4.1. Therapeutic indications

Syncrodin® 3 mg film-coated tablets is indicated for:

I. Short-term treatment of jet-lag in adults.

II. Treatment of delayed sleep wake phase disorder (DSWPD) in children and adolescents aged 6 to 17 years and adults up to 25 years of age, where sleep hygiene measures have been insufficient.

III. Treatment of insomnia in children and adolescents aged 6 to 17 years with attention deficit hyperactivity disorder (ADHD), where sleep hygiene measures have been insufficient.

IV. Treatment of insomnia (prolonged sleep onset) in children and adolescents aged 6 to 17 years with autism spectrum disorder (ASD), where sleep hygiene measures have been insufficient.

4.2. Posology and method of administration

Posology

- Adults with jet-lag

The standard dose is 3 mg (1 tablet) daily for a maximum of 5 days. The dose may be increased to 6 mg (2 tablets taken together) if the standard dose does not adequately alleviate symptoms. The dose that adequately alleviates symptoms should be taken for the shortest period.

The first dose should be taken on arrival at destination at the habitual bed-time.

Due to the potential for incorrectly timed intake of melatonin to have no effect, or to cause an adverse effect, on re-synchronisation following jet-lag, Syncrodin® tablets should not be taken before 20:00 hr or after 04:00 hr at destination.

Food can enhance the increase in plasma melatonin concentration (see section 5.2). Intake of Syncrodin® with carbohydrate-rich meals may impair blood glucose control for several hours (see section 4.4). It is recommended that food is not consumed 2 h before and 2 h after intake of Syncrodin®.

As alcohol can impair sleep and potentially worsen certain symptoms of jet-lag (e. g., headache, morning fatigue, concentration) it is recommended that alcohol is not consumed when taking Syncrodin®.

Syncrodin® may be taken for a maximum of 16 treatment periods per year.

Paediatric population

The safety and efficacy of melatonin in children and adolescents less than 18 years in jet-lag has not been established.

- Delayed sleep wake phase disorder (DSWPD) in children and adolescents aged 6 to 17 years and adults up to 25 years of age, where sleep hygiene measures have been insufficient.

Diagnosis and treatment of DSWPD should be made and initiated by physicians experienced in DSWPD and/or paediatric sleep medicine.

The recommended starting dose is 1 to 2 mg per day given 1 to 2 hours before the fixed desired bedtime or at the time advised by the treating physician.

The dose of melatonin should be adjusted individually until effective up to a maximum of 5 mg per day, independent of age. The lowest effective dose should be sought and taken for the shortest period. Syncrodin® is suitable only when the lowest effective dose has been established to be 3 mg. Other formulations and strengths suitable for paediatric patients may also be available on the market.

After 6 weeks of treatment, the physician should evaluate the effect of treatment and consider stopping treatment if no clinically relevant treatment effect is seen. In patients with significant continuing daytime sleepiness or misaligned circadian rhythm the possibility of high residual melatonin in the morning should be considered. In these cases, Syncrodin® can be stopped and restarted at a lower dose. The dose that adequately alleviates symptoms should be taken for the shortest period. There is insufficient safety data to support long term use of melatonin in children approaching puberty. After the achievement of advanced sleep-wake phase for 6 weeks, treatment should be stopped to evaluate if the patient can independently maintain an advanced sleep-wake schedule. If discontinuation of melatonin leads to clinical relapse, melatonin can be reinstated and continued. The patient should be monitored at regular intervals to check that Syncrodin® is still the most appropriate treatment. During ongoing treatment, especially if the treatment effect is uncertain, discontinuation attempts should take place regularly at the discretion of the treating physician. Limited data are available for up to 3 years of treatment.

Children under 6 years of age

Syncrodin® is not recommended for children under 6 years of age.

Adults over 25 years of age

In adults whose symptoms persist past the age of 25 and who have shown clear benefit from treatment, it may be appropriate to continue treatment. However, initiation of treatment in adults over 25 years of age is not appropriate.

