CIRCADIN

15.02.2019

115988

Page 1 of 4

Patient Leaflet in accordance with the Pharmacists' Regulations

(Preparations) - 1986

This medicine is sold only with a doctor’s prescription

The format of this leaflet was determined by the Ministry of Health and its content

was checked and approved by the Ministry of Health in December 2014 and was

updated in accordance with the

the Ministry of Health's directives on February 15, 2019

Circadin

Prolonged-release tablets

Composition:

Each tablet contains 2 mg melatonin

(Melatonin 2mg)

Inactive ingredients: See list in section 6 and also in the section "Important information

about some of the medicine's ingredients".

-

Read the leaflet in its entirety before using the medicine. This leaflet contains

concise information about the medicine. If you have any further questions, please

contact your doctor or pharmacist.

-

This medicine has been prescribed for you. Do not pass it on to others. It may harm

them, even if you think that their medical condition is similar to yours.

-

The medicine is intended for adults over the age of 55.

1. What is the medicine intended for?

Melatonin, the active ingredient in Circadin, belongs to a group of natural hormones produced

by the body.

Circadin is used for a short-term treatment of primary insomnia (sleeplessness, difficulty

falling asleep or staying asleep or poor quality of sleep) in patients aged 55 or over.

Insomnia is defined as 'primary' when it is not the result of an identified cause, such as a

medical, mental or environmental condition.

Therapeutic group: A hormone secreted by the body.

2. Before you use the medicine

Do not use this medicine if -

you are sensitive (allergic) to the active ingredient or to

any of the other ingredients of this medicine

(a list of the inactive ingredients can be

found in section 6).

Special warnings regarding the use of this medicine:

Before treatment with Circadin , tell your doctor if:

-

You are pregnant or breastfeeding (see "Pregnancy and breastfeeding" section)

-

You are suffering from liver or kidney disorders. Using Circadin is not recommended

in these conditions since no studies on Circadin were conducted in people with liver

or kidney diseases.

-

You are suffering from intolerance to certain sugars.

-

You are suffering from an autoimmune disease (a disease in which the body is

attacked by its own immune system). Using Circadin is not recommended in these

conditions since no studies on Circadin were conducted in people with autoimmune

diseases.

Circadin may cause sleepiness and therefore may impair your ability to perform any

activity requiring alertness, such as driving (see "Driving and using machinery" section).

Smoking may reduce Circadin's effect, since ingredients in the tobacco smoke may

increase the breakdown of melatonin in the liver.

Do not administer the medicine to children 0 to 18 years old, since its effect on them has

not been studied and is unknown.

15.02.2019

115988

Page 2 of 4

If you are taking, or have recently taken, other medicines, including non-prescription

medicines and nutritional supplements, inform the doctor or pharmacist. In particular,

the doctor or pharmacist should be informed if you are taking:

Fluvoxamine (for the treatment of depression and obsessive-compulsive disorder),

psoralens (for the treatment of skin disorders such as psoriasis), Cimetidine (for the

treatment of gastric ulcers), antibiotics from the Quinolone family and Rifampicin

(for treating bacterial infections), estrogens (found in contraceptive pills or in

medicines for hormone replacement therapy) and Carbamazepine (for the treatment

of epilepsy).

Drugs belonging to the family of adrenergic agonists or antagonists, such as certain

medicines for controlling blood pressure by blood vessel contraction, medicines for

reducing nasal congestion, antihypertensive medicines; medicines belonging to the

family of opiate agonists or antagonists such as medicines for treating narcotic

addiction, prostaglandin inhibitors (such as non-steroidal anti-inflammatory drugs),

anti-depression medicines, Tryptophan and alcohol.

Benzodiazepines and other sleep-inducing medicines that do not belong to the

benzodiazepine group, such as Zaleplon, Zolpidem and Zopiclon.

Thioridazine (for the treatment of schizophrenia) and Imipramine (for the treatment

of depression).

Using the medicine and food

Circadin should be taken after a meal.

Using the medicine and alcohol consumption

Do not drink alcohol before, during or after taking Circadin, since alcohol reduces the

medicine's efficacy.

Pregnancy and breastfeeding

Do not use Circadin if you are pregnant, if you think you are pregnant, if you are trying to

become pregnant or if you are breastfeeding.

Consult a doctor or a pharmacist before using this drug.

Driving and use of machinery

Circadin might cause sleepiness. If this is how the medicine affects you, do not drive or

operate dangerous machinery while using the medicine. If you suffer from persistent

sleepiness, consult a doctor.

Important information about some of the medicine's ingredients

Circadin contains lactose monohydrate which may cause an allergic reaction in lactose-

intolerant patients. Consult a doctor before starting treatment, if your doctor tells you that you

are intolerant to certain sugars.

3. How to use this medicine?

Always use according to the doctor’s instructions. If you are not sure, check with your doctor

or pharmacist.

The dosage and manner of treatment will only be determined by the doctor. The standard dose

is usually:

One tablet taken daily (2 mg), after food, 1-2 hours before bedtime. You may continue this

dosage for a period of up to 13 weeks.

Do not exceed the recommended dose.

Instructions for use: Do not chew! The medicine should be swallowed whole after a meal.

Do not cut in half or crush the tablet.

-

If you have accidentally taken a higher dosage proceed to a doctor or a pharmacist

as soon as possible. Exceeding the recommended dosage may make you feel drowsy.

If you have taken an overdose, or if a child has accidentally swallowed the medicine,

proceed immediately to a doctor or a hospital emergency room and bring the package

of the medicine with you.

15.02.2019

115988

Page 3 of 4

-

If you forget to take the medicine, take the tablet as soon as you remember, before

going to sleep, or at the usual time of the next dose and then proceed as usual. Do not

take a double dose.

-

You should follow the treatment course as recommended by your doctor.

-

If you stop taking the medicine: No harmful effect is known when treatment is

discontinued suddenly or prematurely. There are no known withdrawal symptoms

following end of treatment with Circadin.

-

Do not take medicines in the dark! Check the label and the dose each time you take a

medication. Wear glasses if you need them.

If you have further questions about using the medicine, consult a doctor or a pharmacist.

4. Side-effects

Like with any medicine, the use of Circadin may cause side effects in some patients. Do not

be alarmed while reading the list of side effects. You may not suffer from any of them.

Stop use and contact a doctor immediately if the following serious side effects appear:

Appear infrequently (frequency of up to 1:100 patients)

-

Chest pain

Appear rarely (frequency of up to 1:1000 patients):

-

Loss of consciousness or fainting

-

Serious chest pain resulting from angina pectoris

-

Palpitations

-

Depression

-

Vision disorders

-

Blurred vision

-

Disorientation

-

Vertigo (dizziness)

-

Presence of red blood cells in urine

-

Reduced amount of white blood cells in the blood.

-

Reduced amount of platelets in the blood, which increases the risk for bleeding or

contusions

-

Psoriasis

Contact a doctor if the following non-serious side effects appear:

Appear infrequently (frequency of up to 1:100 patients)

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

migraines, headaches, exhaustion, psychomotor hyperactivity (restlessness accompanied with

increased activity), dizziness, fatigue, hypertension, upper abdominal pain, gastrointestinal

disorders, mouth ulceration, dry mouth, nausea, hyperbilirubinaemia (a change in the

composition of the blood which could cause yellowing of the skin or the eyes), dermatitis,

night sweats, pruritus or rash, dry skin, limb pains, menopausal symptoms, weakness feeling,

secretion of glucose or protein in urine, abnormal liver function tests and weight increase.

Appear rarely (frequency of up to 1:1000 patients):

Shingles (Herpes zoster, a viral disease), high levels of lipids in the blood, low levels of

calcium in the blood, low levels of sodium in the blood, mood swings, aggression,

nervousness, crying, stress symptoms, waking up early in the morning, increased libido,

deteriorated mood, memory impairment, concentration disorders, dreaminess, restless legs

syndrome, poor quality of sleep, pins and needles sensation, teary eyes, dizziness when

standing up or sitting down, hot flashes, heartburn (reflux of acid from the stomach to the

esophagus), gastrointestinal disorders, mouth blisters, tongue ulceration, abdominal pain,

vomiting, abnormal sounds from the digestive system, gastric flatulence, increased saliva

secretion, bad breath, abdominal discomfort, stomach disorders, gastritis, eczema, skin rash,

inflammation on the skin of the hands, itchy rash, nail disorders, arthritis, muscle cramps,

neck pain, muscle cramps at night, priapism that might be painful, prostate inflammation,

fatigue, pain, thirst, larger than usual volume of urine, night urination, increased liver

enzymes, abnormal results of blood electrolytes and laboratory tests.

15.02.2019

115988

Page 4 of 4

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.

If one of the side effects aggravates, or when you suffer a side effect not mentioned in this

leaflet, you should consult the doctor.

Side effects may be reported to the Ministry of Health by clicking the “Report Side Effects

from Drug Treatment” found on the home page of the Ministry of Health’s website

(www.health. gov.il) which redirects to the online form for reporting side effects, or by

accessing the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffec

tMedic@moh.gov.il

5. How to store the medicine?

- Avoid poisoning!

This medicine, and all other medicines, must be stored in a safe place out of the reach of

children and/or infants, to avoid poisoning.

Do not induce vomiting unless explicitly instructed to do so by the doctor!

- Do not use the medicine after the expiry date (exp. date) stated on the package.

The expiry date refers to the last day of the mentioned month.

- Storage conditions:

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

- Do not discard medications in the toilet or into residential waste cans. Ask the pharmacist

how to discard unnecessary medications, in order to protect the environment.

6. Further information

- In addition to the active ingredient, this medicine also contains:

Ammonium methacrylate copolymer type B, calcium hydrogen phosphate dihydrate, lactose

monohydrate, silica (colloidal anhydrous), talc and magnesium

stearate.

Each tablet contains 80 mg lactose monohydrate (see "Important information about some of

the medicine's ingredients" section).

How the medicine looks and what are the contents of the package: a tablet, round, double-

concave, of a white to off-white color. The tablets come in a blister pack of 7, 20, 21

tablets or a box containing 2 blister packs of 15 tablets (30 tablets).

It is possible that not all package sizes are marketed.

– The

manufacturer and the registration owner and his address:

Neurim Pharmaceuticals (1991) Limited, 8 Hanechoshet St., Tel Aviv 69710.

Marketed by Teva Pharmaceutical Industries Ltd., POB 3190 Petach Tikva

-

Medicine registration number in the National Medicine Registry of the Ministry of

Health: 139.92.31648

-

For the sake of simplicity and ease of reading, this leaflet is worded in the

masculine/feminine gender, but the medicine is intended for both genders.

References for leaflet escalations and modifications:

EMA approved patient leaflet, 14/08/2013

Page 1 of 9

SUMMARY OF PRODUCT CHARACTERISTICS

The content of this leaflet was approved by the Ministry of Health in December 2014 and updated

according to the guidelines of the Ministry of Health in February 15th 2019

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 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.

No data are available.

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

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 2 of 9

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.

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 C

) 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.

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 3 of 9

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

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.

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

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 4 of 9

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

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 5 of 9

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. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.gov.il

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.

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 6 of 9

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

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 7 of 9

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.

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

occurs after 3 hours in a fed state. The rate of melatonin absorption

and C

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

=3.0 h versus T

=0.75 h) and lower

peak plasma concentration in the fed state (C

=1020pg/ml versus C

=1176 pg/ml).

Distribution

in vitro

plasma protein binding of melatonin is approximately 60%. Circadin is mainly bound to

albumin, alpha

-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

) 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 C

is apparent for women compared to men. A five-fold variability in C

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 C

levels have been reported in older patients compared to younger patients, reflecting the lower

metabolism of melatonin in the elderly. C

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.

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 8 of 9

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.

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

XXXX.XXXX - Revision of SPC according to EMA approved SmPC

Page 9 of 9

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

Neurim Pharmaceuticals (1991) Limited

Hanehoset 8

Tel Aviv

8. Registration Number

139 92 31648