Consumer medicine information

SomniCare

Melatonin

BRAND INFORMATION

Brand name

SomniCare

Active ingredient

Melatonin

Schedule

S3

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using SomniCare.

SUMMARY CMI

SomniCare

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using SomniCare?

SomniCare contains the active ingredient Melatonin. SomniCare is used to improve sleep quality and morning alertness in patients over 55 years of age with poor quality of sleep.

For more information, see Section 1. Why am I using SomniCare? in the full CMI.

2. What should I know before I use SomniCare?

Do not use if you have ever had an allergic reaction to SomniCare or any of the ingredients listed at the end of the CMI.

Talk to your doctor or pharmacist if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SomniCare? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SomniCare and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SomniCare?

  • Adults 55 years and over: Take one tablet after food, 1-2 hours before you go to bed.

More instructions can be found in Section 4. How do I use SomniCare? in the full CMI.

5. What should I know while using SomniCare?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SomniCare.
  • If you become pregnant while taking SomniCare, stop taking the tablets and tell your doctor or pharmacist immediately.
  • Go to bed and arise at the same time daily
  • Engage in relaxing activities before bedtime
  • Exercise regularly but not in the late evening
  • Avoid eating meals or large snacks just before bedtime
  • Eliminate daytime naps
  • Avoid caffeine-containing drinks after midday
  • Avoid alcohol or the use of nicotine late in the evening
  • Minimise external disruption (e.g. light and noise)
  • If you are unable to sleep, do not become anxious; leave the bedroom and participate in relaxing activities such as reading or listening to music until you are tired.
Things you should not do
  • Do not give SomniCare to anyone else, even if they have the same condition as you.
  • Do not take more than the recommended dose unless your doctor or pharmacist tells you to.
  • Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not drink alcohol before or after taking this medicine.
Driving or using machines
  • SomniCare rarely causes drowsiness, nevertheless it is not recommended to drive or operate machinery for 8 hours after you take it.
  • SomniCare does not impair morning alertness, but if you suffer from drowsiness during the day you should consult your doctor or pharmacist.
Drinking alcohol
  • Do not drink alcohol before or after taking this medicine.
Looking after your medicine
  • Keep your tablets in the blister pack until it is time to take them.
  • Keep SomniCare away from sunlight.
  • Keep the medicine in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using SomniCare? in the full CMI.

6. Are there any side effects?

The active ingredient melatonin 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.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

SomniCare

Active ingredient: Melatonin

Consumer Medicine Information (CMI)

This leaflet provides important information about using SomniCare. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SomniCare.

Where to find information in this leaflet:

1. Why am I using SomniCare?
2. What should I know before I use SomniCare?
3. What if I am taking other medicines?
4. How do I use SomniCare?
5. What should I know while using SomniCare?
6. Are there any side effects?
7. Product details

1. Why am I using SomniCare?

SomniCare contains the active ingredient Melatonin. The active substance of SomniCare, melatonin, 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.

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

2. What should I know before I use SomniCare?

Warnings

Do not use SomniCare if:

  • you are allergic to Melatonin or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • you have been drinking alcohol or intend to drink alcohol or believe that you may have alcohol in your blood stream.
  • you are pregnant or breast-feeding. SomniCare has not been studied in pregnant or breast-feeding women.

Check with your doctor or pharmacist if 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
  • take any medicines for any other condition
  • Do not give SomniCare to a child or adolescent. There is no experience with its use in children or adolescents under 18 years old.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

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

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with SomniCare and affect how it works.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SomniCare.

4. How do I use SomniCare?

How much to take / use

  • The standard dose of SomniCare is one tablet once a day. There is no evidence that taking more than the recommended dose will increase the effect of SomniCare.
  • Swallow your tablet whole with a full glass of water.
  • Do not crush, chew or divide your tablet.
  • Each SomniCare 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 the instructions provided with the medicine
  • Do not exceed the recommended dosage.

When to take / use SomniCare

  • SomniCare should be used after food, 1-2 hours before you go to bed.

If you forget to use SomniCare

SomniCare should be used regularly at the same time each day. If you miss your dose at the usual time, take another as soon as you remember, before going to bed or wait until it is time for your next dose.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much SomniCare

If you think that you have used too much SomniCare, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor or pharmacist, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SomniCare?

Things you should do

  • Go to bed and arise at the same time daily
  • Engage in relaxing activities before bedtime
  • Exercise regularly but not in the late evening
  • Avoid eating meals or large snacks just before bedtime
  • Eliminate daytime naps
  • Avoid caffeine-containing drinks after midday
  • Avoid alcohol or the use of nicotine late in the evening
  • Minimise external disruption (e.g. light and noise)
  • If you are unable to sleep, do not become anxious; leave the bedroom and participate in relaxing activities such as reading or listening to music until you are tired.

