1. Clinical Overview
A fixed-dose combination of a selective estrogen receptor modulator (SERM) and a pineal gland hormone. Clomiphene citrate is a non-steroidal agent that stimulates ovulation by blocking estrogen receptors at the hypothalamus and pituitary, increasing gonadotropin secretion. Melatonin is a chronobiotic agent that regulates the sleep-wake cycle and has antioxidant properties. In the context of female infertility, this combination is theorized to potentially improve ovulation induction outcomes by modulating circadian rhythms and reducing oxidative stress, though robust clinical evidence for the combination is limited and it is not a standard first-line therapy.
| Onset | Duration | Bioavailability |
|---|---|---|
| Clomiphene: Ovulation typically occurs 5-10 days after the last dose of a course. Melatonin: Sleep-inducing effects within 30-60 minutes. | Clomiphene: The pharmacodynamic effect on gonadotropin secretion lasts for the duration of the treatment cycle. Melatonin: Plasma half-life is short (30-60 minutes), but its phase-shifting effects on circadian rhythms are longer-lasting. | Clomiphene: Approximately 80-90% orally. Melatonin: Highly variable (10-56%) due to extensive first-pass metabolism; bioavailability is not dose-proportional. |
2. Mechanism of Action
Clomiphene competitively blocks estrogen receptors (ERs) at the level of the hypothalamus and pituitary, decreasing negative feedback. This leads to increased pulsatile secretion of GnRH, followed by increased secretion of pituitary gonadotropins (FSH and LH). The rise in FSH stimulates follicular growth and development. Melatonin, primarily secreted by the pineal gland, acts on MT1 and MT2 receptors in the suprachiasmatic nucleus to synchronize the circadian clock. In the ovary, melatonin receptors are present on granulosa cells. It is a potent antioxidant, scavenging free radicals and upregulating antioxidant enzymes like glutathione peroxidase, potentially protecting developing ovarian follicles from oxidative stress, which is implicated in poor oocyte quality and anovulation.
3. Indications & Uses
- Ovulation induction in anovulatory or oligo-ovulatory women with Polycystic Ovary Syndrome (PCOS) seeking pregnancy
- Management of ovulatory dysfunction associated with infertility
4. Dosage & Administration
Adult Dosage: One tablet (Clomiphene 50mg + Melatonin 3mg) orally once daily, usually at bedtime. For ovulation induction: Treatment starts on day 2, 3, 4, or 5 of the menstrual cycle (spontaneous or induced) for 5 consecutive days. Dosage of clomiphene may be increased in subsequent cycles (e.g., 100mg) if no response, but the fixed-dose combination limits this titration. Melatonin dose is fixed.
Administration: Take tablet at bedtime with a glass of water, with or without food. For ovulation induction, strictly follow the day cycle prescribed by the gynecologist. Avoid taking melatonin during daytime. Do not crush or chew.
5. Side Effects
Common side effects may include:
- Hot flushes (10-20%)
- Abdominal discomfort/bloating
- Nausea
- Headache
- Breast tenderness
- Drowsiness/sedation (melatonin effect)
- Dizziness
- Visual disturbances (blurring, spots, flashes)
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| CYP2C9 Inhibitors (e.g., Fluconazole, Amiodarone) | Increased clomiphene levels, risk of toxicity | Moderate |
| CYP3A4 Inducers (e.g., Rifampicin, Carbamazepine) | Decreased clomiphene efficacy | Moderate |
| CYP1A2 Inhibitors (e.g., Fluvoxamine, Ciprofloxacin) | Increased melatonin levels, enhanced sedation | Moderate |
| Other CNS Depressants (e.g., Benzodiazepines, Opioids, Alcohol) | Additive sedation and impaired motor coordination | Major |
| Anticoagulants (e.g., Warfarin) | Melatonin may increase INR; monitor closely | Moderate |
| Immunosuppressants (e.g., Cyclosporine) | Melatonin may antagonize immunosuppressive effect | Moderate |
| Antidiabetic Drugs | Melatonin may impair glucose tolerance; monitor blood sugar | Moderate |
| Oral Contraceptives/HRT | May interfere with clomiphene's action | Major |
7. Patient Counselling
- DO take the tablet exactly as prescribed, usually at bedtime for 5 days in your cycle.
- DO keep a menstrual cycle diary and track basal body temperature if advised.
- DO attend all scheduled ultrasound monitoring appointments for follicular tracking.
- DO inform your doctor immediately if you experience blurred vision, severe abdominal pain, or shortness of breath.
- DONT take the medicine if you are pregnant or suspect pregnancy.
- DONT consume alcohol while on this medication.
- DONT drive or operate heavy machinery if you feel drowsy.
- DONT take any other sleep aids, supplements, or herbal products without consulting your doctor.
8. Toxicology & Storage
Overdose: Clomiphene: Severe nausea, vomiting, vasomotor flushes, visual disturbances, ovarian enlargement, abdominal pain. Melatonin: Extended drowsiness, confusion, disorientation, headache, ataxia. Combined: Exaggeration of all above effects.
Storage: Store below 30°C in a cool, dry place, protected from light and moisture. Keep out of reach of children. Do not use after the expiry date printed on the pack.