Other topics

Q29: The population sizes are very small
A29: Studies are planned according to the statistical power calculations. There is no justification to recruit more patients than the number that is expected to yield a positive statistical outcome. In four clinical studies, the number of patients treated with Circadin® was over 200; in one study, the number is over 400(Ref. 1). All-in-all, the total patient exposure in the Circadin® EMEA application consists of 1,361 patients from short-term studies; 373 patients who received the compound for 6 months and 146 patients who received Circadin® for one year or longer(Ref. 1). Together with 46 studies performed by independent investigators, the total number of patients receiving Circadin® in clinical studies is 1,972(Ref. 1). These numbers are compatible with standard clinical development in the field.

Q30: What is the longest Circadin® treatment duration in a clinical study?
A30: In the clinical study Neurim V, patients were treated open-label up to 12 months(Ref. 1). In the clinical study NEU 951003, patients were randomised to Circadin® or placebo for 6 months, and then continued on open-label Circadin® for up to 12 months(Ref. 1). For some patients, the total duration of treatment was therefore 18 months.

Q31: Does Circadin® also work in Jet-lag?
A31: Circadin® has been developed for insomnia, and has not been studied for jet lag. However, a Cochrane review (Herxheimer & Petrie, 2002) demonstrated a good effect of melatonin in treating the symptoms of jet lag(Ref. 2). One study (Suhner et al., 1998) found that a slow-release formulation of melatonin was less effective than immediate-release melatonin(Ref. 3).

In conclusion, Circadin®, like natural melatonin, affects the endogenous clock(Ref. 4). However, the effect of Circadin® on jet lag has not been studied.

Q32: Will Circadin® work on the first night?
A32: Onset of sleepiness occurs about 1–2 hours after taking Circadin®(Ref. 5), due to the sleep-promoting effect of melatonin. As Circadin efficacy is measured as improvement in quality, rahter than quantity of sleep, this improvement has not been measured on a day-to-day basis, but a baseline, and again after 3 weeks. This is similar to other disease areas, e.g., depression and hypertension, where full treatment effect is expected after days or weeks, as the body adjusts to the treatment. It is, therefore, recommended to take Circadin® at the same time every night, continuously for 21 days(Ref. 2).

It is important to realise that, while historically, the treatment of insomnia has involved achieving a rapid CNS suppressant effect by using CNS depressants such as BZDs or ‘z’-drugs, Circadin® represents a new paradigm in the treatment of insomnia, in which treatment of insomnia with poor quality of sleep must be approached with the same expectations of gradual improvement as many other diseases, and not a quick ‘knock out’ effect.

Q33: Why should Circadin® be taken for 21 days? Why not more than 21 days? Why not less than 21 days? How many 21-day Circadin® treatment courses could a person have in a year?
A33: Circadin® increases the level of melatonin, facilitating both sleep onset and good quality sleep(Ref. 8, Ref. 9). However, contrary to CNS-suppressant drugs (BZDs and ‘z’-drugs), and similar to treatment in other disease areas (e.g., depression), the effect on quality of sleep is expected to be higher after some days. Therefor, Circadin efficacy was measured at baseline, and again after 21 days. It is therefore recommended to take the 21 Circadin® tablets as a course, and not on an ‘as needed’ basis(Ref. 5). The prescribing information and the clinical data do not, at present, support treatment for longer use due to the fact the placebo-controlled phases of the Circadin® clinical studies have all been of 3 weeks duration(Ref. 8, Ref. 9, Ref.5). Similarly, BZD and ‘z’-drugs are indicated for 2–4 weeks. Long term, open-label studies with Circadin® have shown that there are no particular safety concerns associated with 6 and even 12 months of treatment(Ref. 1). After the 21-day course, the patient must be evaluated with regard to benefit of treatment and a continued need for medication. Treatment for more than 21 days – either continued or as repeated 3-week courses – is ultimately a decision to be made by the treating physician in consultation with the patient, taking into account the benefit of treatment and potential risk.

Q34: What happens when you stop Circadin® after 21 days? Will the insomnia come back again?
A34: Treatment with Circadin® for 21 days ensures a continued effect of Circadin® in this period. Circadin® is, however, a symptomatic treatment. After discontinuation of Circadin®, the beneficial effect remains for some time before sleep variables (time to sleep, quality of sleep, etc.) gradually return to pre-treatment levels(Ref. 1). Stopping Circadin® treatment does not cause rebound insomnia(Ref. 8, Ref. 1).

Q35: Does Circadin® contain any animal ingredients (can vegetarians take it)?
A35: Lactose monohydrate, utilised in the formulation of Circadin®, is of animal origin(Ref. 5, Ref. 1).

Q36: Why is Circadin® a prescription-only medicine? Why is Circadin® not available OTC, when other forms of melatonin are available on the Internet?
A36: Circadin® is the first fully developed melatonin-containing product to be licensed by the regulatory authorities. Circadin® has undergone preclinical toxicology evaluations, has a well defined pharmaceutical characterisation, and has been extensively studied with regard to clinical efficacy, safety and drug interactions(Ref. 1). Other melatonin products may be purchased on the Internet. However, as there is inadequate international legislation with respect to production and manufacturing of those products, they have not been adequately tested, their safety is not monitored, and the consumer has no guarantee of their contents. Therefore, as a new and approved medicinal product, Circadin® is a prescription-only medicine (POM) due to regulatory requirements.

Q37: Primary insomnia doesn’t really exist, does it? Isn’t insomnia always secondary to something else?
A37: It is common to assume that insomnia is a symptom of, or secondary to, other causes. Often this is the case, and proper treatment is then based on identifying the underlying cause. Primary insomnia does indeed exist, however, and is defined in ICD-10 and DSM-IV as sleeplessness that is not attributable to a medical, psychiatric or environmental cause(Ref. 10, Ref. 11). It could be argued that a psychological conditioning process, due to a medical or psychosocial stressor, precedes the development of insomnia. However, due to conditioning, the insomnia may persist even if the original stressor has been resolved. For example, a person losing their job could become anxious and develop insomnia; the person spends more time in bed; the bed becomes associated with the stress of trying to and failing to sleep; this conditioning remains even after resolving the job situation. When other causes of insomnia are ruled out, primary insomnia is characterised by either:

• trouble falling or staying asleep

or

• non-refreshing sleep.

It is important to differentiate between these characteristics, as the appropriate treatment might differ. It is often overlooked that non-refreshing (poor quality) sleep is independent of the number of hours spent asleep. A person may spend the ‘normal’ 7–8 hours in bed asleep, but still wake up feeling unrefreshed. This insomnia is important to treat, as it is linked to fatigue, low daytime performance, depression and anxiety. Circadin® is approved for the treatment of insomnia characterised by poor quality of sleep(Ref. 5). Circadin® also improves sleep latency(Ref. 5, Ref. 9, Ref. 6). These features, together with its favorable safety profile, relative to BZDs and ‘z’-drugs, should place Circadin® as a first-choice treatment of primary insomnia.

Q38: In patients who are distressed and agitated, will Circadin® get them to sleep?
A38: In patients who can’t fall asleep due to agitation or distress, it is important to evaluate whether this is a transient or chronic condition, and whether or not the patient also suffers from poor quality of sleep. Although Circadin® shortens sleep latency to the same extent as ‘z’-drugs(Ref. 6, Ref. 12), Circadin® is not indicated for treatment of transient insomnia(Ref. 5), and does not have an immediate sedative (‘knock-out’) effect. Further, Circadin® should be taken as a course for 21 days of treatment, and not on an ‘as needed’ basis.

Q39: Why does Circadin® smell?
A39: Circadin® has a distinctive smell which is due to the natural excipient smell of resins used in the sustained-release formulation.

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References

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

2. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD001520. DOI: 10.1002/14651858.CD001520.

3. Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998; 15 (6): 655–666.

4. 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.

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

6. Macher JP et al. Poster presented at 19th ESRS Congress 2008.

7. Sharma M, Palacios-Bois J, Schwartz G, et al. Circadian rhythms of melatonin and cortisol in aging. Biol Psychiatry 1989; 25 (3): 305–319.

8. Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res 2007; 16: 372–380.

9. Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness. Curr Med Res Opin 2007; 23 (10): 2597–2605.

10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth edition text revision (DSM-IV-TR). Washington DC: American Psychiatric Association, 2000.

11. World Health Organization. International Statistical Classification of Disease and Related Health Problems, 10th revision. Geneva: World Health Organization, version 2007.

12. Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M. Zaleplon, a novel nonbenzodiazepine hypnotic, effectively treated insomnia in elderly patients without causing rebound effects. Primary Care Companion J Clin Psychiatry 1999; 1 (4): 114–120.