ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Circadin 2 mg prolonged-release tablets
2.
Each prolonged-release tablet contains 2 mg melatonin.
Excipient: each prolonged-release tablet contains 80 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Prolonged-release tablet.
White to off-white, round, biconvex tablets
4.
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.
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.
Renal insufficiency
The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied.
Caution should be used when melatonin is administered to such patients.
Hepatic impairment
There is no experience of the use of Circadin in patients with liver impairment. Published data
demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased
clearance in patients with hepatic impairment. Therefore, Circadin is not recommended for use in
patients with hepatic impairment.
Method of Administration
Oral use. Tablets should be swallowed whole.
Hypersensitivity to the active substance or to any of the excipients.
2
Circadin may cause drowsiness. Therefore the product should be used with caution if the effects of
drowsiness are likely to be associated with a risk to safety.
No clinical data exist concerning the use of Circadin in individuals with autoimmune diseases.
Therefore Circadin is not recommended for use in patients with autoimmune diseases.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or
glucose-galactose malabsorption should not take this medicine.
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
drugs.
•
Melatonin does not induce CYP1A enzymes
in vitro
at supra-therapeutic
concentrations. Therefore, interactions between melatonin and other active substances
as a consequence of melatonin’s effect on CYP1A enzymes are not likely to be
significant.
•
Melatonin’s metabolism is mainly mediated by CYP1A enzymes. Therefore,
interactions between melatonin and other active substances as a consequence of their
effect on CYP1A enzymes is possible.
•
Caution should be exercised in patients on fluvoxamine, which increases melatonin
levels (by 17-fold higher AUC and a 12-fold higher serum C
max
) by inhibiting its
metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19.
The combination should be avoided.
•
Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 and 8-MOP),
which increases melatonin levels by inhibiting its metabolism.
•
Caution should be exercised in patients on cimetidine a CYP2D inhibitor, which
increases plasma melatonin levels, by inhibiting its metabolism.
•
Cigarette smoking may decrease 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
trial, there was clear evidence for a transitory pharmacodynamic interaction between
3
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.
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 intended 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.
Circadin has moderate influence on the ability to drive and use machines. Circadin may cause
drowsiness, therefore the product should be used with caution if the effects of drowsiness are likely to
be associated with a risk to safety.
In clinical trials (in which a total of 1931 patients were taking Circadin and 1642 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.
The following adverse reactions were reported in clinical trials and were defined as possibly, probably
or definitely related to treatment. A total of 9.5% of subjects receiving Circadin reported an adverse
reaction compared with 7.4% of subjects taking placebo. Only those adverse events occurring in
subjects at an equivalent or greater rate than placebo have been included below.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100);
Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), Not known (cannot be established from the
available data).
System Organ
Class
Very
Common
Common
Uncommon
Rare
Infections and
Infestations
Herpes zoster
4
Blood and
Lymphatic
System Disorders
Leukopenia,
Thrombocytopenia
Cardiac Disorders
Angina Pectoris,
Palpitations
Metabolism and
Nutrition
Disorders
Hypertriglyceridaemia,
Hypocalcaemia,
Hyponatraemia
Psychiatric
Disorders
Irritability,
Nervousness,
Restlessness, Insomnia
Abnormal dreams,
Anxiety
Mood altered,
Aggression, Agitation,
Crying, Stress Symptoms,
Disorientation, Early
morning awakening
Libido increased,
Depressed mood,
Depression
Nervous System
Disorders
Migraine, Lethargy,
Psychomotor
hyperactivity,
Dizziness, Somnolence
Syncope, Memory
impairment, Disturbance
in attention, Dreamy
state, Restless Legs
Syndrome, Poor quality
sleep, Paresthesia
Eye Disorders
Visual acuity reduced,
Vision blurred,
Lacrimation increased
Ear and Labyrinth
Disorders
Vertigo positional,
Vertigo
Vascular
Disorders
Hypertension
Hot flush
Gastrointestinal
Disorders
Abdominal pain,
Abdominal pain upper,
Dyspepsia, Mouth
Ulceration, Dry mouth
Gastrooesophageal
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,
Musculoskeletal
and Connective
Tissue Disorders
Pain in extremity
Arthritis, Muscle spasms,
Neck pain, Night cramps,
Reproductive
System and Breast
Disorders
Menopausal
Symptoms
Priapism, Prostatitis
5
General Disorders
and
Administration
Site Conditions
Asthenia, Chest Pain Fatigue, Pain, Thirst
Renal and Urinary
Disorders
Glycosuria,
Proteinuria
Polyuria, Hematuria,
Nocturia
Investigations
Liver Function Test
Abnormal, Weight
increased
Hepatic enzyme
increased, Blood
Electrolyes Abnormal,
Laboratory test abnormal
No case of overdose has been reported. Circadin has been administered at 5 mg daily doses in clinical
trials over 12 months without significantly changing the nature of the adverse reactions reported.