- Insomnia in children and adolescents aged 6 to 17 years with attention deficit hyperactivity disorder (ADHD), where sleep hygiene measures have been insufficient.

Diagnosis and treatment of insomnia associated with ADHD should be made and initiated by physicians experienced in ADHD and/or paediatric sleep medicine.

Syncrodin® is taken 30 to 60 minutes before bedtime.

Syncrodin® is suitable only when the lowest effective dose has been established to be 3 mg. If a patient requires other doses, then alternate formulations should be used. Maximum dose: 5 mg.

The dose of melatonin should be adjusted individually until effective up to a maximum of 5 mg per day, independent of age. The lowest effective dose should be sought. Other formulations and strengths suitable for paediatric patients may also be available on the market.

Within the first 3 months of treatment, the physician should evaluate the effect of treatment and consider stopping treatment if no clinically relevant treatment effect is seen. The patient should be monitored at regular intervals as determined by an appropriate prescriber to check that Syncrodin® is still the most appropriate treatment. Limited data are available for up to 3 years of treatment.

During ongoing treatment discontinuation attempts should be attempted regularly, e. g. once per year and treatment discontinued if it is not effective.

If the sleep disorder has started during treatment with medicinal products for ADHD, dose adjustment or switching to another product should be considered. If significant problems are seen in sleep maintenance or early morning waking, an alternative formulation of melatonin should be considered.

Children under 6 years of age

Syncrodin® is not recommended for children under 6 years of age.

- Insomnia (prolonged sleep onset) in children and adolescents aged 6 to 17 years with autism spectrum disorder (ASD), where sleep hygiene measures have been insufficient.

Diagnosis and treatment of insomnia (prolonged sleep onset) associated with ASD should be made and initiated by physicians experienced in ASD and/or paediatric sleep medicine.

The recommended starting dose is 1 to 2 mg. Syncrodin® is suitable when the effective dose for the patient is 3 mg or multiples of 3 mg. If a patient requires other doses, then alternate formulations should be used. Syncrodin® should be given 30 to 60 minutes before bedtime. If an inadequate response has been observed, the dose should be increased under the supervision of a physician to 5 mg, with a maximal dose of 10 mg. The lowest effective dose should be sought. Other formulations and strengths suitable for paediatric patients may also be available on the market.

Within the first 3 months of treatment, the physician should evaluate the effect of treatment and consider stopping treatment if no clinically relevant treatment effect is seen. If a lower treatment effect is seen after titration to a higher dose, the prescriber should first consider a down-titration to a lower dose before deciding on a complete discontinuation of treatment. The patient should be monitored at regular intervals as determined by an appropriate prescriber to check that Syncrodin® is still the most appropriate treatment. Parents should be encouraged to monitor sleep carefully pre, during and post treatment breaks using paper or online sleep diaries. During ongoing treatment discontinuation attempts should be attempted regularly, e.g. once per year and treatment discontinued if it is not effective. If benefits are maintained there should still be a 5-day break once a year to ensure that the medication is still required. Limited data are available for up to 3 years of treatment.

Children under 6 years of age

Syncrodin® is not recommended for children under 6 years of age.

Special populations

Elderly

As the pharmacokinetics of melatonin (immediate release) is comparable in young adults and elderly persons in general, no specific dose recommendations for elderly persons are provided (see section 5.2).

Renal impairment

There is only limited experience regarding the use of Syncrodin® in patients with renal impairment. Caution should be exercised if Syncrodin® is used by patients with renal impairment. Syncrodin® is not recommended for patients with severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

There is no experience regarding the use of Syncrodin® in patients with hepatic impairment. Limited data indicate that plasma clearance of melatonin is significantly reduced in patients with liver cirrhosis. Syncrodin® is not recommended in patients with moderate or severe hepatic impairment (see sections 4.4 and 5.2).

Children under 6 years of age

Syncrodin® is not recommended for children under 6 years of age.

Method of administration

Oral use.

Tablets should be swallowed whole with fluid. Tablets must not be broken, crushed or chewed.

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

Melatonin may cause drowsiness. Syncrodin® should be used with caution if the effects of drowsiness are likely to be associated with a risk to patient safety.

