Consumer medicine information

Circadin Prolonged Release Tablet

Melatonin

BRAND INFORMATION

Brand name

Circadin

Active ingredient

Melatonin

Schedule

S4 | S3

What is in this leaflet

This leaflet contains answers to some common questions about CIRCADIN.

It is particularly important that you read the sections "When to take it" and "How to take it" before you take this medicine. The leaflet does not contain all the information that is known about CIRCADIN.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CIRCADIN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What CIRCADIN is used for

CIRCADIN is used to improve sleep quality and morning alertness in patients over 55 years of age with poor quality of sleep.

The active substance of CIRCADIN, melatonin (not of plant or animal origin), belongs to a group of naturally occurring hormones produced in the body.

Melatonin works by controlling the circadian rhythms and increasing the propensity to sleep.

Your doctor, however, may prescribe CIRCADIN for another purpose.

Ask your doctor or pharmacist if you have any questions about why it has been prescribed for you. This medicine is only available with a doctor’s prescription.

CIRCADIN is not addictive.

Before you take CIRCADIN

When you must not take it

Do not take CIRCADIN if you are allergic to it or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, or rash, itching or hives on the skin.

Do not take CIRCADIN if you have been drinking alcohol or intend to drink alcohol or believe that you may have alcohol, in your blood stream.

Do not take CIRCADIN if you are pregnant or breast-feeding. CIRCADIN has not been studied in pregnant or breast-feeding women.

Do not take it after the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well. The expiry date refers to the last day of the month.

Do not take it if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start taking CIRCADIN talk to your doctor.

Before you start to take it

Tell your doctor if:

you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.
you are pregnant or plan to become pregnant
you are breast-feeding or planning to breast-feed
you have, or have had the following medical conditions:

suffer from liver problems
suffer from kidney problems
If you suffer from an autoimmune disease
have a rare hereditary problem of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption

Do not give CIRCADIN to a child or adolescent. There is no experience with its use in children or adolescents under 18 years old.

If you have not told your doctor about any of the above, so before you use CIRCADIN.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may affect the way other medicines work.

Some medicines and CIRCADIN may interfere with each other. These include:

hypnotics and tranquilisers (e.g. benzodiazepine),
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)
alcohol
caffeine

The effect of adding CIRCADIN to other medicines used to treat insomnia has not been examined. It is not known if CIRCADIN will increase or decrease the effects of other treatments for insomnia.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking CIRCADIN.

How to take CIRCADIN

How much to take

Take CIRCADIN only when prescribed by your doctor.

The standard dose of CIRCADIN is one tablet once a day.

There is no evidence that taking more than the recommended dose will increase the effect of CIRCADIN.

How to take it

Swallow your tablet whole with a full glass of water.

Do not crush, chew or divide your tablet. Each CIRCADIN tablet has been specially designed to release the right dose of medicine while you sleep. If you crush, chew or divide the tablet they will not work properly

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

When to take it

After food, 1-2 hours before you go to bed.

How long to take it

It is important that you continue taking CIRCADIN for as long as your doctor prescribes. CIRCADIN may be continued for up to thirteen weeks.

If you forget to take it

If you forget to take your tablet, take another as soon as you remember, before going to bed or wait until it is time for your next dose.

Do not take a double dose to make up for a forgotten dose.

If you are not sure what to do, talk to your doctor or pharmacist.

If you have trouble remembering to take your CIRCADIN, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (In Australia 13 11 26 and in New Zealand 0800 POISON [0800 764 766]), or go to your nearest accident and emergency centre, if you think that you or anyone else may have taken too much CIRCADIN. Do this even if there are no signs of discomfort or poisoning.

While you are using CIRCADIN

Things you must do

If you are about to be started on any new medicine tell your doctor and pharmacist that you are taking CIRCADIN.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking CIRCADIN, stop taking the tablets and tell your doctor immediately.

Things you must not do

Do not give CIRCADIN to anyone else, even if they have the same condition as you.

Do not take more than the recommended dose unless your doctor tells you to.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not drink alcohol before or after taking this medicine

Things to be careful of

CIRCADIN rarely causes drowsiness, nevertheless it is not recommended to drive or operate machinery for 8 hours after you take it. Circadin does not impair morning alertness, but if you suffer from drowsiness during the day you should consult your doctor.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CIRCADIN.

CIRCADIN has been shown to improve the sleep of most people aged over 55 years, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you.

