Safety

Q19: What are the risks connected to Circadin® administration?
A19: It is important to understand that adverse events (AEs) are reported regardless of any perceived relationship to drug treatment. In the overall clinical development programme, which included long term open-label studies, patients were treated for longer periods with Circadin® than with placebo. Due to this fact, the AE rates have been measured in patient weeks to allow for a direct comparison between Circadin® and placebo. As measured by the rate of patients with AEs per 100 patient weeks in clinical trials, the AE rate was lower in patients treated with Circadin® than those receiving placebo (3.17 for Circadin® versus 8.21 for placebo)(Ref. 1). The most commonly observed AEs were headache, pharyngitis, back pain, and asthenia, listed as common by MedDRA definition (i.e., with a frequency of =1/100 to < 1/10)(Ref. 1), In both the Circadin®- and placebo-treated groups(Ref. 2). It is very rare that active treatment demonstrates a lower rate of AEs than placebo, but may be explained by the fact that untreated insomnia (placebo group) is associated with many 'adverse events'.

Q20: Is Circadin® contraindicated in any patients?
A20: Circadin® is contraindicated in patients with hypersensitivity to the active substance (melatonin) or to any of the excipients(Ref. 1) It should be remembered that no clinical data exist on the use of Circadin® during pregnancy. Although animal data do not indicate harmful effects, use during pregnancy or lactation is not recommended (for more information, see the Circadin® SPC).

Q21: Can Circadin® be used in patients with hepatic or renal impairment?
A21: There is no experience of the use of Circadin® in patients with liver impairment(Ref. 1). The metabolism of melatonin is reduced in people with hepatic impairment and these individuals demonstrate markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance(Ref. 1). Therefore, Circadin® is not recommended for use in patients with hepatic impairment(Ref. 1).
The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied(Ref. 1). Caution should be used when melatonin is administered to such patients(Ref. 1).

Q22: Can Circadin® be taken with SSRIs or other antidepressants?
A22: Circadin® is mainly metabolised by hepatic enzymes CYP1A1, CYP1A2, and possibly CYP2C19, which is thought to be less important(Ref. 1, Ref. 2). Other drugs that are metabolised by these enzymes may interfere with the metabolism of Circadin®, and vice versa. The SSRI fluvoxamine inhibits CYP1A2, thereby inhibiting Circadin® metabolism and raising melatonin levels(Ref. 1). Therefore, this combination should be avoided(Ref. 1). Escitalopram and citalopram are metabolised by CYP2C19(Ref. 3, Ref. 4). An interaction with Circadin®, in which either drug level may be raised, is hypothetical but cannot be ruled out. In one study patients were administered 20 mg of fluoxetine and 5 mg Circadin and ” No particular side effects were noted from the combination of fluoxetine and slow release melatonin” (Dolberg et al, Am J Psychiatry 1998).

Q23: Can Circadin® be used in patients with diabetes?
A23: Two long-term studies of 5 months and 6 months were conducted in diabetic type II patients suffering from insomnia (NEU 951005; NEU 951005a). No safety concerns were found with Circadin upon long-term treatment (6-months) in diabetes type II patients. Moreover, a decrease in HbA1C level vs. baseline was found(Ref. 2).  

Q24: Can children take Circadin®?
A24: Circadin® is the first fully developed melatonin product authorised by the regulatory authorities, but it is not indicated for use in children(Ref. 1). No other melatonin formulations have been approved for use in children in the EU or elsewhere in the world.

In spite of this, melatonin products – both immediate-release and Circadin® – have been used in the clinical setting to treat sleep–wake cycle disorders in children with underlying neuro-developmental difficulties(Ref. 6, Ref. 7, Ref. 8, Ref. 9, Ref. 10).

Several published studies have investigated the use of Circadin® and immediate-release melatonin in children(Ref. 9, Ref. 10, Ref. 11). Despite the various underlying disorders of the children, and the concomitant use of several other drugs, most studies are positive, with parents reporting improved sleep and health of the children, and very few AEs(Ref. 9, Ref. 10, Ref. 11).

Currently, a so-called ‘compassionate use’ programme for Circadin® in children is ongoing in France, Norway, Iceland and Finland.

In summary, no melatonin product is indicated in children, but melatonin products are still widely used clinically in the treatment of neuro-developmental sleep–wake cycle disorders. As the only pharmaceutical grade melatonin product, Circadin® is a well studied and safe source of melatonin, compared to other, uncontrolled melatonin products.

Q25: Why is there a red triangle on the package if Circadin® doesn’t cause a next-day residual sedative effect, e.g., it has no effect on vigilance, etc?
A25: In some countries, the red triangle is a regulatory requirement to be put on the labelling of all sleep medicines as a warning that the drug should not be used while the patient is driving a car, or using other machinery, because of its sedative effects(Ref. 12).

Q26: What happens if the patient takes Circadin® on an empty stomach?
A26: The release of melatonin from Circadin® is more rapid if the tablet is taken on an empty stomach(Ref. 12).

Q27: What happens if Circadin® is taken in the morning?
A27: If taken in the morning, Circadin® will likely make the individual feel sleepy or drowsy. Also, if taken regularly in the morning, Circadin® may shift the circadian rhythm. Apart from its soporific action effect, exogenous melatonin may affect sleep through its phase-resetting action on the biological clock. Melatonin administration advanced sleep in delayed-sleep phase syndrome patients and synchronised sleep to the day-night cycles in blind subjects(Ref. 13).
For the treatment of insomnia, patients should take Circadin® at night only(Ref. 1).

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References

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

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

3. Cipralex® film-coated tablets. Summary of product characteristics. January 2007.

4. Cipramil® tablets. Summary of product characteristics. February 2008.

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6. De Leersnyder H. Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment. Trends Endocrinol Metab 2006; 17 (7): 291–298.

7. De Leersnyder H, Claustrat B, Munnich A, Verloes A. Circadian rhythm disorder in a rare disease: Smith-Magenis syndrome. Mol Cell Endocrinol 2006; 252 (1–2): 88–91.

8. De Leersnyder H. Traitement par la mélatonine des troubles du sommeil de l’enfant. Arch Pédiatr 2002; 9 (Suppl. 2): 190–191.

9. Giannotti F, Cortesi F, Cerquiglini A, Bernabei P. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord 2006; 36 (6): 741–752.

10. Jan JE, Hamilton D, Seward N, et al. Clinical trials of controlled-release melatonin in children with sleep–wake cycle disorders. J Pineal Res 2000; 29 (1): 34–9.

11. Carr R, Wasdell MB, Hamilton D, et al. Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. J Pineal Res 2007; 43 (4): 351–359.

12. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/c/bluebox_02_2008.pdf

13. Sack RL, Lewy AJ, Blood ML, et al. Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms 1991; 6 (3): 249–261.