Epilepsy

Melatonin may increase seizure frequency in patients experiencing seizures (e. g., epileptic patients). Patients suffering from seizures must be informed about this possibility before using Syncrodin®. Syncrodin® may promote or increase the incidence of seizures in children and adolescents with multiple neurological defects.

Immunological diseases

Occasional case reports have described exacerbation of an autoimmune disease in patients taking melatonin. Syncrodin® is not recommended in patients with autoimmune diseases.

Diabetes/Impaired glucose tolerance

Limited data suggest that melatonin taken in close proximity to ingestion of carbohydrate-rich meals may impair blood glucose control for several hours. Syncrodin® should be taken at least 2 hours before and at least 2 hours after a meal; ideally at least 3 hours after a meal by people with significantly impaired glucose tolerance or diabetes.

Renal and hepatic impairment

Only limited data are available on the safety and efficacy of melatonin in patients with renal impairment or hepatic impairment. Syncrodin® is not recommended for use in patients suffering from severe renal impairment or moderate or severe hepatic impairment (see sections 4.2 and 5.2).

Paediatric population

There is insufficient data to analyse the impact of long-term exposure to melatonin in children and adolescents on the sexual maturation of this population. There are theoretical risks based on biological effects of melatonin, e. g. immunological regulation, effects on the threshold for seizures and endocrinological effects, which could affect puberty development and fertility, respectively. Therefore, treatment should be taken for the shortest period and evaluated on a regular basis as determined by the treating physician to check that Syncrodin® is still the most appropriate treatment.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

• Melatonin is metabolised mainly by the hepatic cytochrome P450 CYP1A enzymes, primarily CYP1A2 (see section 5.2). Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes are possible.

• Caution is indicated in patients treated with fluvoxamine, since this active substance increases melatonin levels (17-fold higher AUC and 12-fold higher serum Cmax) by inhibiting its metabolism via CYP1A2 and CYP2C19. This combination should be avoided.

• Caution is indicated in patients taking 5- or 8-methoxypsoralen (5- or 8-MOP), since this active substance increases melatonin levels by inhibiting its metabolism.

• Caution is indicated in patients taking cimetidine, since this active substance increases plasma melatonin levels by inhibiting its metabolism by CYP2D.

• Caution should be exercised in patients receiving oestrogen therapy (e. g., in the form of contraceptives or hormone replacement therapy), since oestrogens increase melatonin level by inhibiting its metabolism, primarily via inhibition of CYP1A2.

• CYP1A2 inhibitors (such as quinolones) may increase systemic melatonin levels.

• CYP1A2 inducers (such as carbamazepine and rifampicin) may reduce plasma concentrations of melatonin.

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

Pharmacodynamic interactions

Benzodiazepine-related hypnotics

• Melatonin may enhance the sedative effect of benzodiazepines (e. g., midazolam, temazepam) and non-benzodiazepine hypnotics (e. g., zaleplon, zolpidem, zopiclone). Concomitant treatment with melatonin should be avoided.

Alcohol

• Alcohol should not be used concomitantly with melatonin since it may reduce the effect of melatonin on sleep.

Nifedipine

• Melatonin may reduce the hypotensive effect of nifedipine. Caution must be taken during the concomitant use of melatonin, and adjustment of the nifedipine dose may be needed. As it is not known if this is a class effect, caution should be exercised when combining melatonin with other calcium channel blockers.

Warfarin

• It has been reported in case studies that the concomitant use of melatonin and vitamin K antagonists such as warfarin can lead to either increased or decreased prothrombin levels, and a study has shown decreased levels of factor VIII and fibrinogen. The combination of warfarin and other vitamin K antagonists with melatonin may require dose adjustment of the anticoagulant medicinal product and should be avoided.

NSAIDs

• Prostaglandin synthesis inhibitors (NSAIDs) such as acetylsalicylic acid and ibuprofen, taken in the evening, may suppress the night-time release of endogenous melatonin levels. If possible, administration of NSAIDs should be avoided in the evening.