These are considered to be uncommon side effects (i.e., likely to occur in fewer than 1 in 100 patients):

Irritability, nervousness, restlessness insomnia, abnormal dreams, anxiety, nightmares, migraine, lethargy, psychomotor hyperactivity (restlessness associated with increased activity), dizziness, somnolence (tiredness), headache, high blood pressure, (upper) abdominal pain, indigestion, mouth ulceration, dry mouth, nausea, hyperbilirubinaemia (changes in the composition of your blood which could cause yellowing of the skin or eyes (jaundice), inflammation of the skin (dermatitis), night sweats, pruritis (itching), rash, dry skin, pain in extremities, menopausal symptoms, asthenia (feeling of weakness), chest pain, excretion of glucose in urine, excess proteins in the urine, abnormal liver function and weight increase.

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 (palpitations). 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 (paresthesia) reduced visual acuity (visual impairment), blurred vision, watery eyes, dizziness when standing or sitting, vertigo, hot flushes, gastrooesophageal reflux, gastrointestinal disorder, blistering in the mouth, tongue ulceration, gastrointestinal upset, vomiting, abnormal bowel sounds, flatulence (wind), salivary hypersecretion (excess saliva production), halitosis (bad breath), abdominal discomfort, gastric disorder, inflammation of the stomach lining, eczema, erythema (skin rash), hand dermatitis, psoriasis, pruritic rash (itchy rash), nail disorder, arthritis, muscle spasms, neck pain, night cramps, increased duration of erection, inflammation of the prostate gland, tiredness, pain, thirst, passing large volumes or urine, presence of red blood cells in the urine, urination during the night, increased liver enzymes, abnormal blood electrolytes and abnormal laboratory tests.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them

After using CIRCADIN

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Keep CIRCADIN away from sunlight.

Keep the medicine in a cool dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and damp can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking the tablets or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What CIRCADIN looks like

CIRCADIN 2 mg tablets are white to off-white round bi-convex shaped tablets

CIRCADIN tablets are available in a 30 tablet pack and a 7 tablet sample pack.

Ingredients

Active ingredient
Each CIRCADIN 2 mg tablet contains 2 mg melatonin as the active ingredient

Inactive ingredients:

Ammonio methacrylate copolymer type B,
calcium hydrogen phosphate,
lactose,
colloidal anhydrous silica,
purified talc
magnesium stearate.

Australian Sponsor

RAD Data Australia Pty Ltd
PKF Melbourne
Level 12, 440 Collins Street
Melbourne, VIC, 3000

Distributed in Australia by:

Aspen Pharma Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065

Distributed in New Zealand by:

Pharmacy Retailing t/a
Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Mangere
Auckland

This leaflet was prepared in May 2016

Australian Registration Number:
AUST R: 153959

CIRCADIN is a registered trademark of Neurim Pharmaceuticals.

Published by MIMS May 2017

BRAND INFORMATION

Brand name

Circadin

Active ingredient

Melatonin

Schedule

S4 | S3

Notes

Distributed by Aspen Pharmacare Australia Pty Ltd

1 Name of Medicine

Melatonin.

2 Qualitative and Quantitative Composition

Circadin 2 mg prolonged release tablets.
The active ingredient in Circadin prolonged release tablets is a melatonin not of plant or animal origin.

Excipient with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Prolonged release tablet.
White to off-white, round, biconvex tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

Monotherapy for the short term treatment of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over.

4.2 Dose and Method of Administration

Oral use. Tablets should be swallowed whole.
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 use.

Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

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.

4.3 Contraindications

Circadin prolonged release tablets are contraindicated in patients with a known hypersensitivity to any ingredient of the product (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Drowsiness.

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.

Autoimmune diseases.

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.

Excipients.

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in the elderly.

Paediatric use.

Circadin is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

Effects on laboratory tests.

No information is available on the effect of melatonin on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacokinetic interactions.

Hepatic enzymes.

Melatonin has been observed to induce CYP3A in vitro at supratherapeutic concentrations. The clinical relevance of the finding is unknown. If induction occurs, plasma concentrations of concomitantly administered drugs can be reduced.
Melatonin does not appear to induce CYP1A enzymes in vitro at supratherapeutic 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.

Quinolones.

CYP1A2 inhibitors such as quinolones may give rise to increased melatonin exposure.

Carbamazepine and rifampicin.

CYP1A2 inducers such as carbamazepine and rifampicin may give rise to reduced plasma concentrations of melatonin.

Fluvoxamine.

Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (17-fold higher AUC and 12-fold higher serum C_max) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided.

5 or 8-methoxypsoralen.

Caution should be exercised in patients on 5 or 8-methoxypsoralen (5 and 8-MOP), which increases melatonin levels by inhibiting its metabolism.

Cimetidine.

