Circadin 2 mg prolonged-release tablets

Each prolonged-release tablet contains 2 mg melatonin.

Excipient: each prolonged-release tablet contains 80 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Prolonged-release tablet.

White to off-white, round, biconvex tablets

Circadin is indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.

Oral use. Tablets should be swallowed whole.

The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food. This dosage should be continued for three weeks.

Paediatric use

Circadin is not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy.

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.

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.

Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 drugs.

• 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 C_max) 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 melantonin 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 nonbenzodiazepine hypnotics, such as zalepon, zolpidem and zopiclone. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Circadin and zolpidem one hour following codosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone.

• Circadin has been coadministered 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 coadministration 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.

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 (see section 5.3). In view of the lack of clinical data, use in pregnant women and by women intended to become pregnant is not recommended.

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.

Circadin has moderate influence on the ability to drive and use machines. 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.

In clinical trials (in which a total of 1361 patients were taking Circadin and 1247 patients were taking placebo), 37.0% of patients receiving Circadin reported an adverse reaction compared with 31.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than Circadin (8.21 – placebo vs. 3.17 – Circadin). The most common adverse reactions were headache, pharyngitis, back pain, and asthenia, which were common, by MedDRA definition, in both the Circadin and placebo treated groups.

The following adverse reactions were reported in clinical trials and were defined as possibly, probably or definitely related to treatment. A total of 6.9% of subjects receiving Circadin reported an adverse reaction compared with 5.9% of subjects taking placebo. Only those adverse events occurring in subjects at an equivalent or greater rate than placebo have been included below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common ( 1/10); Common ( 1/100 to <1/10); Uncommon ( 1/1,000 to <1/100); Rare ( 1/10,000 to <1/1,000); Very rare (<1/10,000), Not known (cannot be established from the available data).

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.

Pharmacotherapeutic group: Melatonin Receptor Agonists, ATC code: N05CH01

Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin. Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep.

Mechanism of action

The activity of melatonin at the MT1, MT2 and MT3 receptors is believed to contribute to its sleep-promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep regulation.

Rationale for use

Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.

Clinical efficacy

In clinical trials, where patients suffering from primary insomnia received Circadin 2 mg every evening for 3 weeks, benefits were shown in treated patients compared to placebo in sleep latency (as measured by objective and subjective means) and in subjective quality of sleep and daytime functioning (restorative sleep) with no impairment of vigilance during the day.

In a polysomnographic (PSG) study with a run-in of 2 weeks (single-blind with placebo treatment), followed by a treatment period of 3 weeks (double-blind, placebo-controlled, parallel group design) and a 3-week withdrawal period, sleep latency (SL) was shortened by 9 minutes compared to placebo. There were no modifications of sleep architecture and no effect on REM sleep duration by Circadin. Modifications in diurnal functioning did not occur with Circadin 2 mg.

In an outpatient study with 2 week run-in baseline period with placebo, a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks and 2 week withdrawal period with placebo, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 47% in the Circadin group as compared to 27% in the placebo group. In addition, quality of sleep and morning alertness significantly improved with Circadin compared to placebo. Sleep variables gradually returned to baseline with no rebound, no increase in adverse events and no increase in withdrawal symptoms.

In a second outpatient study with two week run in baseline period with placebo and a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 26% in the Circadin group as compared to 15% in the placebo group. Circadin shortened patients' reported sleep latency by 24.3 minutes vs 12.9 minutes with placebo. In addition, patients' self-reported quality of sleep, number of awakenings and morning alertness significantly improved with Circadin compared to placebo. Quality of life was improved significantly with Circadin 2 mg compared to placebo.

Absorption

The absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly. The kinetics of melatonin are linear over the range of 2-8 mg.

Bioavailability is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85%. T_max occurs after 3 hours in a fed state. The rate of melatonin absorption and C_max following Circadin 2 mg oral administration is affected by food. The presence of food delayed the absorption of the melatonin resulting in a later (T_max=3.0 h versus T_max=0.75 h) and lower peak plasma concentration in the fed state (C_max=1020pg/ml versus C_max=1176 pg/ml).

Distribution

The in vitro plasma protein binding of melatonin is approximately 60%. Circadin is mainly bound to albumin, alpha₁-acid glycoprotein and high density lipoprotein.

Biotransformation

Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The excretion of the metabolite is completed within 12 hours after ingestion.

Elimination

Terminal half life (t_½) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as melatonin (unchanged drug).

Gender

A 3-4-fold increase in C_max is apparent for women compared to men. A five-fold variability in C_max between different members of the same sex has also been observed. However, no pharmacodynamic differences between males and females were found despite differences in blood levels.

Special populations

Elderly

Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and C_max levels have been reported in older subjects compared to younger subjects, reflecting the lower metabolism of melatonin in the elderly. C_max levels around 500 pg/ml in adults (18-45) versus 1200 pg/ml in elderly (55-69); AUC levels around 3,000 pg*h/mL in adults versus 5,000 pg*h/mL in the elderly.

Renal impairment

Company data indicates that there is no accumulation of melatonin after repeated dosing. This finding is compatible with the short half-life of melatonin in humans.

The levels assessed in the blood of the patients at 23:00 (2 hours after administration) following 1 and 3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ml respectively, and are similar to those found in in healthy volunteers following a single dose of Circadin 2 mg.

Hepatic impairment

The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels.

Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

The No Observed Adverse Effect Level (NOAEL) at 15 mg/kg/day in rats, is equivalent to an AUC which is considerably higher (x 15000) than the human exposure after ingestion of Circadin 2 mg.

The carcinogenicity study in the rat did not reveal any effect which may be relevant for humans.

In reproductive toxicology, oral administration of melatonin in pregnant female mice, rats or rabbits did not result in adverse effects on their offspring, measured in terms of foetal viability, skeletal and visceral abnormalities, sex ratio, birthweight and subsequent physical, functional and sexual development. A slight effect on postnatal growth and viability was found in rats only at very high doses, equivalent to approximately 2000 mg/day in humans.

Ammonio methacrylate copolymer type B

Calcium hydrogen phosphate dihydrate

Lactose monohydrate

Silica, colloidal anhydrous

Talc

Magnesium stearate

Not applicable.

5 years

Do not store above 25°C. Store in the original package in order to protect from light.

The tablets are packed in PVC/PVDC opaque blister strips with aluminium foil backing. The pack consists of one blister strip containing 20 or 21 tablets. The blisters are then packed in cardboard boxes.

Not all pack sizes may be marketed.

Medicines no longer required should not be disposed of via wastewater or the municipal sewage system. Return them to a pharmacy or ask your pharmacist how to dispose of them in accordance with the national regulations. These measures will help to protect the environment.

RAD Neurim Pharmaceuticals EEC Limited

One Forbury Square

The Forbury

Reading

Berkshire RG1 3EB

United Kingdom

e-mail: neurim@neurim.com

EU/1/07/392/001

EU/1/07/392/002

29/06/2007

19/03/2009

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu