Circadin

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Circadin 2 mg prolonged-release tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
 
3. PHARMACEUTICAL FORM 
 
Prolonged-release tablet. 
 
White to off-white, round, biconvex tablets 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
Posology 
 
The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food.  This dosage may 
be continued for up to thirteen weeks. 
 
Paediatric population 
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. 
 
Renal impairment 
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. 
 
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. 
 
Method of Administration 
 
Oral use.  Tablets should be swallowed whole to maintain prolonged release properties.  Crushing or 
chewing should not be used to facilitate swallowing. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 



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4.4 Special warnings and precautions for use 
 
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. 
 
Circadin contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP 
lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
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 
medicinal products. 

• 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 Cmax) 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 melatonin 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 

non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone.  In a clinical 



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trial, there was clear evidence for a transitory pharmacodynamic interaction between 
Circadin and zolpidem one hour following co-dosing.  Concomitant administration 
resulted in increased impairment of attention, memory and co-ordination compared to 
zolpidem alone. 

• Circadin has been co-administered 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 
co-administration 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. 

 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
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 intending to become pregnant is not recommended. 
 
Breastfeeding 
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. 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
In clinical trials (in which a total of 1,931 patients were taking Circadin and 1,642 patients were taking 
placebo), 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 rate 
was higher for placebo than Circadin (5.743– placebo vs. 3.013– Circadin).  The most common 
adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by 
MedDRA definition, in both the Circadin and placebo treated groups. 
 
Tabulated list of adverse reactions 
The following adverse reactions were reported in clinical trials and from post-marketing spontaneous 
reporting. 
In clinical trials a total of 9.5% of patients receiving Circadin reported an adverse reaction compared 
with 7.4% of patients taking placebo.  Only those adverse reactions reported during clinical trials 
occurring in patients at an equivalent or greater rate than placebo have been included below. 
 



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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). 
 
System Organ 

Class 
Very 

Common 
Common Uncommon Rare Not known:  

(Cannot be 
established 

from the 
available data) 

Infections and 
infestations 

   Herpes zoster  

Blood and 
lymphatic 
system disorders 

   Leukopenia, 
thrombocytopenia 

 

Immune system 
disorders 

    Hyper-
sensitivity 
reaction 

Metabolism and 
nutrition 
disorders 

   Hypertriglyceridaemia, 
hypocalcaemia, 
hyponatraemia 

 

Psychiatric 
disorders 

  Irritability, 
nervousness, 
restlessness, 
insomnia, abnormal 
dreams, nightmares, 
anxiety 

Mood altered, 
aggression, agitation, 
crying, stress 
symptoms, 
disorientation, early 
morning awakening, 
libido increased, 
depressed mood, 
depression 

 

Nervous system 
disorders 

  Migraine, headache, 
lethargy, 
psychomotor 
hyperactivity, 
dizziness, 
somnolence 

Syncope, memory 
impairment, 
disturbance in 
attention, dreamy state, 
restless legs syndrome, 
poor quality sleep, 
paraesthesia 

 

Eye disorders    Visual acuity reduced, 
vision blurred, 
lacrimation increased  

 

Ear and 
labyrinth 
disorders 

   Vertigo positional, 
vertigo 

 

Cardiac 
disorders 

   Angina pectoris, 
palpitations 

 

Vascular 
disorders 

  Hypertension Hot flush  



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System Organ 
Class 

Very 
Common 

Common Uncommon Rare Not known:  
(Cannot be 
established 

from the 
available data) 

Gastrointestinal 
disorders 

  Abdominal pain, 
abdominal pain 
upper,  dyspepsia, 
mouth ulceration, 
dry mouth, nausea 

Gastro-oesophageal 
reflux disease, 
gastrointestinal 
disorder, oral mucosal 
blistering, tongue 
ulceration, 
gastrointestinal upset, 
vomiting, bowel 
sounds abnormal, 
flatulence, salivary 
hypersecretion, 
halitosis, abdominal 
discomfort, gastric 
disorder, gastritis  

 

Hepatobiliary 
disorders 

  Hyperbilirubinaemia   

Skin and 
subcutaneous 
tissue disorders 

  Dermatitis, night 
sweats, pruritus, 
rash, pruritus 
generalised, dry skin 

Eczema, erythema, 
hand dermatitis, 
psoriasis, rash 
generalised, rash 
pruritic, nail disorder  

Angioedema, 
oedema of 
mouth, tongue 
oedema 

Musculoskeletal 
and connective 
tissue disorders 

  Pain in extremity Arthritis, muscle 
spasms, neck pain, 
night cramps 

 

Renal and 
urinary disorders 

  Glycosuria, 
proteinuria 

Polyuria, haematuria, 
nocturia 

 

Reproductive 
system and 
breast disorders 

  Menopausal 
symptoms 

Priapism, prostatitis Galactorrhoea 

General 
disorders and 
administration 
site conditions 

  Asthenia, chest pain  Fatigue, pain, thirst  

Investigations   Liver function test 
abnormal, weight 
increased 

Hepatic enzyme 
increased, blood 
electrolyes abnormal, 
laboratory test 
abnormal 

 

 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Several cases of overdose have been reported post-marketing. Somnolence was the most reported 
adverse event. Most were mild to moderate in severity. 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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group:  Psycholeptics, 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 and safety 
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 
reactions 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 



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compared to placebo.  Quality of life was improved significantly with Circadin 2 mg compared to 
placebo. 
 
An additional randomised clinical trial (n=600) compared the effects of Circadin and placebo for up to 
six months. Patients were re-randomised at 3 weeks. The study demonstrated improvements in sleep 
latency, 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 failed 
the primary analysis set at 6 months. At 3 months, about an extra 10% of responders were seen in the 
Circadin treated group. 
 
Paediatric population 
A Paediatric study (n=125) with doses of 2, 5 or 10 mg prolonged-release melatonin in multiples of 
1 mg minitablets (age-appropriate pharmaceutical form), with two week run in baseline period on 
placebo and a randomised, double blind, placebo controlled, parallel group treatment period of 
13 weeks, demonstrated an improvement in total sleep time (TST) after 13 weeks of double-blind 
treatment; 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 to 
the 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 more 
common in the active group with 42% patients, compared to 23% in the placebo group, mainly driven 
by somnolence and headache more frequent in the active group. 
 
5.2 Pharmacokinetic properties 
 
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%.  Tmax occurs after 3 hours in a fed state.  The rate of melatonin absorption 
and Cmax following Circadin 2 mg oral administration is affected by food.  The presence of food 
delayed the absorption of the melatonin resulting in a later (Tmax=3.0 h versus Tmax=0.75 h) and lower 
peak plasma concentration in the fed state (Cmax=1020pg/ml versus Cmax=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 (t½) 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 active substance). 
 



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Gender 
A 3-4-fold increase in Cmax is apparent for women compared to men.  A five-fold variability in Cmax 
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 
 
Older People 
Melatonin metabolism is known to decline with age.  Across a range of doses, higher AUC and Cmax 

levels have been reported in older patients compared to younger patients, reflecting the lower 
metabolism of melatonin in the elderly.  Cmax  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. 
 
5.3 Preclinical safety data 
 
Non-clinical data revealed no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction 
and development. 
 
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the 
maximum 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 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 post-natal growth and viability was found in rats only at very high 
doses, equivalent to approximately 2000 mg/day in humans. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Ammonio methacrylate copolymer type B 
Calcium hydrogen phosphate dihydrate 
Lactose monohydrate 
Silica, colloidal anhydrous 
Talc 
Magnesium stearate 
 



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6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Do not store above 25°C.  Store in the original package in order to protect from light. 
 
6.5 Nature and contents of container 
 
The tablets are packed in PVC/PVDC opaque blister strips with aluminium foil backing.  The pack 
consists of one blister strip containing 7, 20 or 21 tablets, or two blister strips containing 15 tablets 
each (30 tablets).  The blisters are then packed in cardboard boxes. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements for disposal. Any unused medicinal product or waste material should be 
disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
RAD Neurim Pharmaceuticals EEC SARL 
4 rue de Marivaux 
75002 Paris 
France 
e-mail: regulatory@neurim.com 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/392/001 
EU/1/07/392/002 
EU/1/07/392/003 
EU/1/07/392/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 June 2007 
Date of latest renewal:  20 April 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{DD month YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



11 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



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A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Temmler Pharma GmbH & Co. KG 
Temmlerstrasse 2 
35039 Marburg 
Germany 
 
Iberfar - Indústria Farmacêutica S.A. 
Rua Consiglieri Pedroso, n.o 121-123 - Queluz de Baixo 
Barcarena, 2734-501 
Portugal 
 