Call your doctor or pharmacist straight away if you:

  • If you become pregnant while taking SomniCare, stop taking the tablets and tell your doctor or pharmacist immediately.
  • Remind any doctor, dentist or pharmacist you visit that you are using SomniCare.

Things you should not do

  • Do not give SomniCare to anyone else, even if they have the same condition as you.
  • Do not take more than the recommended dose unless your doctor or pharmacist tells you to.
  • Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not drink alcohol before or after taking this medicine.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SomniCare affects you.

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

Drinking alcohol

Tell your doctor or pharmacist if you drink alcohol.

Do not drink alcohol before or after taking this medicine.

Looking after your medicine

  • Keep SomniCare away from sunlight.
  • Store below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Uncommon side effects

Less serious side effectsWhat to do
Psychiatric Disorders
  • Irritability, nervousness, restlessness insomnia, abnormal dreams, anxiety, nightmares
Nervous System Disorders
  • Migraine, lethargy, psychomotor hyperactivity (restlessness associated with increased activity), dizziness, somnolence (tiredness), headache
Vascular Disorders
  • High blood pressure
Gastrointestinal Disorders
  • Abdominal pain (upper), indigestion, mouth ulceration, dry mouth, nausea
Hepatobiliary Disorders
  • Hyperbilirubinaemia (changes in the composition of your blood which could cause yellowing of the skin or eyes (jaundice)
Skin and Subcutaneous Tissue Disorders
  • Inflammation of the skin (dermatitis), night sweats, pruritis (itching), rash, dry skin
Musculoskeletal and Connective Tissue Disorders
  • Pain in extremities
Reproductive System and Breast Disorders
  • Menopausal symptoms
General Disorders and Administration Site Conditions
  • Asthenia (feeling of weakness), chest pain
Renal and Urinary Disorders
  • Excretion of glucose in urine, excess proteins in the urine
Investigations
  • Liver Function Test Abnormal, weight increase
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Rare side effects

Serious side effectsWhat to do
Infections and Infestations
  • Shingles
Blood and Lymphatic System Disorders
  • Reduced number of white blood cells in the blood, decreased number of platelets in the blood
Cardiac Disorders
  • Severe chest pain due to angina, feeling your heartbeat (palpitations).
Immune System Disorders
  • Hypersensitivity reaction
Metabolism and Nutrition Disorders
  • High level of fatty molecules in the blood, low serum calcium levels in the blood, low sodium levels in the blood
Psychiatric Disorders
  • Altered mood, aggression, agitation, crying, stress symptoms, disorientation, early morning awakening, increased sex drive, depressed mood, depression
Nervous System Disorders
  • Loss of consciousness or fainting, memory impairment, disturbance in attention, dreamy state, restless legs syndrome, poor quality sleep, ‘pins and needles’ feeling (paresthesia)
Eye Disorders
  • Reduced visual acuity (visual impairment), blurred vision, watery eyes
Ear and Labyrinth Disorders
  • Dizziness when standing or sitting, vertigo
Vascular Disorders
  • Hot flushes
Gastrointestinal Disorders
  • Gastro-oesophageal 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
Skin and Subcutaneous Tissue Disorders
  • Eczema, erythema (skin rash), hand dermatitis, psoriasis, pruritic rash (itchy rash), nail disorder
Musculoskeletal and Connective Tissue Disorders
  • Arthritis, muscle spasms, neck pain, night cramps
Reproductive System and Breast Disorders
  • Increased duration of erection, inflammation of the prostate gland
General Disorders and Administration Site Conditions
  • Tiredness, pain, thirst
Renal and Urinary Disorders
  • Passing large volumes or urine, presence of red blood cells in the urine, urination during the night
Investigations
  • Increased liver enzymes, abnormal blood electrolytes and abnormal laboratory tests.
Call your doctor or pharmacist straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is available over-the-counter without a doctor's prescription.

What SomniCare contains

Active ingredient
(main ingredient)		Each SomniCare 2 mg tablet contains 2 mg melatonin as the active ingredient
Other ingredients
(inactive ingredients)
  • ammonio methacrylate copolymer,
  • calcium hydrogen phosphate dihydrate,
  • lactose monohydrate,
  • anhydrous colloidal silica,
  • talc,
  • magnesium stearate.

Do not take this medicine if you are allergic to any of these ingredients.

What SomniCare looks like

SomniCare tablets are white to off-white round bi-convex shaped tablets (AUST R 422124).