Administration of daily doses of up to 300 mg of melatonin without causing clinically significant
adverse reactions have been reported in the literature.
If overdose occurs, drowsiness is to be expected. Clearance of the active substance is expected within
12 hours after ingestion. No special treatment is required.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Melatonin Receptor Agonists, ATC code: N05CH01
Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to
serotonin. Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4
am and diminishes during the second half of the night. Melatonin is associated with the control of
circadian rhythms and entrainment to the light-dark cycle. It is also associated with a hypnotic effect
and increased propensity for sleep.
Mechanism of action
The activity of melatonin at the MT1, MT2 and MT3 receptors is believed to contribute to its
sleep-promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation
of circadian rhythms and sleep regulation.
Rationale for use
Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease
in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in
patients who are over 55 with primary insomnia.
Clinical efficacy 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.
6
There were no modifications of sleep architecture and no effect on REM sleep duration by Circadin.
Modifications in diurnal functioning did not occur with Circadin 2 mg.
In an outpatient study with 2 week run-in baseline period with placebo, a randomised, double blind,
placebo controlled, parallel group treatment period of 3 weeks and 2 week withdrawal period with
placebo, the rate of patients who showed a clinically significant improvement in both quality of sleep
and morning alertness was 47% in the Circadin group as compared to 27% in the placebo group. In
addition, quality of sleep and morning alertness significantly improved with Circadin compared to
placebo. Sleep variables gradually returned to baseline with no rebound, no increase in adverse events
and no increase in withdrawal symptoms.
In a second outpatient study with two week run in baseline period with placebo and a randomised,
double blind, placebo controlled, parallel group treatment period of 3 weeks, the rate of patients who
showed a clinically significant improvement in both quality of sleep and morning alertness was 26%
in the Circadin group as compared to 15% in the placebo group. Circadin shortened patients’ reported
sleep latency by 24.3 minutes vs 12.9 minutes with placebo. In addition, patients’ self-reported
quality of sleep, number of awakenings and morning alertness significantly improved with Circadin
compared to placebo. Quality of life was improved significantly with Circadin 2 mg compared to
placebo.
An additional Randomised Clinical Trial (n=600) compared the effects of Circadin and placebo for up
to six months. Patients were re-randomized 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
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%. T
max
occurs after 3 hours in a fed state. The rate of melatonin absorption
and C
max
following Circadin 2 mg oral administration is affected by food. The presence of food
delayed the absorption of the melatonin resulting in a later (T
max
=3.0 h versus T
max
=0.75 h) and lower
peak plasma concentration in the fed state (C
max
=1020pg/ml versus C
max
=1176 pg/ml).
Distribution
The
in vitro
plasma protein binding of melatonin is approximately 60%. Circadin is mainly bound to
albumin, alpha
1
-acid glycoprotein and high density lipoprotein.
Biotransformation
Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the
cytochrome P450 system are involved in melatonin metabolism. The principal metabolite is
6-sulphatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The
excretion of the metabolite is completed within 12 hours after ingestion.
Elimination
Terminal half life (t
½
) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% as
sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as melatonin
(unchanged drug).