Rovi Pharma Industrial Services, S.A. 
Vía Complutense, 140 
Alcalá de Henares 
Madrid, 28805 
Spain 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency. 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 



13 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



15 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Circadin 2 mg prolonged-release tablets 
melatonin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2 mg melatonin. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate 
See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Prolonged-release tablets 
20 tablets 
21 tablets 
30 tablets 
7 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



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9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
RAD Neurim Pharmaceuticals EEC SARL 
4 rue de Marivaux 
75002 Paris 
France 
e-mail: regulatory@neurim.com 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/392/001 21 tablets 
EU/1/07/392/002 20 tablets 
EU/1/07/392/003 30 tablets 
EU/1/07/392/004   7 tablets 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Circadin 2 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



17 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



18 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER STRIP 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Circadin 2 mg prolonged-release tablets 
melatonin 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
RAD Neurim Pharmaceuticals EEC SARL 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



20 

Package Leaflet: Information for the patient 
 

Circadin 2 mg prolonged-release tablets 
Melatonin 

 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See Section 4. 
 
 
What is in this leaflet: 
1. What Circadin is and what it is used for 
2. What you need to know before you take Circadin 
3. How to take Circadin 
4. Possible side effects 
5. How to store Circadin 
6. Contents of the pack and other information 
 
 
1. What Circadin is and what it is used for 
 
The active substance of Circadin, melatonin, belongs to a natural group of hormones produced by the 
body. 
 
Circadin is used on its own for the short-term treatment of primary insomnia (persistent difficulty in 
getting to sleep or staying asleep, or poor quality of sleep) in patients aged 55 years and older. 
‘Primary’ means that the insomnia does not have any identified cause, including any medical, mental 
or environmental cause. 
 
 
2. What you need to know before you take Circadin 
 
Do not take Circadin 
- if you are allergic to melatonin or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Circadin. 
 
- If you suffer from liver or kidney problems. No studies on the use of Circadin in people with 

liver or kidney diseases have been performed, you should speak to your doctor before taking 
Circadin as its use is not recommended. 

- If you have been told by your doctor that you have an intolerance to some sugars. 
- If you have been told you suffer from an autoimmune disease (where the body is ‘attacked’ by 

its own immune system). No studies on the use of Circadin in people with auto-immune 
diseases have been performed; therefore, you should speak to your doctor before taking 
Circadin as its use is not recommended. 

- Circadin can make you feel drowsy, you should be careful if the drowsiness affects you as it 
may impair your ability on tasks such as driving. 

- Smoking may make Circadin less effective, because the components of tobacco smoke can 
increase the breakdown of melatonin by the liver. 



21 

 
Children and adolescents 
Do not give this medicine to children between the ages of 0 to 18 years as it has not been tested and its 
effects are unknown. Another medicine containing melatonin may be more appropriate for 
administration to children between the ages of 2 to 18 - please ask your doctor or pharmacist for 
advice. 
 
Other medicines and Circadin 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  These medicines include: 
 
− Fluvoxamine (used for the treatment of depression and obsessive compulsive disorder), 

psoralens (used in the treatment of skin disorders e.g. psoriasis), cimetidine (used in the 
treatment of stomach problems such as ulcers), quinolones and rifampicin (used in the treatment 
of bacterial infections), oestrogens (used in contraceptives or hormone replacement therapy) and 
carbamazepine (used in the treatment of epilepsy). 

− Adrenergic agonists/antagonists (such as certain types of medicines used to control blood 
pressure by constricting blood vessels, nasal decongestants, blood pressure lowering medicines), 
opiate agonists/antagonists (such as medicinal products used in the treatment of drug addiction), 
prostaglandin inhibitors (such as nonsteroidal anti-inflammatory medicines), antidepressant 
medication, tryptophan and alcohol. 

− Benzodiazepines and non-benzodiazepine hypnotics (medicines used to induce sleep such as 
zaleplon, zolpidem and zopiclone) 

− Thioridazine (for the treatment of schizophrenia) and imipramine (for the treatment of 
depression). 

 
Circadin with food, drink and alcohol 
Take Circadin after you have eaten.  Do not drink alcohol before, during or after taking Circadin, 
because it reduces the effectiveness of Circadin. 
 