Coadministration of Circadin with cimetidine resulted in a 1.7-fold increase in exposure to melatonin with no change in the exposure to cimetidine.
Caution should be exercised in patients on cimetidine, a CYP2D inhibitor which increases plasma melatonin levels by inhibiting its metabolism.

Cigarette smoking.

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

Oestrogens.

Caution should be exercised in patients on oestrogens (e.g. contraceptives or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2.

Other.

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.

Alcohol should not be taken with Circadin, because it reduces the effectiveness of Circadin on sleep. The prolonged release characteristics of Circadin may be altered by alcohol, resulting in immediate release of melatonin.

Hypnotics.

Circadin may enhance the sedative properties of benzodiazepines and nonbenzodiazepine 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 codosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to zolpidem alone.

Thioridazine and imipramine.

Circadin has been coadministered 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 coadministration 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

Effects on fertility.

No significant effects on fertility or reproductive performance were observed in rats given oral melatonin prior to mating through to early gestation at doses over 900-fold the recommended clinical dose, based on body surface area.
(Category B3)
No significant effects on embryofetal development were observed in rats given oral melatonin during the period of organogenesis at doses over 900-fold the recommended clinical dose, based on body surface area.
No clinical data on exposed pregnancies are available. In view of the lack of clinical data, use in pregnant women and by women intending to become pregnant is not recommended.
Maternal transfer of exogenous melatonin to the fetus via the placenta or milk has been demonstrated in several animal species including rats, hamsters, goats, monkeys and cows. A slight reduction in postnatal growth, viability and development was found in rats given oral melatonin during gestation through weaning at doses over 900-fold the recommended clinical dose, based on body surface area; the no-effect dose was over 250-fold the clinical dose.
Endogenous melatonin has been detected in human breast milk, thus exogenous melatonin is likely excreted into human milk. The effects of melatonin on the nursing infant have not been established. Therefore, breastfeeding is not recommended in women under treatment with melatonin.

4.7 Effects on Ability to Drive and Use Machines

Circadin has negligible influence on the ability to drive and use machines. Nevertheless, patients should avoid engaging in hazardous activities (such as driving or operating machinery) after taking Circadin.

4.8 Adverse Effects (Undesirable Effects)

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. In the Circadin group, there were 72 cases (2.9% of the safety population) of adverse events leading to discontinuation of the patient. In the placebo group there were 62 cases (4.0% of the safety population) of adverse events leading to discontinuation of the patient. See Table 1.
The adverse reactions in Table 2 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.
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).

Postmarketing data.

Psychiatric disorders.

Nightmares.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

In general, the main therapy for all overdoses is supportive and symptomatic care.

Symptoms.

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.

Treatment.

Clearance of the active substance is expected within 12 hours after ingestion. No special treatment is required.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or National Poisons Centre on 0800 764 766 (New Zealand).

5 Pharmacological Properties

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 and MT2 receptors is believed to contribute to its sleep promoting properties via their distinct actions on the circadian clock. The MT1 receptors are thought to inhibit neuronal firing, while the MT2 receptors have been implicated in the phase shifting response.

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 trials.

Three phase 3 studies and a sleep laboratory study were considered pivotal. These studies enrolled patients with primary insomnia who were aged at least 55 years. Patients suffering from severe neurological, psychiatric or neurosurgical diseases or taking CNS medications including benzodiazepines or other hypnotic agents were excluded.
The primary assessment tool was the Leeds Sleep Evaluation Questionnaire (LSEQ), comprising 10 self rated 100 mm line analogue questions concerning aspects of sleep and early morning behaviour. The LSEQ measures ease of getting to sleep (GTS), quality of sleep (QOS), ease of waking from sleep (AFS) and behaviour following wakefulness (BFW). The primary outcome variable in the pivotal clinical trials was QOS, or a combination on QOS and BFW, where a patient had to show a clinically relevant improvement on both QOS and BFW. Time to onset of sleep and duration of sleep were measured objectively only in a polysomnography study. Efficacy of Circadin in combination with other hypnotic agents has not been assessed.
In a polysomnographic (PSG) study (N = 40; 20 Circadin, 20 placebo) 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, time to onset of sleep was shortened significantly by 9 minutes compared to placebo. A statistically significant difference favouring Circadin was seen for total duration of time awake prior to sleep onset (approx change from 10 to 11 minutes for Circadin and from 21 to 20 minutes for 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. Circadin did not prolong the duration of sleep significantly compared to placebo.
In the outpatient studies patients who failed to meet the inclusion criteria at the end of the run in period due to the instability of their disorder (16% of the total population) were not included in the efficacy analysis.
In an outpatient study (Neurim VII: N = 170; 82 Circadin, 88 placebo) with two week run in baseline period with placebo, a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks and two week withdrawal period with placebo, the primary efficacy endpoint was Quality of Sleep (QOS). 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. There was a mean difference of approximately 6 mm in quality of sleep and approximately 9 mm in morning alertness, both favouring 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 (N = 334; 169 Circadin, 165 placebo) 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 time to onset of sleep 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.
A third study involved more than 600 patients over 55, over 400 of whom were on Circadin treatment for up to 6 months. Patients given Circadin demonstrated a difference from placebo in mean change from baseline in subjective sleep latency, assessed using a sleep diary, of -7.8 minutes after 3 weeks (p = 0.014). Small differences in sleep latency were generally maintained over 13 weeks of placebo controlled treatment.
The percentage of patients showing both remission of insomnia (PSQI of < 6) and a clinically relevant improvement of 10% in quality of life scores (WHO-5 index) increased from 16.7% (cf. 10.6% placebo, p = 0.044) at week 3 to 25.8% at week 13 (cf. 15.7% placebo, p = 0.006).
This study also examined the effect of Circadin on sleep latency in younger subjects with primary insomnia and low excretion of melatonin. Clinically significant effects on sleep latency were not demonstrated in these patients.