Beta-blockers

• Beta-blockers may suppress the night-time release of endogenous melatonin and should therefore be administered in the morning.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of melatonin in pregnant women.

Exogenous melatonin readily crosses the human placenta. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Syncrodin® is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

There is insufficient information on the excretion of melatonin / metabolites in human milk. Endogenous melatonin is excreted in human milk. Available pharmacodynamic / toxicological data in animals have shown excretion of melatonin / metabolites in milk (for details see 5.3). A risk to the breast-fed new-born, infant and child cannot be excluded. Syncrodin® should not be used during breast-feeding.

Fertility

High doses of melatonin and use for longer periods than indicated may compromise fertility in humans. Animal studies are insufficient with respect to effects on fertility (see section 5.3).

Syncrodin® is not recommended in women and men planning pregnancy.

4.7. Effects on ability to drive and use machines

Melatonin has a moderate influence on the ability to drive and use machines. Melatonin may cause drowsiness and may decrease alertness for several hours, therefore use of Syncrodin® is not recommended prior to driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

Drowsiness / sleepiness, headache, and dizziness / disorientation are the most frequently reported adverse reactions when Syncrodin® is taken on a short-term basis to treat jet-lag. Drowsiness, headache, dizziness, and nausea are also the adverse reactions reported most frequently when typical clinical doses of melatonin have been taken for periods of several days to several weeks by healthy persons and patients.

Tabulated summary of adverse reactions

The following adverse reactions to melatonin in general have been reported in clinical trials or spontaneous case reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class

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)

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

leucopenia,

thrombocytopenia

Immune system disorders

hypersensitivity reaction

Metabolism and nutrition disorders

hypertriglyceridaemia

hyperglycaemia

Psychiatric disorders

irritability,

nervousness,

restlessness,

abnormal dreams,

anxiety

mood altered,

aggressive behaviour,

disorientation,

libido increased

Nervous system disorders

headache,

somnolence

dizziness

syncope,

memory impairment,

restless legs syndrome,

paraesthesia

Eye disorders

visual acuity reduced,

vision blurred,

lacrimation increased

Cardiac disorders

palpitations

Vascular disorders

hypertension

hot flushes

Gastrointestinal disorders

abdominal pain,

upper abdominal pain,

dyspepsia,

oral ulceration,

dry mouth,

nausea

vomiting,

flatulence,

salivary hypersecretion,

halitosis,

gastritis

Skin and subcutaneous tissue disorders

pruritus,

rash,

dry skin

nail disorder

tongue oedema,

oral mucosa swollen

Musculoskeletal and connective tissue disorders

arthritis,

muscle spasms

Renal and urinary disorders

glycosuria,

proteinuria

polyuria,

haematuria

Reproductive system and breast disorders

priapism,

prostatitis

galactorrhoea

General disorders and administration site conditions

chest pain,

malaise

thirst

Investigations

weight increased

blood electrolytes abnormal

Paediatric population

A low frequency of mild adverse reactions has been reported in the paediatric population. The number of adverse reactions in patients given melatonin or placebo is not significantly different. The most common adverse reactions include headache, hyperactivity, dizziness and abdominal pain. No serious adverse reactions have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Drowsiness, headache, dizziness, and nausea are the most reported signs and symptoms of overdose with oral melatonin.

Daily ingestion of melatonin, in the dose range 20 to 300 mg, for time periods of up to 2 years, have been reported in the literature, without any clinically significant adverse reactions. One dose of 250 mg taken 4 times daily over a period of 25 to 30 days has been reported to cause only drowsiness/sleepiness.

Also, in several cases of reported overdosing, mildly to moderately severe somnolence was the most reported adverse reaction. Flushes, abdominal cramps, diarrhoea, headache, and scotoma lucidum have been reported after ingestion of extremely high melatonin doses (3,000 to 6,600 mg) for several weeks. Due to the short half-life of melatonin, clearance of the active substance is expected within 12 hours of ingestion. A physician should assess if conventional overdose measures should be taken. General supportive measures should be employed.