7
Gender
A 3-4-fold increase in C
max
is apparent for women compared to men. A five-fold variability in C
max
between different members of the same sex has also been observed. However, no pharmacodynamic
differences between males and females were found despite differences in blood levels.
Special populations
Elderly
Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and C
max
levels have been reported in older subjects compared to younger subjects, reflecting the lower
metabolism of melatonin in the elderly. C
max
levels around 500 pg/ml in adults (18-45) versus
1200 pg/ml in elderly (55-69); AUC levels around 3,000 pg*h/mL in adults versus 5,000 pg*h/mL in
the elderly
.
Renal impairment
Company data indicates that there is no accumulation of melatonin after repeated dosing. This finding
is compatible with the short half-life of melatonin in humans.
The levels assessed in the blood of the patients at 23:00 (2 hours after administration) following 1 and
3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ml respectively,
and are
similar to those found in in healthy volunteers following a single dose of Circadin 2 mg.
Hepatic impairment
The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in
higher endogenous melatonin levels.
Plasma melatonin levels in patients
with cirrhosis were significantly increased during daylight
hours.
Patients had a significantly
decreased total
excretion of 6-sulfatoxymelatonin compared with controls.
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.
6.1 List of excipients
Ammonio methacrylate copolymer type B
Calcium hydrogen phosphate dihydrate
Lactose monohydrate
Silica, colloidal anhydrous
Talc
Magnesium stearate
8
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 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 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
Medicines no longer required should not be disposed of via wastewater or the municipal sewage
system. Return them to a pharmacy or ask your pharmacist how to dispose of them in accordance with
the national regulations. These measures will help to protect the environment.
7.
RAD Neurim Pharmaceuticals EEC Limited
One Forbury Square
The Forbury
Reading
Berkshire RG1 3EB
United Kingdom
e-mail: neurim@neurim.com
8.
EU/1/07/392/001
EU/1/07/392/002
EU/1/07/392/003
9.
29/06/2007
Detailed information on this product is available on the website of the European Medicines
Agencyhttp://www.ema.europa.eu
9
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
10
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Penn Pharmaceutical Services Ltd
Units 23-24 Tafarnaubach Industrial Estate
Tredegar
Gwent
NP22 3AA
UK
Catalent Germany Schorndorf GmbH
Steinbeisstrasse 2
D-73614 Schorndorf
Germany
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 OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2 of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated Risk Management Plan should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
11
ANNEX III
LABELLING AND PACKAGE LEAFLET
12
A. LABELLING
13
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
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.
Prolonged-release tablets
20 tablets
21 tablets
30 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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25ºC. Store in the original package in order to protect from light.
14
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
RAD Neurim Pharmaceuticals EEC Limited
One Forbury Square
The Forbury
Reading
Berkshire RG1 3EB
United Kingdom
e-mail: neurim@neurim.com
EU/1/07/392/001 21 tablets
EU/1/07/392/002 20 tablets
EU/1/07/392/003 30 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
15
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER STRIP
1.
Circadin 2 mg prolonged-release tablets
melatonin
2.
RAD Neurim Pharmaceuticals EEC Limited
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
Lot:
5.
OTHER
16
B. PACKAGE LEAFLET
17
PACKAGE LEAFLET: INFORMATION FOR THE USER
Circadin 2 mg prolonged-release tablets
Melatonin
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What Circadin is and what it is used for
2. Before you take Circadin
3. How to take Circadin
4. Possible side effects
5.
How to store Circadin
6.
Further 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 as monotherapy for the short-term treatment of primary insomnia (difficulty in getting
to sleep or staying asleep, or poor quality of sleep for at least one month), characterised by poor
quality of sleep in patients aged 55 years and older.
2.
BEFORE YOU TAKE CIRCADIN
Do not take Circadin
-
if you are allergic (hypersensitive) to melatonin or any of the other ingredients of Circadin.
