Dosing and Administration

Q10: What is the optimal dose for Circadin®? Will Circadin® be available at different dosages in the future?
A10: Circadin® dose-ranging studies indicated that a 2 mg dose of Circadin® would provide a beneficial effect in insomnia patients aged 55 years or over(Ref. 1).

Q11: What happens if I take a higher dose than Circadin® 2 mg?
A11: In clinical trials over 12 months, Circadin® has been administered at 5 mg daily doses without significantly changing the nature of the adverse reactions reported(Ref. 2). There are reports in the literature of the administration of daily doses of up to 300 mg melatonin without causing clinically significant adverse reactions(Ref. 2). No case of Circadin® overdose has been reported(Ref. 2). If overdose of Circadin® occurs, drowsiness is to be expected(Ref. 2) Clearance of the active substance is expected within 12 hours of ingestion(Ref. 2). No special treatment is required(Ref. 2).

Q12: Is the prolonged-release formulation really needed? What about fast/immediate-release melatonin?
A12: Under normal circumstances, physiological melatonin has a very short half-life, but full-night melatonin levels are ensured via the continued production and release of melatonin throughout the night. With the onset of darkness, melatonin levels increase, are sustained during sleep, and fall off again at the end of the sleeping period, thus melatonin acts as a signal for the entire night. Exogenous (fast/immediate-release) melatonin – unless modified in a prolonged-release formulation such as Circadin® – will not provide continuous melatonin throughout the night(Ref. 3). Immediate-release melatonin reaches maximum levels shortly after being taken at the beginning of the night and, due to the very short half-life(Ref. 4), melatonin levels will diminish within a short period thereafter. Thus, in the later part of the night, immediate-release melatonin will already have been cleared from the body. Further, there has been no thorough clinical development programme to demonstrate the effects of immediate-release formulations of melatonin on quality of sleep, morning alertness and quality of life. Circadin®, the prolonged-release formulation of melatonin, circumvents the fast clearance of the hormone and provides a melatonin profile in the blood more closely matched to normal physiological release(Ref. 5).

Q13: Why can’t I take Circadin® together with alcohol? How long do you have to wait between dinner with a couple of glasses of wine and intake of Circadin®?
A13: The effect of alcohol on Circadin® has not been formally studied. Data from the literature indicate that alcohol directly inhibits pineal gland function (endogenous secretion of melatonin)(Ref. 6). It is recommended that alcohol should not be taken with Circadin. because it reduces the effectiveness of Circadin on sleep(Ref. 2). As alcohol is cleared from the body at a rate of approximately one unit per hour, one unit of alcohol (e.g., a glass of wine) taken at 6 pm should, theoretically, have been cleared from the body and therefore would not be able to interact with Circadin® taken at 9 pm. However, metabolism differs between individuals and a firm recommendation on time of alcohol intake prior to Circadin® cannot be made. However, although the efficacy of Circadin®, if taken with alcohol, might be diminished, there is no safety concern resulting from the interaction with Circadin® and alcohol. In particular, there is no CNS-depressant effect such as that resulting from the interaction of Circadin® with the BZDs(Ref. 2).

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References

1. EPAR, Assessment Report for Circadin. Procedure No. EMEA/H/C/695. 2007.

2. Circadin® 2 mg prolonged-release tablets. Summary of product characteristics. 2008.

3. Zisapel N. Development of a melatonin-based formulation for the treatment of insomnia in the elderly. Drug Devel Res 2000; 50: 226- 234.

4. DeMuro RL, Nafziger AN, Blask DE, et al. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000; 40 (7): 781-784.

5. Wade A, Zisapel N, Lemoine P. Prolonged-release melatonin for the treatment of insomnia: targeting quality of sleep and morning alertness. Aging Health 2008; 4 (1): 11-21.

6. Schmitz MM, Sepandj A, Pichler PM, Rudas S. Disrupted melatonin-secretion during alcohol withdrawal. Prog Neuropsychopharmacol Biol Psychiatry 1996; 20 (6): 983-995.