4.1. Therapeutic indications

Melatonin is indicated for:

• For short-term treatment of jet-lag in adults.

• Sleep onset insomnia in children and adolescents aged 6-17 years with attention- deficit hyperactivity disorder (ADHD) where sleep hygiene measures have been inadequate.

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

• Single use for short-term sedation under medical supervision to facilitate electroencephalograms (EEG) in children and adolescents from 1 to 18 years.

4.2. Posology and method of administration

Posology

For the short-term treatment of jet lag in adults:

The standard dose is 3 mg (3.0 ml) daily for a maximum of 5 days. The dose may be increased to 6 mg (6.0 ml) 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 should not be taken before 20:00 hr or after 04:00 hr at destination.

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.

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

Sleep onset insomnia in children and adolescents aged 6-17 years with ADHD:

Treatment should be initiated by physicians experienced in ADHD and/or paediatric sleep medicine.

Recommended starting dose is 1-2 mg (0.5-1.0 ml) 30-60 minutes before bedtime.

The dose of melatonin can be increased by 1 mg (0.5 ml) every week until effect up to a maximum 5 mg (2.5 ml) per day, independent of age. The lowest effective dose that controls symptoms should be taken for the shortest period.

There is limited data available for up to 3 years of treatment. After at least 3 months of treatment, the physician should evaluate the treatment effect and consider discontinuing the treatment if no clinically relevant treatment effect is seen. The patient should be monitored at regular intervals (at least every 6 months) to check that Melatonin is still the most appropriate treatment. During ongoing treatment, especially if the treatment effect is uncertain, discontinuation attempts should be done regularly at least once per year.

If insomnia has occurred during treatment with ADHD medication, dose adjustment or change of the treatment should be considered.

Adults

In adolescents whose symptoms persist into adulthood and who have shown clear benefit from treatment, it may be appropriate to continue treatment into adulthood.

However, initiation of treatment in adults is not appropriate.

Delayed sleep wake phase disorder:

In children and adolescents (6-17 years) and adults up to 25 years of age:

Treatment should be initiated by physicians experienced in DSWPD and/or paediatric sleep medicine.

The recommended starting dose is 1 to 2 mg (0.5 – 1.0 ml) once a day, 1-2 hours before the fixed desired bedtime. The dose of melatonin should be adjusted individually until effective up to a maximum of 5 mg (2.5 ml) per day, independent of age. The lowest effective dose that controls symptoms should be taken for the shortest period.

After 6 weeks of treatment, the physician should evaluate the treatment effect 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 melatonin can be stopped and restarted at a lower dose.

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 withdrawal of melatonin results in clinical relapse, melatonin can be resumed and continued.

Limited data are available for up to 3 years of treatment (please see section 4.4).

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.

Single use for short-term sedation under medical supervision to facilitate EEG in children and adolescents from 1 to 18 years:

Melatonin should be given 30-45 minutes before the anticipated start of the procedure as a single dose of 3mg (3.0 ml) for children weighing less than 15 kg and 6 mg (6.0 ml) for those weighing more than 15 kg. Where possible this dose should be administered after a period of sleep deprivation to maximise the sedative effects. One further dose at 50% of the initial dose - 1.5 mg (<15 kg) or 3 mg (>15 kg) may be given if sleep is not achieved after 45 minutes. Therefore the maximum daily dose is 4.5 mg (4.5 ml) in children weighing less than 15 kg and 9 mg (9.0 ml) for those weighing more than 15 kg.

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). However, individual elderly patients may be more likely to be slow metabolisers of melatonin with the potential for high residual morning levels of melatonin. In cases where there is excessive morning sleepiness, a lack of effect on DLMO and / or advancing sleep phase the possibility of impaired melatonin clearance, too high a dose, or too late a time of administration should be considered.

Genetic polymorphisms of CYP enzymes and other slow metabolisers

Polymorphisms in CYP1A2, CYP1A1 and CYP2C19 may affect first pass metabolism and systemic clearance of melatonin contributing to interindividual variability.

Renal impairment

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

Hepatic impairment

There is only limited experience regarding the use of Melatonin in patients with hepatic impairment. Limited data indicate that plasma clearance of melatonin is significantly reduced in patients with liver cirrhosis. Melatonin is not recommended in patients with moderate or severe hepatic impairment (see section 5.2).

Method of administration

For oral use.

The required dose should be drawn from the container into the graduated syringe using the syringe adaptor (see section 6.6).

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.

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 should be used with caution if the effects of drowsiness are likely to be associated with a risk to patient safety.

Melatonin has been reported to increase, decrease and have no effect on seizure frequency in patients experiencing seizures (e.g. epileptic patients). Caution should be exercised when prescribing to patients with epilepsy and/or with multiple neurological defects and/or with concomitant medications that could increase seizure frequency.

Occasional case reports have described exacerbation of an autoimmune disease in patients taking melatonin. There are no data regarding use of Melatonin in patients with autoimmune diseases. Melatonin 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 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 is not recommended for use in patients suffering from severe renal impairment or moderate or severe hepatic impairment.

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 (at least every 6 months) to check that melatonin is still the most appropriate treatment.

Elderly (65 years old and over)

Exposure levels to melatonin after oral administration in young and moderately older adults are comparable. Although prolonged elevated levels of melatonin have been seen in some elderly patients it is unclear if all significantly older persons are especially sensitive to exogenous melatonin. Caution should therefore be exercised in the treatment of this age group and individual dosage is recommended.

Switching between formulations

Care should be exercised when changing between different formulations/products as the plasma concentrations with this solution may be higher than that observed with other formulations. Changing formulations may increase the risk of drowsiness or somnolence.

Excipient warning:

Propylene glycol (E1520): This medicinal product contains 174.25mg propylene glycol in each 5ml which is equivalent to 34.85mg/ml.

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

Interaction studies have only been performed in adults.

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 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

• Melatonin may enhance the sedative effect of benzodiazepines (e.g. midazolam, temazepam) and non-benzodiazepine hypnotics (e.g. 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.

• As alcohol can impair sleep and potentially worsen certain symptoms e.g. headache, morning fatigue, concentration it is recommended that alcohol is not consumed when taking melatonin.

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 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 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 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 is not recommended prior to driving and using machines.

4.8. Undesirable effects

Summary of the safety profile

After single doses of melatonin, nausea and vomiting were common adverse effects.

Drowsiness / sleepiness, headache, and dizziness / disorientation are the most frequently reported adverse effects when melatonin is taken on a short-term basis.

Gastrointestinal symptoms, drowsiness, headache and dizziness are also 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.

In longer term treatment of up to several months no additional long term adverse effects were seen, except an uncommon effect of abnormal dreams.

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.

The frequency of adverse reactions is defined as follows: very common (≥1 / 10), common (≥1 / 100 <1/10), uncommon (≥1 / 1,000 <1/100), rare (≥1 / 10,000 <1/1,000), very rare (<1 / 10,000), not known (frequency cannot be estimated from the available data).

System organ class

Common

Uncommon

Rare

Not known (cannot be estimated from the available data)

Infections and infestations

herpes zoster

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, depressed mood, depression

Nervous system disorders

headache, somnolence

migraine, lethargy, psychomotor hyperactivity, dizziness

syncope (fainting), memory impairment, restless legs syndrome, disturbance in attention, poor quality sleep, paraesthesia

drowsiness, sedation

Eye disorders

visual acuity reduced, vision blurred, lacrimation increased

Ear and labyrinth disorders

vertigo positional, vertigo

Cardiac disorders

angina pectoris, palpitations

Vascular disorders

hypertension

hot flushes

Gastrointestinal disorders

abdominal pain, upper abdominal pain, dyspepsia, oral ulcers, dry mouth, nausea

gastroesophageal reflux disease, gastrointestinal disorder, oral mucosal blistering, tongue ulceration, gastrointestinal upset vomiting, bowel sounds abnormal, flatulence, salivary hypersecretion, halitosis, gastritis

Hepatobiliary disorders

hyperbilirubinemia

Skin and subcutaneous tissue disorders

dermatitis, night sweats, pruritus, rash, generalised itching, dry skin

eczema, erythema, hand dermatitis, psoriasis, generalised skin rash, itchy skin rash, nail disorder

angioedema, oedema of the tongue, oral mucosal oedema

Musculoskeletal and connective tissue disorders

pain in extremity

arthritis, muscle cramps, muscle spasms, neck pain, night cramps

Renal and urinary disorders

glycosuria, proteinuria

polyuria, haematuria, night urination

Reproductive system and breast disorders

menopause symptoms

priapism, prostatitis

galactorrhoea

General disorders and administration site conditions

chest pain, malaise

exhaustion, pain, thirst

Investigations

abnormal liver function, weight increased

elevated liver enzymes, abnormal electrolytes

Paediatric population

In the paediatric population, a low frequency of generally mild side effects have been reported. The number of side effects did not differ significantly between children who received placebo and children who received melatonin. The most common side effects were headache, hyperactivity, dizziness and abdominal pain. No serious side effects have been observed.

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 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.