Take special care with Circadin
-
if drowsiness is likely to cause a risk to your safety;
-
if you suffer from any liver problems;
-
if you suffer from any autoimmune disease (where the body is ‘attacked’ by its own
immune system).
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription BEFORE you start the treatment as they may
affect the action of Circadin. These medicines include hypnotics and tranquilisers (e.g.
benzodiazepines), fluvoxamine, thioridazine and imipramine (used to treat depression or psychiatric
problems), oestrogen (contraceptives or hormone replacement therapy), cimetidine and psoralens
(used to treat skin problems e.g. psoriasis).
18
-
Keep this leaflet. You may need to read it again.
-
if you suffer from kidney problems;
Taking Circadin with food and drink
Take Circadin after you have eaten. Do not drink alcohol before, during or after taking Circadin.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
It is not recommended to take Circadin if you are pregnant or suspect that you may be pregnant. It is
not recommended to take Circadin if you are breast feeding.
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.
Important information about some of the ingredients of Circadin
Each prolonged-release tablet contains 80 mg of 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 Circadin exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The dose is one Circadin tablet 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.
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 product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Circadin can cause side effects, although not everybody gets them. The following
events are considered to be uncommon (i.e. likely to occur in fewer than 1 in 100 patients):
Irritability, nervousness, restlessness, insomnia, abnormal dreams, anxiety, migraine, lethargy,
restlessness associated with increased activity, dizziness, tiredness, high blood pressure, upper
abdominal pain, indigestion, mouth ulceration, dry mouth, 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, chest pain, excretion of
glucose in the urine, excess proteins in the urine, abnormal liver function and weight increase.
19
The following events are considered to be rare (i.e., likely to occur in fewer than 1 in 1,000 patients):
Shingles, reduced number of white blood cells in the blood, decreased number of platelets in the blood,
high level of fatty molecules in the blood, severe chest pain due to angina, feeling your heartbeat , low
serum calcium levels in the blood, low sodium levels in the blood, altered mood, aggression, agitation,
crying, stress symptoms, disorientation, early morning awakening, increased sex drive, depressed
mood, depression, loss of consciousness or fainting, memory impairment, disturbance in attention,
dreamy state, restless legs syndrome, poor quality sleep, ‘pins and needles’ feeling, visual impairment,
blurred vision, watery eyes, dizziness when standing or sitting, vertigo, 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, psoriasis, 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, presence of
red blood cells in the urine, urinating during the night, increased liver enzymes, abnormal blood
electrolytes and abnormal laboratory tests.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE CIRCADIN
Keep out of the reach and sight of children.
Do not use Circadin after the expiry date which is stated on the carton. 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.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER 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 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.
20
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
RAD Neurim Pharmaceuticals EEC Limited
One Forbury Square
The Forbury
Reading
Berkshire RG1 3EB
United Kingdom
e-mail: neurim@neurim.com
Manufacturer:
Sites responsible for Batch Release in the EEA:-
Penn Pharmaceutical Services Ltd
Units 23-24 Tafarnaubach Industrial Estate
Tredegar
Gwent
NP22 3AA
UK
Catalent Germany Schorndorf GmbH
Steinbeisstrasse 2
D-73614 Schorndorf
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder
België/Belgique/Belgien
Nycomed Belgium
Chaussée de Gand 615
Gentsesteenweg
B-1080 Bruxelles / Brussel / Brüssel
Tél/Tel: +32 2 464 06 11
nycomed-belgium@nycomed.com
Luxembourg/Luxemburg
Nycomed Belgium
Chaussée de Gand 615,
Gentsesteenweg
B-1080 Bruxelles / Brüssel
Belgique / Belgien
Tél/Tel: +32 2 464 06 11
nycomed-belgium@nycomed.com
България
Lundbeck Export A/S Representative Office
EXPO 2000
Vaptzarov Blvd. 55
Sofia 1407
Tel: +359 2 962 4696
Magyarország
Lundbeck Hungaria Kft.
Montevideo utca 3/B
H-1037 Budapest,
Tel: +36 1 4369980
Česká republika
Lundbeck Česká republika s.r.o.
