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21 X 2 mg
30 X 2 mg
The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food This dosage may be continued for up to thirteen weeks.
Paediatric use: The safety and efficacy of Circadin in children aged 0 to 18 years has not yet been established. No data are available.
Renal insufficiency: The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to such patients.
Hepatic impairment: There is no experience of the use of Circadin in patients with liver impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, Circadin is not recommended for use in patients with hepatic impairment.
Short-term treatment of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over.
Hypersensitivity to the active substance or to any of the excipients.
Circadin may cause drowsiness. Therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety. No clinical data exist concerning the use of Circadin in individuals with autoimmune diseases. Therefore Circadin is not recommended for use in patients with autoimmune diseases. Circadin contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and lactation: In view of the lack of clinical data, use in pregnant women and by women intending to become pregnant is not recommended. Breast-feeding is not recommended in women under treatment with melatonin.
Summary of the safety profile In clinical trials (in which a total of 1,931 patients were taking Circadin and 1,642 patients were taking placebo), 48.8% of patients receiving Circadin reported an adverse reaction compared with 37.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than Circadin (5.743 – placebo vs. 3.013 – Circadin). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the Circadin and placebo treated groups.
For full details see prescribing information.
Interaction studies have only been performed in adults. Pharmacokinetic interactions, Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations. The clinical relevance of the finding is unknown. If induction occurs, this can give rise to reduced plasma concentrations of concomitantly administered medicinal products. Melatonin does not induce CYP1A enzymes in vitro at supra-therapeutic concentrations. Therefore, interactions between melatonin and other active substances as a consequence of melatonin’s effect on CYP1A enzymes are not likely to be significant. Melatonin’s metabolism is mainly mediated by CYP1A enzymes. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes is possible. Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided. Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 and 8- MOP), which increases melatonin levels by inhibiting its metabolism. Caution should be exercised in patients on cimetidine a CYP2D inhibitor, which increases plasma melatonin levels, by inhibiting its metabolism. Cigarette smoking may decrease melatonin levels due to induction of CYP1A2. Caution should be exercised in patients on oestrogens (e.g. contraceptive or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2. CYP1A2 inhibitors such as quinolones may give rise to increased melatonin exposure. CYP1A2 inducers such as carbamazepine and rifampicin may give rise to reduced plasma concentrations of melatonin. There is a large amount of data in the literature regarding the effect of adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressant medicinal products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion. Whether or not these active substances interfere with the dynamic or kinetic effects of Circadin or vice versa has not been studied.
Pharmacodynamic interactions: Alcohol should not be taken with Circadin, because it reduces the effectiveness of Circadin on sleep. Circadin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Circadin and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone. Circadin has been co-administered in studies with thioridazine and imipramine, active substances which affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, Circadin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone.
Pregnancy and Lactation
Pregnancy: For melatonin, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. In view of the lack of clinical data, use in pregnant women and by women intended to become pregnant is not recommended.
Breastfeeding: Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probably secreted into human milk. There are data in animal models including rodents, sheep, bovine and primates that indicate maternal transfer of melatonin to the foetus via the placenta or in the milk. Therefore, breast-feeding is not recommended in women under treatment with melatonin.
No case of overdose has been reported. Circadin has been administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported. Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature. If overdose occurs, drowsiness is to be expected. Clearance of the active substance is expected within 12 hours after ingestion. No special treatment is required.