CIRCADIN 2mg prolonged-release tablets medication leaflet

Circadin 2 mg prolonged-release tablets

Each prolonged-release tablet contains 2 mg melatonin.

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

For the 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 characterisedby poor quality of sleep in patients who are aged 55 or over.

The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food. This dosage maybe continued for up to thirteen weeks.

The safety and efficacy of Circadin in children aged 0 to 18 years has not yet been established.

Other pharmaceutical forms/strengths may be more appropriate for administration to this population.

Currently available data are described in section 5.1.

The effect of any stage of renal impairment on melatonin pharmacokinetics has not been studied.

Caution should be used when melatonin is administered to such patients.

There is no experience of the use of Circadin in patients with liver impairment. Published datademonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreasedclearance in patients with hepatic impairment. Therefore, Circadin is not recommended for use inpatients with hepatic impairment.

Oral use. Tablets should be swallowed whole to maintain prolonged release properties. Crushing orchewing should not be used to facilitate swallowing.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Circadin may cause drowsiness. Therefore the product should be used with caution if the effects ofdrowsiness 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.

Circadin contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPPlactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction studies have only been performed in adults.

- Melatonin has been observed to induce CYP3A in vitro at supra-therapeuticconcentrations. The clinical relevance of the finding is unknown. If induction occurs,this can give rise to reduced plasma concentrations of concomitantly administeredmedicinal products.

- Melatonin does not induce CYP1A enzymes in vitro at supra-therapeuticconcentrations. Therefore, interactions between melatonin and other active substancesas a consequence of melatonin’s effect on CYP1A enzymes are not likely to besignificant.

- Melatonin’s metabolism is mainly mediated by CYP1A enzymes. Therefore,interactions between melatonin and other active substances as a consequence of theireffect on CYP1A enzymes is possible.

- Caution should be exercised in patients on fluvoxamine, which increases melatoninlevels (by 17-fold higher AUC and a 12-fold higher serum Cmax) by inhibiting itsmetabolism 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 increasesplasma melatonin levels, by inhibiting its metabolism.

- Cigarette smoking may decrease melatonin levels due to induction of CYP1A2.

- Caution should be exercised in patients on oestrogens (e.g. contraceptive or hormonereplacement 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 reducedplasma concentrations of melatonin.

- There is a large amount of data in the literature regarding the effect of adrenergicagonists/antagonists, opiate agonists/antagonists, antidepressant medicinal products,prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenousmelatonin secretion. Whether or not these active substances interfere with the dynamicor kinetic effects of Circadin or vice versa has not been studied.

- Alcohol should not be taken with Circadin, because it reduces the effectiveness of

Circadin on sleep.

- Circadin may enhance the sedative properties of benzodiazepines andnon-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a clinicaltrial, there was clear evidence for a transitory pharmacodynamic interaction between

Circadin and zolpidem one hour following co-dosing. Concomitant administrationresulted in increased impairment of attention, memory and co-ordination compared tozolpidem alone.

- Circadin has been co-administered in studies with thioridazine and imipramine, activesubstances which affect the central nervous system. No clinically significantpharmacokinetic interactions were found in each case. However, Circadinco-administration resulted in increased feelings of tranquility and difficulty inperforming 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 indicatedirect or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturitionor postnatal development (see section 5.3). In view of the lack of clinical data, use in pregnantwomen and by women intending to become pregnant is not recommended.

Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probablysecreted into human milk. There are data in animal models including rodents, sheep, bovine andprimates 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 causedrowsiness, therefore the product should be used with caution if the effects of drowsiness are likely tobe associated with a risk to safety.

In clinical trials (in which a total of 1,931 patients were taking Circadin and 1,642 patients were takingplacebo), 48.8% of patients receiving Circadin reported an adverse reaction compared with 37.8%taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the ratewas higher for placebo than Circadin (5.743- placebo vs. 3.013- Circadin). The most commonadverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by

MedDRA definition, in both the Circadin and placebo treated groups.

The following adverse reactions were reported in clinical trials and from post-marketing spontaneousreporting.