Bozděchova 7
CZ-150 00 Praha 5
Tel: +420 225 275 600
Malta
H. Lundbeck A/S
Ottiliavej 9
DK-2500 Valby
Id-Danimarka
Tel: + 45 36301311
21
Danmark
Nycomed Danmark ApS
Langebjerg 1
DK-4000 Roskilde
Tlf: +45 46 77 11 11
info@nycomed.com
Nederland
Nycomed Nederland B.V.
Jupiterstraat 250
NL-2132 HK Hoofddorp
Tel: +31 23 566 8777
infonl@nycomed.com
Deutschland
Lundbeck GmbH
Karnapp 25
D-21079 Hamburg
Tel: +49 40 23649 0
Norge
Nycomed Pharma AS
Drammensveien 852
N-1372 Asker
Tlf: +47 6676 3030
infonorge@nycomed.no
Eesti
Nycomed SEFA AS
Pirita tee 20T
EE-10127 Tallinn
Tel: +372 6112 569
info@nycomed.ee
Österreich
Nycomed Pharma GmbH
EURO PLAZA, Gebäude F
Technologiestraße 5
A-1120 Wien
Tel: + 43 1 815 0202-0
nycomed-austria@nycomed.com
Ελλάδα
Nycomed Hellas SA
196 Kifissias Avenue
Halandri 152 31, Athens
Τηλ: +30 210 6729570
info@nycomed.gr
Polska
Lundbeck Poland Sp. z o. o.
ul. Krzywickiego 34
PL-02-078 Warszawa
Tel.: + 48 22 626 93 00
España
Lundbeck España S.A.
Av. Diagonal, 605, 9-1a
E-08028 Barcelona
Tel: +34 93 494 9620
Portugal
Lundbeck Portugal Lda
Quinta da Fonte
Edifício D. João I – Piso 0 Ala A
P-2770-203 Paço d’Arcos
Tel: +351 21 00 45 900
France
Lundbeck SAS
37-45, quai du Président Roosevelt
F-92445 Issy-les-Moulineaux Cedex
Tél: + 33 1 79 41 29 00
România
Lundbeck Romania
Str. Ghiocei no.7A
Sector 2 Bucuresti
Postal code 020571 - RO
Tel: +40 21319 88 26
Ireland
Lundbeck (Ireland) Limited
7 Riverwalk
Citywest Business Campus
IRL - Dublin 24
Tel: +353 1 468 9800
Slovenija
Lundbeck Pharma d.o.o.
Titova cesta 8
SI-2000 Maribor
Tel.: +386 2 229 4500
22
Ísland
Nycomed
Langebjerg 1
DK-4000 Roskilde
Danmörk
Simi: +45 46 77 11 11
info@nycomed.com
Slovenská republika
Lundbeck Slovensko s.r.o.
Zvolenská 19
SK-821 09 Bratislava 2
Tel: +421 2 53412262
Italia
Lundbeck Italia S.p.A.
Via G. Fara 35
I-20124 Milan
Tel: +39 02 677 4171
Suomi/Finland
Oy Leiras Finland Ab
PL/PB 1406
FIN-00101 Helsinki
Puh/Tel: +358 20 746 5000
info@leiras.fi
Κύπρος
Lundbeck Hellas A.E
Θεμ. Δέρβη-Φλωρίνης
STADYL BUILDING
CY-1066 Λευκωσία
Τηλ.: +357 22490305
Sverige
Nycomed AB
Box 27264
SE-102 53 Stockholm
Tel: +46 8 731 28 00
infosweden@nycomed.com
United Kingdom
Lundbeck Limited
Lundbeck House
Caldecotte Lake Business Park
Caldecotte
Milton Keynes MK7 8LG - UK
Tel: +44 1908 649966
Lietuva
"Nycomed", UAB
Gynéjų 16
LT-01109 Vilnius
Tel: +370 521 09 070
Info@nycomed.lt
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
23
Source: European Medicines Agency
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