-progestogen combinations.
Increased risk of ischemic heart disease and stroke comparable to continuous combined oral HRT.

7.2 Breast and Endometrial Cancer

Increased risk of endometrial cancer (~doubling, OR ~2.04) particularly in women with intact uterus.
Breast cancer risk is elevated in women with previous history (OR ~1.5), though not in those without such history.
Vaginal bleeding or spotting must prompt evaluation before or during therapy.

7.3 Androgenic Side Effects

Acne, oily skin, and increased facial or body hair reported in about 3–6% of users due to androgenic activity.
Libido and mood often improve, especially in women with low sexual desire.

7.4 Other Precautions

Monitor liver function in women with hepatic disease.
May reduce sex hormone-binding globulin (SHBG) by ~50%, modify lipid profile (reduce triglycerides and HDL modestly).
Not recommended in women with undiagnosed vaginal bleeding.
Limited experience in women aged ≥65 years; cautious use advised.

8. Adverse Effects

8.1 Common (>10%)

Vaginal bleeding or spotting (unscheduled), especially in early months.
Breast tenderness, pelvic pain, abdominal cramps.
Headache, nausea.
Weight changes, fluid retention.
Mood swings; mixed effects on libido.

8.2 Less Common (3–6%)

Androgenic effects: acne, increased facial hair (hirsutism).
Arthralgia, myalgia.
Edema.

8.3 Rare / Serious

Stroke, myocardial infarction in predisposed individuals.
Endometrial or breast cancer in long-term users.
Gallbladder disease, cholestatic jaundice in susceptible women.

9. Drug Interactions

Enzyme-inducing drugs (e.g. carbamazepine, rifampicin, phenytoin, phenobarbital): may accelerate metabolism, reducing therapeutic effect.
Concomitant progestogens should not be added, as tibolone itself provides progestogenic activity.
Estrogen receptor modulators, anticoagulants, and lipid-altering therapies: use with caution and tailored monitoring.
No well-established pharmacokinetic interactions with other common medications, but theoretical interactions exist via CYP enzymes and hormonal modulation.

10. Use in Specific Populations

10.1 Age Groups and Menopausal Status

Natural menopause (>1 year): can initiate therapy following 12 months amenorrhea.
Surgical menopause or GnRH-induced menopause: can begin immediately.
Elderly women (≥65 years): limited data; caution due to increased risk of stroke and cardiovascular events. No dose adjustment.

10.2 Hepatic and Renal Function

Severe hepatic impairment is a contraindication.
Renal impairment: no formal dose adjustment, but metabolites excreted partly renally; monitor as needed.

10.3 Pregnancy and Breastfeeding

Contraindicated in pregnancy.
Use not recommended during breastfeeding due to potential exposure to neonate.

10.4 Pediatric Use

Not indicated for use in children or adolescents.

11. Monitoring and Follow‑Up

Baseline and periodic endometrial evaluation (via ultrasound or biopsy) in women with uterus if bleeding occurs.
Baseline mammography and breast examination, then per routine screening guidelines.
Monitor blood pressure, lipid profile, and liver function periodically.
Assessment of fracture risk and bone mineral density if used for osteoporosis prevention.
Monitor for stroke symptoms, cardiovascular events, and new hormone-sensitive malignancies.
Vigilance for androgenic symptoms and patient comfort with changes.

12. Overdose and Withdrawal

12.1 Overdose

Accidental single extra dose is generally well tolerated.
No specific antidote; supportive management of symptoms as needed.

12.2 Withdrawal / Cessation

Cessation may lead to recurrence of menopausal symptoms (hot flashes, vaginal dryness).
No requirement for tapering, but abrupt discontinuation may lead to symptom rebound.
Clinicians may switch to alternative HRT if needed.

13. Storage and Handling

Store tablets at room temperature (15–25 °C).
Protect from excessive moisture and light.
Keep tablets in original packaging until use.
Keep out of reach of children.
Do not crush or chew tablets.

14. Clinical Considerations

Tibolone offers a combined vasomotor, urogenital, bone-protective, and sexual function benefit, attributed to its estrogenic and androgenic metabolites.
Its once-daily oral dosing makes adherence easier than more complex regimens.
Tissue-selective activity may reduce some risks present in traditional estrogen‑progestogen combinations, though endometrial and breast cancer risk remains increased in select populations.
Stroke and cardiovascular risk may limit use in older women or those with underlying conditions.
Women with intact uterus do not require additional progestogens with tibolone, due to its intrinsic progestogenic activity. However, uterine surveillance remains necessary.
Improved libido and mood compared to conventional HRT are notable benefits in many users.
Overall risk–benefit assessment must consider age, menopausal status, comorbidities, cancer history, and cardiovascular or thromboembolic risk before initiation and during therapy.

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Monday, July 28, 2025

Tibolone