Pregnancy and breast-feeding 
Do not take Circadin if you are pregnant, think you may be pregnant, trying to become pregnant or 
breast-feeding.  Ask your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
Circadin may cause drowsiness.  If you are affected, you should not drive or operate machinery.  If 
you suffer from continued drowsiness, then you should consult your doctor. 
 
Circadin contains lactose monohydrate. 
Circadin contains lactose monohydrate.  If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3. How to take Circadin 
 
Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended dose is one Circadin tablet (2 mg) taken daily by mouth, after food, 1-2 hours 
before bedtime. This dosage may be continued for up to thirteen weeks. 
 
You should swallow the tablet whole.  Circadin tablets should not be crushed or cut in half. 
 
If you take more Circadin than you should 
If you have accidentally taken too much of your medicine, contact your doctor or pharmacist as soon 
as possible. 



22 

 
Taking more than the recommended daily dose may make you feel drowsy. 
 
If you forget to take Circadin 
If you forget to take your tablet, take another as soon as you remember, before going to sleep, or wait 
until it is time to take your next dose, then go on as before. 
 
Do not take a double dose to make up for a forgotten dose. 
 
If you stop taking Circadin 
There are no known harmful effects if treatment is interrupted or ended early.  The use of Circadin is 
not known to cause any withdrawal effects after treatment completion. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
If you experience any of the following serious side effects, stop taking the medicine and contact your 
doctor immediately:- 
 
Uncommon: (may affect up to 1 in 100 people) 
• Chest pain 
 
Rare: (may affect up to 1 in 1000 people) 
• Loss of consciousness or fainting 
• Severe chest pain due to angina 
• Feeling your heartbeat 
• Depression 
• Visual impairment 
• Blurred vision 
• Disorientation 
• Vertigo (a feeling of dizziness or “spinning”) 
• Presence of red blood cells in the urine 
• Reduced number of white blood cells in the blood 
• Reduced blood platelets, which increases risk of bleeding or bruising 
• psoriasis 
 
If you experience any of the following non-serious side effects contact your doctor and/or seek 
medical advice:- 
 
Uncommon: (may affect up to 1 in 100 people) 
 
Irritability, nervousness, restlessness, insomnia, abnormal dreams, nightmares, anxiety, migraine, 
headache, lethargy (tiredness, lack of energy), restlessness associated with increased activity, 
dizziness, tiredness, high blood pressure, upper abdominal pain, indigestion, mouth ulceration, dry 
mouth, nausea, changes in the composition of your blood which could cause yellowing of the skin or 
eyes, inflammation of the skin, night sweats, itching, rash, dry skin, pain in extremities, menopausal 
symptoms, feeling of weakness, excretion of glucose in the urine, excess proteins in the urine, 
abnormal liver function and weight increase. 
 
Rare: (may affect up to 1 in 1000 people) 
 



23 

Shingles, high level of fatty molecules in the blood, low serum calcium levels in the blood, low 
sodium levels in the blood, altered mood, aggression, agitation, crying, stress symptoms, early 
morning awakening, increased sex drive, depressed mood,  memory impairment, disturbance in 
attention, dreamy state, restless legs syndrome, poor quality sleep, ‘pins and needles’ feeling, watery 
eyes, dizziness when standing or sitting, hot flushes, acid reflux, stomach disorder, blistering in the 
mouth, tongue ulceration, stomach upset, vomiting, abnormal bowel sounds, wind, excess saliva 
production, bad breath, abdominal discomfort, gastric disorder, inflammation of the stomach lining, 
eczema, skin rash, hand dermatitis, itchy rash, nail disorder, arthritis, muscle spasms, neck pain, night 
cramps, prolonged erection that might be painful, inflammation of the prostate gland, tiredness, pain, 
thirst, passing large volumes of urine, urinating during the night, increased liver enzymes, abnormal 
blood electrolytes and abnormal laboratory tests. 
 
Frequency not known: (cannot be established from the available data) 
 
Hypersensitivity reaction, swelling of mouth or tongue, swelling of the skin and abnormal milk 
secretion. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side effects 
not listed in this leaflet.  You can also report side effects directly via the national reporting system 
listed in Appendix V.  By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Circadin 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton (EXP).  The expiry date 
refers to the last day of that month. 
 
Do not store above 25°C.  Store in the original package in order to protect from light. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Circadin contains 
- The active substance is melatonin.  Each prolonged-release tablet contains 2 mg melatonin. 
- The other ingredients are ammonio methacrylate copolymer type B, calcium hydrogen 

phosphate dihydrate, lactose monohydrate, silica (colloidal anhydrous), talc and magnesium 
stearate. 

 
What Circadin looks like and contents of the pack 
Circadin 2 mg prolonged-release tablets are available as white to off-white round bi-convex shaped 
tablets.  Each carton of tablets contains one blister strip of 7, 20 or 21 tablets, or alternatively in a 
carton containing two blister strips of 15 tablets each (30 tablet pack).  Not all pack sizes may be 
marketed. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


24 

Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
 
RAD Neurim Pharmaceuticals EEC SARL 
4 rue de Marivaux 
75002 Paris 
France 
e-mail: regulatory@neurim.com 
 
Manufacturer: 
 
Sites responsible for Batch Release in the EEA:- 
 
Temmler Pharma GmbH & Co. KG 
Temmlerstrasse 2 
35039 Marburg 
Germany 
 
Iberfar - Indústria Farmacêutica S.A. 
Rua Consiglieri Pedroso, n.o 121-123 - Queluz de Baixo 
Barcarena, 2734-501 
Portugal 
 
Rovi Pharma Industrial Services, S.A. 
Vía Complutense, 140 
Alcalá de Henares 
Madrid, 28805 
Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder 
 
België/Belgique/Belgien 
Takeda Belgium 
Tél/Tel: +32 2 464 06 11 
Takeda-Belgium@takeda.com 
 

Lietuva 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail: neurim@neurim.com 
 

България 
RAD Neurim Pharmaceuticals EEC SARL 
Teл: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 

Luxembourg/Luxemburg 
Takeda Belgium 
Tél/Tel: +32 2 464 06 11 (BE) 
Takeda-Belgium@takeda.com 
 

Česká republika 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 

Magyarország 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 

Danmark 
Takeda Pharma A/S 
Tlf: +45 46 77 11 11 
 

Malta 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 



25 

Deutschland 
MEDICE Arzneimittel Pütter GmbH & Co. KG 
Tel: +49 (0)2371 9370 
info@medice.de 
 

Nederland 
Takeda Nederland bv 
Tel: +31 20 203 5492 
medinfoEMEA@takeda.com 
 

Eesti 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail: neurim@neurim.com 
 

Norge 
Takeda AS 
Tlf: +47 6676 3030 
infonorge@takeda.com 
 

Ελλάδα 
TAKEDA ΕΛΛΑΣ Α.Ε. 
Τηλ: +30 210 6387800gr.info@takeda.com 
 

Österreich 
SANOVA PHARMA GesmbH 
Tel.:  +43 (01) 80104-0 
e-mail:  sanova.pharma@sanova.at 
 

España 
EXELTIS HEALTHCARE, S.L. 
Tfno:  +34 91 7711500 
 

Polska 
MEDICE Arzneimittel Pütter GmbH & Co. KG  
Tel.:  + 48-(0)22 642 2673 
e-mail:  office@medice.pl 
 

France 
BIOCODEX 
Tél:  +33 (0)1 41 24 30 00 
e-mail:  medinfo@biocodex.com 
 

Portugal 
Italfarmaco, Produtos Farmacêuticos, Lda. 
Tel. +351 214 342 530 
e-mail:  geral@itf-farma.pt 
 

Hrvatska 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 

România 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 

Ireland 
RAD Neurim Pharmaceuticals EEC SARL 
Tel:  +33 185149776 (FR) 
e-mail: neurim@neurim.com 
 

Slovenija 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 

Slovenská republika 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 

Italia 
Fidia Farmaceutici S.p.A. 
Tel:  +39 049 8232222 
e-mail:  info@fidiapharma.it 
 

Suomi/Finland 
Takeda Oy  
Puh/Tel: +358 20 746 5000  
 
 

Κύπρος 
RAD Neurim Pharmaceuticals EEC SARL 
Τηλ : +33 185149776 (FR) 
e-mail:  neurim@neurim.com 
 

Sverige 
Takeda Pharma AB 
Tel: +46 8 731 28 00 
infosweden@takeda.com 
 

Latvija 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail: neurim@neurim.com 
 

United Kingdom (Northern Ireland) 
RAD Neurim Pharmaceuticals EEC SARL 
Tel: +33 185149776 (FR) 
e-mail: neurim@neurim.com 
 

 
 



26 

This leaflet was last revised in { month/YYYY}. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET