ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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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 Very Common Uncommon Rare Not known:

Class Common (Cannot be
established
from the
available data)
Infections and Herpes zoster
infestations
Blood and Leukopenia,
lymphatic thrombocytopenia
system disorders
Immune system Hyper-
disorders sensitivity
reaction
Metabolism and Hypertriglyceridaemia,
nutrition hypocalcaemia,
disorders hyponatraemia
Psychiatric Irritability, Mood altered,
disorders nervousness, aggression, agitation,
restlessness, crying, stress
insomnia, abnormal symptoms,
dreams, nightmares, disorientation, early
anxiety morning awakening,
libido increased,
depressed mood,
depression
Nervous system Migraine, headache, Syncope, memory
disorders lethargy, impairment,
psychomotor disturbance in
hyperactivity, 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 vertigo
disorders
Cardiac Angina pectoris,
disorders palpitations
Vascular Hypertension Hot flush
disorders

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 System Organ Very Common Uncommon Rare Not known:
Class Common (Cannot be
established
from the
available data)
Gastrointestinal Abdominal pain, Gastro-oesophageal
disorders abdominal pain reflux disease,
upper, dyspepsia, gastrointestinal
mouth ulceration, disorder, oral mucosal
dry mouth, nausea blistering, tongue
ulceration,
gastrointestinal upset,
vomiting, bowel
sounds abnormal,
flatulence, salivary
hypersecretion,
halitosis, abdominal
discomfort, gastric
disorder, gastritis
Hepatobiliary Hyperbilirubinaemia
disorders
Skin and Dermatitis, night Eczema, erythema, Angioedema,
subcutaneous sweats, pruritus, hand dermatitis, oedema of
tissue disorders rash, pruritus psoriasis, rash mouth, tongue
generalised, dry skin generalised, rash oedema
pruritic, nail disorder
Musculoskeletal Pain in extremity Arthritis, muscle
and connective spasms, neck pain,
tissue disorders night cramps
Renal and Glycosuria, Polyuria, haematuria,
urinary disorders proteinuria nocturia
Reproductive Menopausal Priapism, prostatitis Galactorrhoea
system and symptoms
breast disorders
General Asthenia, chest pain Fatigue, pain, thirst
disorders and
administration
site conditions
Investigations Liver function test Hepatic enzyme
abnormal, weight increased, blood
increased 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.

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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
compared to placebo. Quality of life was improved significantly with Circadin 2 mg compared to
placebo.

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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).

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.

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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

6.2 Incompatibilities

Not applicable.

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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: [email protected]

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

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 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.

Estrada Consiglieri Pedroso 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.

12
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time.

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 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: [email protected]

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.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

17
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

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B. PACKAGE LEAFLET

19
 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.

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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.

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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)

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

22
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.

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Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

RAD Neurim Pharmaceuticals EEC SARL

4 rue de Marivaux
75002 Paris
France
e-mail: [email protected]

Manufacturer:

Sites responsible for Batch Release in the EEA:-

Temmler Pharma GmbH & Co. KG

Temmlerstrasse 2
35039 Marburg
Germany

Iberfar Indústria Farmacêutica S.A.

Estrada Consiglieri Pedroso 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 Lietuva
Takeda Belgium RAD Neurim Pharmaceuticals EEC SARL
Tél/Tel: +32 2 464 06 11 Tel: +33 185149776 (FR)
e-mail: [email protected] e-mail: [email protected]

България Luxembourg/Luxemburg
RAD Neurim Pharmaceuticals EEC SARL Takeda Belgium
Teл: +33 185149776 (FR) Tél/Tel: +32 2 464 06 11 (BE)
e-mail: [email protected] e-mail: [email protected]

Česká republika Magyarország

RAD Neurim Pharmaceuticals EEC SARL RAD Neurim Pharmaceuticals EEC SARL
Tel: +33 185149776 (FR) Tel: +33 185149776 (FR)
e-mail: [email protected] e-mail: [email protected]

Danmark Malta
Takeda Pharma A/S RAD Neurim Pharmaceuticals EEC SARL
Tlf: +45 46 77 11 11 Tel: +33 185149776 (FR)
e-mail: [email protected]

24
Deutschland Nederland
INFECTOPHARM Arzneimittel Takeda Nederland bv
und Consilium GmbH Tel: +31 20 203 5492
Tel: +49 6252 957000 e-mail: [email protected]
e-mail: [email protected]

Eesti Norge
RAD Neurim Pharmaceuticals EEC SARL Takeda AS
Tel: +33 185149776 (FR) Tlf: +47 800 800 30
e-mail: [email protected] e-mail: [email protected]

Ελλάδα Österreich
TAKEDA ΕΛΛΑΣ Α.Ε. SANOVA PHARMA GesmbH
Τηλ: +30 210 6387800 Tel.: +43 (01) 80104-0
e-mail: [email protected] e-mail: [email protected]

España Polska
EXELTIS HEALTHCARE, S.L. MEDICE Arzneimittel Pütter GmbH & Co. KG
Tfno: +34 91 7711500 Tel.: + 48-(0)22 642 2673
e-mail: [email protected]

France Portugal
BIOCODEX Italfarmaco, Produtos Farmacêuticos, Lda.
Tél: +33 (0)1 41 24 30 00 Tel. +351 214 342 530
e-mail: [email protected] e-mail: [email protected]

Hrvatska România
RAD Neurim Pharmaceuticals EEC SARL RAD Neurim Pharmaceuticals EEC SARL
Tel: +33 185149776 (FR) Tel: +33 185149776 (FR)
e-mail: [email protected] e-mail: [email protected]

Ireland Slovenija
RAD Neurim Pharmaceuticals EEC SARL RAD Neurim Pharmaceuticals EEC SARL
Tel: +33 185149776 (FR) Tel: +33 185149776 (FR)
e-mail: [email protected] e-mail: [email protected]

Ísland Slovenská republika

Vistor hf. RAD Neurim Pharmaceuticals EEC SARL
Sími: +354 535 7000 Tel: +33 185149776 (FR)
e-mail: [email protected]

Italia Suomi/Finland
Fidia Farmaceutici S.p.A. Takeda Oy
Tel: +39 049 8232222 Puh/Tel: +358 20 746 5000
e-mail: [email protected]

Κύπρος Sverige
RAD Neurim Pharmaceuticals EEC SARL Takeda Pharma AB
Τηλ : +33 185149776 (FR) Tel: +46 8 731 28 00
e-mail: [email protected] e-mail: [email protected]

Latvija United Kingdom (Northern Ireland)

RAD Neurim Pharmaceuticals EEC SARL RAD Neurim Pharmaceuticals EEC SARL
Tel: +33 185149776 (FR) Tel: +33 185149776 (FR)
e-mail: [email protected] e-mail: [email protected]

25
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

26