Who distributes SomniCare

AFT Pharmaceuticals Pty Ltd.
113 Wicks Road
North Ryde, NSW 2113, Australia
Email: [email protected]

This leaflet was prepared in September 2023.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

SomniCare

Active ingredient

Melatonin

Schedule

S3

 

1 Name of Medicine

Melatonin.

2 Qualitative and Quantitative Composition

SomniCare 2 mg prolonged release tablets.
The active ingredient in SomniCare prolonged release tablets is a melatonin not of 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.

SomniCare 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 melatonin prolonged release 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, SomniCare is not recommended for use in patients with hepatic impairment.

4.3 Contraindications

SomniCare 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.

SomniCare 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 melatonin prolonged release tablets in individuals with autoimmune diseases. Therefore SomniCare 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.

Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and Cmax levels have been reported in older subjects compared to younger subjects, reflecting the lower metabolism of melatonin in the elderly.

Paediatric use.

SomniCare 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 supra-therapeutic 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 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.

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 Cmax) 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 melatonin prolonged release tablets 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 melatonin prolonged release tablets or vice versa has not been studied.

Pharmacodynamic interactions.

Alcohol.

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

Hypnotics.

SomniCare 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 melatonin prolonged release tablets and zolpidem one hour following co dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone.

Thioridazine and imipramine.

Melatonin prolonged release tablets have 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, melatonin prolonged release tablets 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

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 intended 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 post-natal 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, breast-feeding is not recommended in women under treatment with melatonin.

4.7 Effects on Ability to Drive and Use Machines

SomniCare 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 SomniCare.

4.8 Adverse Effects (Undesirable Effects)

In clinical trials (in which a total of 1931 patients were taking melatonin prolonged release tablets and 1642 patients were taking placebo), 48.8% of patients receiving melatonin prolonged release tablets 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 melatonin prolonged release tablets (5.743 - placebo vs. 3.013 - melatonin prolonged release tablets). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the melatonin prolonged release tablets and placebo treated groups. In the melatonin prolonged release tablet 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 melatonin prolonged release tablets 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).

Post-marketing 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. Melatonin prolonged release tablets have 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 melatonin prolonged release tablets in combination with other hypnotic agents has not been assessed.
In a polysomnographic (PSG) study (N=40; 20 melatonin prolonged release tablets, 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 melatonin prolonged release tablets was seen for total duration of time awake prior to sleep onset (approx change from 10 to 11 minutes for melatonin prolonged release tablets and from 21 to 20 minutes for placebo). There were no modifications of sleep architecture and no effect on REM sleep duration by melatonin prolonged release tablets. Modifications in diurnal functioning did not occur with melatonin prolonged release tablets 2 mg. Melatonin prolonged release tablets 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 (N=170; 82 melatonin prolonged release tablets, 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 melatonin prolonged release tablet 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 melatonin prolonged release tablets 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 melatonin prolonged release tablets, 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 melatonin prolonged release group as compared to 15% in the placebo group. Melatonin prolonged release tablets 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 melatonin prolonged release tablets compared to placebo. Quality of life was improved significantly with melatonin prolonged release tablets 2 mg compared to placebo.
A third study involved more than 600 patients over 55, over 400 of whom were on melatonin prolonged release tablets treatment for up to 6 months. Patients given melatonin prolonged release tablets 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 melatonin prolonged release tablets 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 melatonin prolonged release tablets no tolerance, rebound or withdrawal effects were reported.

5.2 Pharmacokinetic Properties

Absorption.

The absolute bioavailability of melatonin from melatonin prolonged release tablets 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 melatonin prolonged release tablets 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 melatonin prolonged release tablets.
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 assess from other oral formulations of melatonin. Tmax occurs after 2.6 hours in a fed state. The rate of melatonin absorption following melatonin prolonged release tablet 2 mg oral administration is affected by food. The presence of food delayed the absorption of the melatonin resulting in a later Tmax (Tmax= 2.6 hours versus Tmax= 1.6 hours). Cmax 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 (t½) 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 Cmax is apparent for women compared to men. A five-fold variability in Cmax between different members of the same sex has also been observed.
However, no pharmacodynamic differences between males and females were found despite differences in blood levels.

Elderly.

Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and Cmax levels have been reported in older subjects compared to younger subjects, reflecting the lower metabolism of melatonin in the elderly. Cmax 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 melatonin prolonged release tablets. 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 melatonin prolonged release tablet 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, anhydrous colloidal silica, 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

Opaque PVC-PVDC/Aluminium blister packs of 30 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.

CAS number.

73-31-4.

7 Medicine Schedule (Poisons Standard)

Schedule 3 - Pharmacist Only Medicine.

Summary Table of Changes