4.1. Therapeutic indications

Melatonin 1mg/ml oral solution is indicated for:

(i) 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.

(ii) Short-term treatment of jet lag in adults.

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

(iv) For use in short-term sedation under medical supervision for non-operating theatre diagnostic procedures such as electroencephalograms (EEG), auditory brain response (ABR) testing and Magnetic Resonance Imaging (MRI) in children and adolescents from 1 to 18 years.

4.2. Posology and method of administration

Posology

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 once a day, 1-2 hours before the fixed desired bedtime, given as 1-2 ml of the oral solution. 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.

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. 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 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.

Short-term treatment of jet lag in adults

The standard dose is 3mg daily for a maximum of 5 days. The dose may be increased to 6mg 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 resynchronisation following jet-lag, Melatonin 1mg/ml oral solution should not be taken before 20:00hr or after 04:00hr 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 2h before and 2h after intake of melatonin 1mg/ml oral solution.

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 1mg/ml oral solution.

Melatonin 1mg/ml oral solution may be taken for a maximum of 16 treatment periods per year.

Insomnia in children and adolescents aged 6-17 years with attention deficit hyperactivity disorder

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

The recommended starting dose is 1-2 mg, 30-60 minutes before bedtime.

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.

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 at least 3 months of treatment, the physician should evaluate the treatment effect and consider stopping 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 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 other medicinal products, 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.

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

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.

Use for short-term sedation under medical supervision to facilitate non-operating theatre diagnostic procedures 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 for children weighing less than 15 kg and 6 mg 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 in children weighing less than 15 kg and 9 mg for those weighing more than 15 kg.

Due to the presence of benzyl alcohol in the formulation and the risk of accumulation especially in younger children it is not recommended to perform more than one diagnostic procedure in each 24 hour period.

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 1mg/ml oral solution in patients with renal impairment. Caution should be exercised if melatonin is used by patients with renal impairment.Melatonin 1mg/ml Oral Solution is not recommended for patients with severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

There is no experience of the use of Melatonin 1mg/ml Oral Solution in patients with hepatic impairment. Limited data indicate that plasma clearance of melatonin is significantly reduced in patients with liver cirrhosis. Melatonin 1mg/ml Oral Solution is not recommended in patients with hepatic impairment (see sections 4.4 and 5.2).

Method of administration

Melatonin Oral Solution is for oral use only. A 10 ml graduated oral syringe with intermediate graduations of 0.5 ml and a “Press-In” Bottle Adapter (PIBA) are provided with the product.

1. Open the bottle and at first use, insert the “Press-In” Bottle Adapter (PIBA).

2. Insert the syringe into the PIBA and draw out the required volume from the inverted bottle.

3. Remove the filled syringe from the bottle in the upright position

4. Discharge the syringe contents into the mouth.

5. Repeat steps 2-4 if doses greater than 5ml are required.

6. Rinse the syringe and replace the cap on the bottle (PIBA remains in place).

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 and 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 1mg/ml oral solution. 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 1mg/ml oral solution in patients with autoimmune diseases. Melatonin 1mg/ml oral solution 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 1mg/ml oral solution should be taken at least 2 hours before or 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 1mg/ml oral solution is not recommended for use in patients suffering from severe renal impairment or moderate or severe hepatic impairment.

Melatonin may not be effective in some patients. Other treatment options should be considered in cases of inadequate response to melatonin treatment.

Melatonin 1mg/ml Oral Solution contains methyl parahydroxybenzoate (E218) as an excipient. This may cause an allergic reaction. This allergy may be a delayed reaction.

Children and Adolescents

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.

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 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

No clinical data on exposed pregnancies are available for melatonin. Animal studies do not indicate direct or indirect adverse effects with respect to pregnancy, embryonic/foetal development, birth or postnatal development (see section 5.3). Given the lack of clinical data, use in pregnant women and by women intending to become pregnant is not recommended.

Breast-feeding

Endogenous melatonin is found in human breast thus it can be assumed that melatonin is secreted in human milk. There are data in animal models including rodents, sheep, bovine and primates that indicate maternal transfer of melatonin to the foetus via the placenta or breast milk. A risk to the suckling child cannot be excluded. Therefore, the use of melatonin in women who are breast-feeding is not recommended.

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 1mg/ml oral solution 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 1mg/ml oral solution 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 reported 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.

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.

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).

System Organ Class

Very Common

Common

Uncommon

Rare

Not known: (Cannot be established from the available data)

Blood and lymphatic system disorders

Leukopenia, thrombocytopenia

Immune system disorders

Hypersensitivity reaction

Metabolism and nutrition disorders

Hypertriglyceridaemia,

hyperglycaemia

Psychiatric disorders

Irritability, nervousness, restlessness, abnormal dreams, anxiety

Mood alteration, 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 flush

Gastrointestinal disorders

Abdominal pain, upper abdominal pain, dyspepsia, mouth ulceration, dry mouth, nausea

vomiting, flatulence, salivary hypersecretion, halitosis, gastritis

Skin and subcutaneous tissue disorders

pruritus, rash, dry skin

nail disorder

tongue oedema, oedema of 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

Investigations

weight increased

blood electrolytes abnormal,

Paediatric population

A low frequency of in general mild adverse reactions have been reported in the paediatric population. The number of adverse reactions has not differed significantly between children who have received placebo compared to melatonin. The most common adverse reactions were dizziness, headache, gastrointestinal symptoms and increased excitability. No serious adverse reactions have been observed when high quality synthetic melatonin was given together with the currently recommended posology.

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 commonly reported signs and symptoms or overdose with oral melatonin.

Administration of daily doses of up to 300mg of melatonin without causing clinically significant adverse reactions have been reported in the literature.

Flushes, abdominal cramps, diarrhoea, headache, and scotoma lucidum have been reported after ingestion of extremely high melatonin doses (3000mg-6600mg) 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 after ingestion although prolonged residual systemic melatonin could be seen in slow metabolisers of melatonin.