In clinical trials a total of 9.5% of patients receiving Circadin reported an adverse reaction comparedwith 7.4% of patients taking placebo. Only those adverse reactions reported during clinical trialsoccurring in patients 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 theavailable data).

System Organ Very Common Uncommon Rare Not known:

Class Common (Cannot beestablishedfrom theavailable data)

Infections and Herpes zosterinfestations

Blood and Leukopenia,lymphatic thrombocytopeniasystem disorders

Immune system Hyper-disorders sensitivityreaction

Metabolism and Hypertriglyceridaemia,nutrition hypocalcaemia,disorders hyponatraemia

Psychiatric Irritability, Mood altered,disorders nervousness, aggression, agitation,restlessness, crying, stressinsomnia, abnormal symptoms,dreams, nightmares, disorientation, earlyanxiety morning awakening,libido increased,depressed mood,depression

Nervous system Migraine, headache, Syncope, memorydisorders lethargy, impairment,psychomotor disturbance inhyperactivity, attention, dreamy state,dizziness, restless legs syndrome,somnolence poor quality sleep,paraesthesia

Eye disorders Visual acuity reduced,vision blurred,lacrimation increased

Ear and Vertigo positional,labyrinth vertigodisorders

Cardiac Angina pectoris,disorders palpitations

Vascular Hypertension Hot flushdisorders

System Organ Very Common Uncommon Rare Not known:

Class Common (Cannot beestablishedfrom theavailable data)

Gastrointestinal Abdominal pain, Gastro-oesophagealdisorders abdominal pain reflux disease,upper, dyspepsia, gastrointestinalmouth ulceration, disorder, oral mucosaldry mouth, nausea blistering, tongueulceration,gastrointestinal upset,vomiting, bowelsounds abnormal,flatulence, salivaryhypersecretion,halitosis, abdominaldiscomfort, gastricdisorder, gastritis

Hepatobiliary Hyperbilirubinaemiadisorders

Skin and Dermatitis, night Eczema, erythema, Angioedema,subcutaneous sweats, pruritus, hand dermatitis, oedema oftissue disorders rash, pruritus psoriasis, rash mouth, tonguegeneralised, dry skin generalised, rash oedemapruritic, nail disorder

Musculoskeletal Pain in extremity Arthritis, muscleand connective spasms, neck pain,tissue disorders night cramps

Renal and Glycosuria, Polyuria, haematuria,urinary disorders proteinuria nocturia

Reproductive Menopausal Priapism, prostatitis Galactorrhoeasystem and symptomsbreast disorders

General Asthenia, chest pain Fatigue, pain, thirstdisorders andadministrationsite conditions

Investigations Liver function test Hepatic enzymeabnormal, weight increased, bloodincreased electrolyes abnormal,laboratory testabnormal

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Several cases of overdose have been reported post-marketing. Somnolence was the most reportedadverse event. Most were mild to moderate in severity. Circadin has been administered at 5 mg dailydoses in clinical trials over 12 months without significantly changing the nature of the adversereactions reported.

Administration of daily doses of up to 300 mg of melatonin without causing clinically significantadverse reactions have been reported in the literature.

If overdose occurs, drowsiness is to be expected. Clearance of the active substance is expected within12 hours after ingestion. No special treatment is required.

Pharmacotherapeutic group: Psycholeptics, melatonin receptor agonists, ATC code: N05CH01

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

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

Rationale for use

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

In clinical trials, where patients suffering from primary insomnia received Circadin 2 mg everyevening for 3 weeks, benefits were shown in treated patients compared to placebo in sleep latency (asmeasured by objective and subjective means) and in subjective quality of sleep and daytimefunctioning (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 withplacebo, the rate of patients who showed a clinically significant improvement in both quality of sleepand morning alertness was 47% in the Circadin group as compared to 27% in the placebo group. Inaddition, quality of sleep and morning alertness significantly improved with Circadin compared toplacebo. Sleep variables gradually returned to baseline with no rebound, no increase in adversereactions 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 whoshowed 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’ reportedsleep latency by 24.3 minutes vs 12.9 minutes with placebo. In addition, patients’ self-reportedquality of sleep, number of awakenings and morning alertness significantly improved with Circadincompared to placebo. Quality of life was improved significantly with Circadin 2 mg compared toplacebo.