Long-term safety.

The safety profile both during 3 weeks and during the 26 week periods was comparable to placebo with no withdrawal and rebound effects.
In an open study where 96 subjects completed 12 months treatment with Circadin no tolerance, rebound or withdrawal effects were reported.

5.2 Pharmacokinetic Properties

Absorption.

The absolute bioavailability of melatonin from Circadin has not been assessed. Other oral formulations of melatonin have an absolute bioavailability in the region of 15% but this is highly variable with high first-pass metabolism. The relative bioavailability of melatonin from Circadin is comparable to that of an oral melatonin solution.
Data from other formulations of melatonin indicate that 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 is linear over the range of 2-8 mg as obtained from published results using a formulation other than Circadin.
Bioavailability as assessed from other oral formulations of melatonin is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85% as assessed from other oral formulations of melatonin. T_max occurs after 2.6 hours in a fed state. The rate of melatonin absorption 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 (T_max = 2.6 hours versus T_max = 1.6 hours). C_max and AUC levels were not affected by food.

Distribution.

The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin is mainly bound to albumin, alpha₁-acid glycoprotein and high density lipoprotein. The binding to the other serum proteins is insignificant. The melatonin binding was constant over the range of the studied concentrations in serum. Literature data indicates that melatonin is distributed in all body fluids and is accessible at all tissues.

Metabolism.

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.

Excretion.

Terminal half life (t_½) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% as sulphated and glucuronide conjugates of 6-hydroxymeltonin and 2% is excreted as melatonin (unchanged drug).

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.

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 picogram/mL in adults (18-45) versus 1200 picogram/mL in the elderly (55-65); AUC levels around 3000 picogram*h/mL in adults versus 6000 picogram*h/mL in the elderly.

Renal impairment.

Melatonin did not accumulate after repeated dosing with Circadin. This finding is compatible with the short half-life of melatonin in humans.
The levels assessed in the blood of 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 picogram/mL respectively, and are similar to those found 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

Genotoxicity.

Results from a standard battery of in vitro and in vivo assays showed no evidence of a genotoxic potential for melatonin.

Carcinogenicity.

An oral lifetime carcinogenicity study with melatonin in rats showed an increased incidence of thyroid follicular cell adenomas in males at doses around 700-fold the recommended clinical dose, based on body surface area. No neoplastic tissue histopathology was examined at lower doses and therefore the no-effect dose could not be determined. These effects were associated with liver enzyme induction in this species and are unlikely to be relevant to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ammonio methacrylate copolymer, calcium hydrogen phosphate dihydrate, lactose monohydrate, colloidal anhydrous silica, purified talc, magnesium stearate.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Blister packs (PVC/PVdC/Al) of 21, 30, 42, 60, 90 or 7 (sample pack) tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Melatonin is a slightly off white, odourless crystalline powder. Melatonin is very slightly soluble in water and in dilute hydrochloric acid.

Chemical structure.

Chemical name: N-[2-(5-methoxyindol-3-yl)ethyl]acetamide.
Structural formula:

Molecular formula: C₁₃H₁₆N₂O₂.
Molecular weight: 232.27. pKa: 12.3-12.7.

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Circadin Prolonged Release Tablet

Melatonin

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BRAND INFORMATION

Circadin 2 mg Tablets