Q&A

Circadin.com December 8, 2014

Here you can find answers to some of the most common questions concerning Circadin®.
For more specific questions, we invite you to contact us – our Medical Advisers and Experts are always happy to help.

General information

What is Circadin®?

Circadin® 2 mg is a prolonged release formulation of highest grade of pure melatonin (the prolonged release mechanism of Circadin® is due to a polymer matrix), indicated for primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over1. The melatonin in Circadin® is a synthetic molecule, 100% equal to the human melatonin molecule (N-acetyl-5-methoxytryptamine).

How does melatonin help me to sleep?

Melatonin is a natural hormone released in the body during the evening and night, signaling ‘darkness’, associated with sleepiness and the sleep-wake cycle. Thereby melatonin facilitates the feeling of sleepiness and the ability to induce and maintain sleep.

Melatonin is a naturally occurring neuro-hormone mainly released from the pineal gland in the head in the evening and during the night1 2 3. Melatonin signals ‘darkness’, is associated with feeling sleepy, and regulates the sleep-wake cycle1 2 3 4.

Individual levels of melatonin vary, but it has been found that otherwise healthy people suffering from insomnia often have lower levels of melatonin than people without insomnia, and that melatonin therapy ameliorates the symptoms of insomnia5. Circadin® is prolonged-release melatonin, which adds exogenous melatonin to the endogenous melatonin throughout the night, thereby facilitating the feeling of sleepiness, the ability to fall asleep, and improving sleep quality and daytime functioning1.

How does Circadin® work compared to other melatonin formulations?

Circadin® is a prolonged-release formulation of melatonin, which circumvents the fast clearance of the hormone by releasing the melatonin over an extended period of time12, thereby mimicking physiological patterns of melatonin secretion. Administration of exogenous melatonin does not affect the endogenous secretion of melatonin14. Other melatonin formulations are immediate-release – meaning that they are rapidly absorbed and metabolised with an elimination half-life of ~60 minutes15. Following oral administration of immediate-release melatonin, peak plasma levels that are 5-10 fold higher than those of Circadin®, are reached after ~50 minutes15, rapidly falling off again due to the first-pass hepatic metabolism. Immediate-release melatonin is quickly cleared from the circulation. The differences in the effects of fast vs slow release formulations is best exemplified by their effects on the blood pressure rhythm. Whereas Circadin improves blood pressure control in nocturnal hypertension fast release formulations are not efficacious16. Despite common beliefs, the effect of Circadin® on sleep latency is no less than that of fast release melatonin because the brain is very sensitive to low doses of melatonin in the beginning of the night17 11.
In a study that was performed in the UK in order to assess the efficacy and safety of melatonin in treating patients with REM sleep behaviour disorder it was found out that Circadin® is more effective than standard melatonin preparations (Freeman A, Muza R, Leschziner G, et al. Sustained Release and Standard Preparation Melatonin for the Treatment of REM Sleep Behavioural Disorder. Sleep 2011; 34: A197-A198).

What are the most important benefits to patients?

Circadin® provides good quality natural sleep for patients, while offering an effective and safe treatment for their sleep problems, unlike old common sedative treatments.

Untreated insomnia may lead to various health problems6 7. Market research has shown that many people suffering from insomnia are reluctant to take sleep medications due to fear of dependency and side effects. Therefore, many patients, although suffering with the consequences of insomnia, e.g., fatigue, low daytime performance and even anxiety and depression, do not seek medical consultation but use various over-the-counter (OTC) and herbal remedies, and even alcohol, with limited efficacy at best9 10.

Circadin® decreases time getting to sleep, improves Quality of Sleep, Quality of Life and next-day alertness, while maintaining a very good safety profile5, with no evidence of dependence.

When is it recommended to take Circadin® before bedtime? Circadin® and food intake?

The recommendation according to SPC (Summary of Product Characteristics) is as follows:
“The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food”1.

In the PK studies a meal was served 1/2 an hour before drug administration – the meal was not big and contained fat. The patients were instructed to have a light meal before (30 minutes) they take Circadin®. If Circadin® is ingested on an empty stomach it will have a somewhat faster release.

How quickly will Circadin® make me fall asleep?

Circadin® shortens sleep latency (time to get to sleep)57. Although the effect of Circadin® on sleep latency is comparable to that of the ‘z’-drugs29.

Circadin® should not be considered a traditional ‘hypnotic’ as it is not a CNS depressant and does not work on the same receptors, causing much less side effects, and improving the sleep quality over time. In line with this, Circadin® should not be taken ‘as needed’, but in a course of 3-13 weeks1.

Will Circadin® work on the first night?

Onset of sleepiness occurs about 1–2 hours after taking Circadin®1, 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 and then up to 6 months. 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 days50. Benefit may be greater with continuous use of up to 3 months.

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.

How is Circadin® metabolised and how long does it stay in the body?

Circadin®‘s prolonged-release formulation releases melatonin gradually over 8-10 hours, providing a terminal (apparent) half-life of 3.5–4 hours12. The released melatonin is rapidly metabolised by the liver (half-life 40–50 minutes)12 1. The principal metabolite is 6-sulphatoxy-melatonin (6-SMT), which is inactive and accounts for ~80% of the dose excreted in the urine1. Excretion of the metabolites is completed within 12 hours after ingestion12.

Does the use of Circadin® make the body less able to manufacture its own melatonin; i.e., does the natural melatonin system ‘switch off’ and, if so, does it switch back on again when Circadin® treatment is stopped?

Published literature has shown that administration of exogenous melatonin does not affect the endogenous production of melatonin18 19 14. A long term study of Circadin®, for up to 1 year, showed that melatonin rhythms are preserved in the patients even after 6 months of treatment20.

Should melatonin levels be measured prior to treatment with Circadin®?

The age-related decline in melatonin production, that is proposed to contribute to poor sleep quality, is well-documented21. Additionally, it has been demonstrated that elderly insomnia sufferers exhibit lower melatonin levels than elderly people without insomnia5. However, the inter-individual variations in ‘normal’ levels of melatonin are large. Therefore, measurement of melatonin is not considered relevant in clinical practice. Age is a good surrogate marker of melatonin deficiency in the primary insomnia patient population22.

I am perfectly satisfied with my benzodiazepine treatment, why should I change to Circadin®?

BZDs have been associated with rebound insomnia, dependence, and neuropsychiatric reactions such as hostility and depression. Also, although effective in getting patients to sleep, these hypnotics further disrupt sleep architecture and structure – primarily by reducing ‘deep sleep’ (NREM stages 3 and 4) as well as REM stages of sleep36 37, a phenomenon that may impair memory consolidation.

In addition, the use of sedative hypnotics has been associated with road traffic accidents and a higher risk of falls8 38, especially in the elderly population.

Circadin® is safe and is not associated with any of these adverse effects. Furthermore, Circadin® shortens sleep latency to the same extent as most of the ‘z’-drugs but, in addition and unlike BZDs and ‘z’-drugs, Circadin® improves the restorative value of sleep which translates into improved quality of sleep, daytime functioning, and quality of life34 29 31 30.

If a physician wants to switch a patient from Benzodiazepines (BZD) and ‘z’-drugs to Circadin®, what should be the prescribing regimen?

Discontinuation of BZD should be gradual and well controlled because of the risk of withdrawal symptoms and rebound insomnia. Circadin® is indicated as monotherapy for the short-term treatment of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over.

If the physician wishes to switch a patient from BZD / ‘z’-drugs to Circadin®, a reduction in BZD / ‘z’-drugs should be gradual59. It is recommended to reduce the BZD / ‘z’-drugs dose to 50% in the first few weeks while initiating Circadin® co-administration and then to 25% for another several weeks. The dose adjustments and duration of the switching have to be according to medical consultation and under medical supervision.

According to Circadin® SmPC, there can be a pharmacodynamic interaction between BZD / ‘z’-drugs and Circadin® by which Circadin® augments the hypnotic effects of the BZD / ‘z’-drugs1. This is the reason why the dose of BZD / ‘z’-drugs should be reduced to 50% of the usual dose in the first weeks of initiation of Circadin® co-administration while maintaining good sleep.

Why does Circadin® smell?

Circadin® has a distinctive smell which is due to the natural excipient used in the prolonged-release formulation.

Are there any new trials on the horizon?

Neurim is now conducting a Phase III clinical study with Circadin-Ped for the treatment of sleep problems in children with Pervasive Developmental Disorders (PDD) and neurogenetic diseases.

Dosing and administration

What is the optimal dose for Circadin®? Will Circadin® be available at different dosages in the future?

Circadin® dose-ranging studies indicated that a 2 mg dose of Circadin® would provide a beneficial effect in insomnia patients aged 55 years or over12.

What happens if I take a higher dose than Circadin® 2 mg?

In clinical trials over 12 months, Circadin® has been administered at 5 mg daily doses without significantly changing the nature of the adverse reactions reported1. There are reports in the literature of the administration of daily doses of up to 300 mg melatonin without causing clinically significant adverse reactions1. No case of Circadin® overdose has been reported1. If overdose of Circadin® occurs, drowsiness is to be expected1. Clearance of the active substance is expected within 12 hours of ingestion1. No special treatment is required1.

Is the prolonged-release formulation really needed? What about fast / immediate-release melatonin?

The prolonged-release formulation is needed to ensure continuous melatonin action throughout the night, mimicking the body’s physiological pattern, whereas fast-release melatonin would act only for 2-3 hours.

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, even the small increase is sufficient to induce fatigue in healthy individuals. Melatonin levels are then 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 night23. Immediate-release melatonin reaches maximum levels shortly after being taken at the beginning of the night and, due to the very short half-life15, 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 or on patients’ safety.

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 release24. It has been studied extensively in clinical trials to show its efficacy and safety profiles.

Can I cut or crush a Circadin® tablet?

Crushing a Circadin® tablet will not damage the active ingredient (melatonin). There are no safety concerns with crushing Circadin®, however it will affect prolonged-release properties of the product.

The tablet matrix maintains its prolonged-release properties as long as it is ingested as a whole. The prolonged-release properties will be maintained to some extent also if the tablet is halved or divided into 4 quarters. If it is crushed it will release melatonin similarly to an immediate release formulation.
According to the SmPC the tablets should be swallowed whole in order to get the full prolonged-release properties1.

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®?

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)25. It is recommended that alcohol should not be taken with Circadin® because it reduces the effectiveness of Circadin® on sleep1. 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 1.

Clinical relevance

Why is Circadin® only for people aged 55 and over? Can Circadin® be used in adult patients younger than 55 years?

Circadin® works by increasing the levels of melatonin in the body1. There is a general decline in melatonin production with age26 21 27. Also, insomnia sufferers have shown poorer melatonin production than people without insomnia across all age groups5. Therefore, the impairment in melatonin production as a result of ageing may be a cause of insomnia.

Insomnia sufferers aged 55 years and older were selected to be studied in clinical trials as they would, theoretically, have poorer melatonin production (due to both age and insomnia) and were hypothesised to benefit the most from therapy with Circadin®1. As there are large inter-individual variations in ‘normal’ physiologic levels of melatonin across (as well as within) age groups, younger adults with insomnia may benefit from Circadin®. Circadin® was given to insomnia patients aged 20-80 years in clinical trials showing its safety for 6 and 12 months11 20.
However, the current indication for Circadin®, as stated in the Summary of Product Characteristics (SPC), is for use in people aged 55 and over1. The physicians would need to make their own clinical judgement, in consultation with the patient, if they were to use Circadin® to treat younger adults suffering from insomnia.

Zolpidem is as good as Circadin® (and cheaper), so why use Circadin®?

Circadin® provides good quality natural sleep for patients, offering an effective and safe treatment for their sleep problems. unlike old common hypnotics sedative treatments (like Zolpidem). Sleep quality, even more than sleep latency, impacts morning alertness and quality of life of patients. Circadin® is the only sleep drug that improves both sleep quality and daytime functioning.

Circadin’s® patented formulation mimics the natural melatonin profile by releasing melatonin gradually over 8-10 hours, which results in a restorative and natural sleep. Patients gain good sleep quality and subsequently improved daytime functioning without the residual feeling in the morning following the old hypnotic intake. Circadin® is not a CNS-depressant hypnotic and does not bind to GABAA receptors, which are associated with anxiolytic, myorelaxant, and amnesic effects.

Apart from the risk of dependence, ‘z’-drugs such as zolpidem and zopiclone have been associated with residual sedative effects, marked rebound insomnia, strange behaviour at night, anterograde memory disturbances and an increased risk of falls8 32 33. In contrast, Circadin® does not cause impairment of cognitive skills or a negative effect on next-morning vigilance34 35. In fact, in clinical trials, Circadin® improved morning alertness and functioning30 31 12. Circadin® does not alter sleep architecture, and there is no evidence of increased risk of falls, dependence, rebound or withdrawal effects34 31 30. Furthermore, Circadin® shortens sleep latency to the same extent as the ‘z’-drugs34 30 29. Unlike zolpidem and the other hypnotics, Circadin® improves quality of sleep, daytime functioning, and quality of life30 31 34 12.

Drug safety

What are the risks connected to Circadin® administration?

It is important to understand that adverse events are reported regardless of any perceived relationship to drug treatment. In the overall clinical development program, which included long term open-label studies, patients were treated for longer periods with Circadin® than with placebo. Due to this fact, adverse event 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 adverse events per 100 patient weeks in clinical trials, the adverse event rate was lower in patients treated with Circadin® than those receiving placebo (3.17 for Circadin® versus 8.21 for placebo)1. The most commonly observed adverse events were headache, pharyngitis, back pain, and asthenia, listed as common by MedDRA definition (i.e., with a frequency of =1/100 to < 1/10)1, In both the Circadin® and placebo-treated groups12. It is very rare that active treatment demonstrates a lower rate of adverse events than placebo, but may be explained by the fact that untreated insomnia (placebo group) is associated with many ‘adverse events’.

What happens when you stop Circadin® after the recommended treatment period? Will the insomnia come back again?

Treatment with Circadin® was found to be beneficial in several parameters, while maintaining its safety in long term use. This is the reason that Circadin® is the only insomnia drug approved for the duration of 13 weeks.

Treatment with Circadin® for 13 weeks ensures a continued effect of Circadin® in this period. Circadin® is, however, a symptomatic treatment. After discontinuation of Circadin®, the beneficial effects remain for some time before sleep variables (time to sleep onset, quality of sleep, etc.) gradually return to pre-treatment levels12. Stopping Circadin® treatment does not cause rebound insomnia12 31 49 56. Treatment can be restarted when / if the insomnia symptoms reoccur.

A study that was published in 2011 supports the efficacy and safety of Circadin® in primary insomnia patients aged 20-80 throughout 6-12 months of continuous therapy. Circadin® discontinuation even after 12 months was not associated with adverse events, withdrawal symptoms or suppression of endogenous melatonin production, on the contrary, residual benefit was observed20.

Can Circadin® be taken for long periods of time (more than 13 weeks)?

Long term, open label and double blind placebo controlled studies in patients aged 20-8020 and patients aged 18-80 49 11 have shown that there are no particular safety concerns associated with 6-12 months treatment with Circadin® in all age groups. Efficacy was maintained without tolerance development. There is no warning against renewal of prescription following medical evaluation.

At the end of the treatment period the physician should reevaluate the need for treatment.

Can Circadin® be used in patients with hepatic or renal impairment?

There is no experience of the use of Circadin® in patients with liver impairment1. 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 clearance1. Therefore, Circadin® is not recommended for use in patients with hepatic impairment1.
The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied1. Caution should be used when melatonin is administered to such patients1.

Can Circadin® be taken with SSRIs or other antidepressants?

Circadin® is mainly metabolised by hepatic enzymes CYP1A1, CYP1A2, and possibly CYP2C19, which is thought to be less important1 12. 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 levels1. Therefore, this combination should be avoided1. Escitalopram and citalopram are metabolised by CYP2C1939 40. 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).

Can Circadin® be used in patients with diabetes?

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, positive effects in decreasing HbA1C levels vs. baseline were found12.

Can Circadin® be used in patients with hypertension or cardiovascular disease?

All clinical trials with Circadin included patients with hypertension and/or cardiovascular diseases as the insomnia patient population is quite enriched with such comorbidities41.
Circadin® was found safe and effective in such patients (data on file). In a study in patients with nocturnal hypertension Circadin® significantly improved nocturnal blood pressure42 in a meta analysis of published studies it was found that only controlled release melatonin preparations are beneficial in alleviating nocturnal hypertension whereas fast release formulations are not efficacious16. Reduction innocturnal hypertension is of major importance in the prevention of cardiovascular and cerebrovascular morbidity.

Can Circadin® be taken for long terms?

Long term, open label studies have shown that there are no particular safety concerns associated with 12 months treatment20. Long term placebo controlled study in patients 18-80 has demonstrated good safety profile in all ages49 56. It is however recommended to continuously monitor the efficacy and safety of Circadin® treatment irrespective of how long the patient is treated with Circadin®. The company received reports regarding patients that are treated with Circadin® for longer periods with good effect and no safety problems.

Can children take Circadin®?

Circadin® is the first fully developed melatonin product authorised by the regulatory authorities, but it is not indicated for use in children1. 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 difficulties22 43 44 45 46.

Several published studies have investigated the use of Circadin® and immediate-release melatonin in children45 46 47. 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 AEs45 46 47. Sleep maintenance problems in children are better addressed with prolonged release formulations. Therefore Circadin® is recommended as first line treatment for children with neurodevelopmental disorders in 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.

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?

In some countries, the red triangle is a regulatory requirement to be put on the labeling 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 effects48.

What happens if the patient takes Circadin® on an empty stomach?

The release of melatonin from Circadin® is more rapid if the tablet is taken on an empty stomach48.

What happens if Circadin® is taken in the morning?

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 subjects46. Such activities are usually desired in shift workers and travelers suffering from jet lag.
For the treatment of insomnia, patients should take Circadin® at night only1.

Other topics

What is the longest Circadin® treatment duration in a clinical study?

In the clinical study Neurim V, patients were treated with Circadin® up to 12 months12. In the clinical study NEU 951003, patients were randomized to Circadin® or placebo for 6 months, and then continued Circadin® for up to 12 months20. For some patients, the total duration of treatment was therefore 18 months.

In a study of long term treatment with Circadin® in which the treatment duration ranged from 6-72 months in 88 children (aged 5-15) with neurodevelopmental disorders Circadin’s® efficacy and good safety profile was confirmed58.

Does Circadin® also work in jet-lag?

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 lag50. One study (Suhner et al., 1998) found that a slow-release formulation of melatonin was somewhat less effective than immediate-release melatonin51 but recent studies showed that fast and controlled release formulation are equally potent in phase shifting 52.

In conclusion, Circadin®, like natural melatonin, affects the endogenous clock53. However, the effect of Circadin® on jet-lag has not been studied in a clinical trial.

Why should Circadin® be taken for 21 days? Why up to 3 months? Why not less than 21 days? How many 13-weeks Circadin® treatment courses could a person have in a year?

Circadin® increases the level of melatonin, facilitating both sleep onset and good quality sleep31 30. 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. Therefore, 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’ basis1. Treatment may continue with added benefits up to 13 weeks without interruption. 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 up to 6 months duration31 30 1. 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 treatment12 49 11 20. 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 13 weeks – either continued or as repeated 13-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.

Does Circadin® contain any animal ingredients (can vegetarians take it)?

Circadin® doesn’t contain any animal ingredients (it does contain a small amount of lactose monohydrate, utilized in the formulation of Circadin®)1 12.

Does Circadin® contain gluten?

No, Circadin® is gluten free.

Why is Circadin® a prescription-only medicine? Why is Circadin® not available OTC, when other forms of melatonin are available online?

Circadin® (prolonged-release melatonin) is the first of a new class of drug for insomnia, melatonin receptor activators approved by the regulatory medicines authorities. Circadin® has been used in multiple clinical trials, showing statistically significant and clinically meaningful efficacy in insomnia parameters.

The food supplements containing melatonin and melatonin pharmacy preparations are not considered medicinal products and therefore are not regulated by the health authorities and have not been adequately tested in clinical controlled studies, their safety is not monitored, and the consumer has no guarantee of their quality.

Circadin®, as a prolonged-release formulation, has a unique secretion profile that mimics the physiological secretion and profile of melatonin and allows preserving the natural sleep architecture. The food supplements containing melatonin and melatonin pharmacy preparations are immediate release products and have not been proven effective and safe in insomnia.

Primary insomnia doesn’t really exist, does it? Isn’t insomnia always secondary to something else?

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 cause54 55. 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. Insomnia can exists with various comorbidities, hypertension, diabetes, etc., which are not considered to impair sleep41.

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 Sleep1. Circadin® also improves sleep latency1 30 34. 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.

In patients who are distressed and agitated, will Circadin® get them to sleep?

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’-drugs34 29, Circadin® is not indicated for treatment of transient insomnia1, 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 because it needs time to stabilize the clock system.

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