An additional randomised clinical trial (n=600) compared the effects of Circadin and placebo for up tosix months. Patients were re-randomised at 3 weeks. The study demonstrated improvements in sleeplatency, quality of sleep and morning alertness, with no withdrawal symptoms and rebound insomnia.

The study showed that the benefit observed after 3 weeks is maintained for up to 3 months but failedthe primary analysis set at 6 months. At 3 months, about an extra 10% of responders were seen in the

Circadin treated group.

A Paediatric study (n=125) with doses of 2, 5 or 10 mg prolonged-release melatonin in multiples of1 mg minitablets (age-appropriate pharmaceutical form), with two week run in baseline period onplacebo and a randomised, double blind, placebo controlled, parallel group treatment period of13 weeks, demonstrated an improvement in total sleep time (TST) after 13 weeks of double-blindtreatment; participants slept more with active treatment (508 minutes), compared to placebo(488 minutes).

There was also a reduction in sleep latency with active treatment (61 minutes) compared to placebo(77 minutes) after 13 weeks of double-blind treatment, without causing earlier wake-up time.

In addition, there were fewer dropouts in the active treatment group (9 patients; 15.0%) compared tothe placebo group (21 patients; 32.3%). Treatment emergent adverse events were reported by 85%patients in the active group and by 77% in the placebo group. Nervous system disorders were morecommon in the active group with 42% patients, compared to 23% in the placebo group, mainly drivenby somnolence and headache more frequent in the active group.

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 firstpass metabolism of 85%. Tmax occurs after 3 hours in a fed state. The rate of melatonin absorptionand Cmax following Circadin 2 mg oral administration is affected by food. The presence of fooddelayed the absorption of the melatonin resulting in a later (Tmax=3.0 h versus Tmax=0.75 h) and lowerpeak plasma concentration in the fed state (Cmax=1020pg/ml versus Cmax=1176 pg/ml).

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

Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of thecytochrome P450 system are involved in melatonin metabolism. The principal metabolite is6-sulphatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. Theexcretion of the metabolite is completed within 12 hours after ingestion.

Terminal half life (t½) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% assulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as melatonin(unchanged active substance).

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

Older People

Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and Cmaxlevels have been reported in older patients compared to younger patients, reflecting the lowermetabolism of melatonin in the elderly. Cmax levels around 500 pg/ml in adults (18-45) versus1200 pg/ml in elderly (55-69); AUC levels around 3,000 pg*h/mL in adults versus 5,000 pg*h/mL inthe elderly.

Company data indicates that there is no accumulation of melatonin after repeated dosing. This findingis 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 and3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ml respectively, and aresimilar to those found in in healthy volunteers following a single dose of Circadin 2 mg.

The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results inhigher 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 safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of themaximum human exposure indicating little relevance to clinical use.

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 rabbitsdid not result in adverse effects on their offspring, measured in terms of foetal viability, skeletal andvisceral abnormalities, sex ratio, birthweight and subsequent physical, functional and sexualdevelopment. A slight effect on post-natal growth and viability was found in rats only at very highdoses, 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.

3 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. Each packconsists of one blister strip containing 7, 20 or 21 tablets, two blister strips containing 15 tablets each(30 tablets), or 30 x 1 tablets in perforated unit dose blisters. The blisters are then packed in cardboardboxes.

Not all pack sizes may be marketed.

No special requirements for disposal. Any unused medicinal product or waste material should bedisposed of in accordance with local requirements.

RAD Neurim Pharmaceuticals EEC SARL4 rue de Marivaux75002 Paris

Francee-mail: regulatory@neurim.com

EU/1/07/392/001

EU/1/07/392/002

EU/1/07/392/003

EU/1/07/392/004

EU/1/07/392/005

Date of first authorisation: 29 June 2007

Date of latest renewal: 20 April 2012

{DD month YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu