4.1. Therapeutic indications

Melatonin 3 mg film-coated tablets are indicated for short-term treatment of jet-lag in adults.

4.2. Posology and method of administration

Posology

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 an adverse effect, on re-synchronisation following jet-lag, Melatonin 3 mg film-coated 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 melatonin 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 Melatonin 3 mg film-coated tablets.

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 Melatonin 3 mg film-coated tablets.

Melatonin 3 mg film-coated tablets may be taken for a maximum of 16 treatment periods per year.

Elderly

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

Renal impairment

There is only limited experience regarding the use of Melatonin 3 mg film-coated tablets in patients with renal impairment. Caution should be exercised if melatonin is used by patients with renal impairment. Melatonin 3 mg film-coated tablets is not recommended for patients with severe renal impairment (see Section 5.2).

Hepatic impairment

There is no experience regarding the use of Melatonin 3 mg film-coated tablets in patients with hepatic impairment. Limited data indicate that plasma clearance of melatonin is significantly reduced in patients with liver cirrhosis. Melatonin 3 mg film-coated tablets is not recommended in patients with moderate or severe hepatic impairment (see Section 5.2).

Paediatric population

The safety and efficacy of Melatonin 3 mg film-coated tablets in children and adolescents aged 0 – 18 years have not been established. Melatonin 3 mg film-coated tablets should not be used in children and adolescents due to safety and efficacy concerns (see Sections 4.4 and 5.1).

Method of administration

For oral use. Tablets should be swallowed whole with fluid.

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. Melatonin 3 mg film-coated tablets should be used with caution if the effects of drowsiness are likely to be associated with a risk to patient safety.

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 Melatonin 3 mg film-coated tablets. Melatonin may promote or increase the incidence of seizures in children and adolescents with multiple neurological defects.

Occasional case reports have described exacerbation of an autoimmune disease in patients taking melatonin. There are no data regarding use of Melatonin 3 mg film-coated tablets in patients with autoimmune diseases. Melatonin 3 mg film-coated tablets is not recommended in patients with autoimmune diseases.

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

Only limited data are available on the safety and efficiency of melatonin in patients with renal impairment or hepatic impairment. Melatonin 3 mg film-coated tablets is not recommended for use in patients suffering from severe renal impairment or moderate or severe hepatic impairment.

Paediatric population

The safety and efficacy of Melatonin 3 mg film-coated tablets in children and adolescents aged 0 – 18 years have not been established. Melatonin 3 mg film-coated tablets should not be used in children and adolescents due to safety and efficacy concerns (see Section 5.1).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per 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. 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 agent 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 agent increases melatonin levels by inhibiting its metabolism.

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

• Caution should be exercised in patients receiving estrogen therapy (e.g. in the form of contraceptives or hormone replacement therapy), since estrogens 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

• Melatonin may enhance the sedative effect of benzodiazepines (e.g. midazolam, temazepam) and non-benzodiazepine hypnotics (e.g. zaleplon, zolpidem, zopiclone). In a study of jet-lag therapy the combination of melatonin and zolpidem resulted in a higher incidence of morning sleepiness, nausea, and confusion, and reduced activity during the first hour after getting up, compared to zolpidem alone.

• Melatonin may affect the anticoagulation activity of warfarin.

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 for 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).

Melatonin 3 mg film-coated tablets is not recommended during pregnancy or in women of childbearing potential not using contraception.

Breast-feeding

There is insufficient data on the excretion of melatonin / metabolites in human milk. Endogenous melatonin is secreted in human milk.

Available pharmacodynamic / toxicological data in animals have shown excretion of melatonin / metabolites milk (see Section 5.3).

A risk to the suckling child cannot be excluded.

Melatonin 3 mg film-coated tablets 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).

Melatonin 3 mg film-coated tablets 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 Melatonin 3 mg film-coated tablets is not recommended prior to driving and using machines.

4.8. Undesirable effects

Summary of the safety profile

Drowsiness / sleepiness, headache, and dizziness / disorientation are the most frequently report adverse effects when melatonin is taken on a short-term basis to treat jet-lag. Drowsiness, headache, dizziness, and nausea are also the adverse effects 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 list 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 established 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 (fainting), 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 ulcers, dry mouth, nausea

vomiting, flatulence, salivary hypersecretion, halitosis, gastritis

Skin and subcutaneous tissue disorders

pruritus, rash, dry skin

nail disorder

tongue edema, edema of the oral mucosa

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

Laboratory and other examinations

weight increased

blood electrolytes abnormal

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: 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 commonly reported signs and symptoms of overdose with oral melatonin.

Ingestion of daily doses of up to 300 mg of melatonin did not cause clinically significant adverse reactions.

Flushes, abdominal cramps, diarrhoea, headache, and scotoma lucidum have been reported after ingestion of extremely high melatonin doses (3000 – 6600 mg) for several weeks.

General supportive measures should be employed. Gastric lavage and administration of activated charcoal can be considered.

Clearance of the active substance is expected within 12 hours of ingestion.