4.1. Therapeutic indications

Melatonin 1 mg/ ml oral solution is indicated 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.

4.2. Posology and method of administration

Posology

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

The standard dose is 3 mg daily for a maximum of 5 days. The dose may be increased to 6 mg 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 1 mg/ ml oral solution 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 1 mg/ ml oral solution.

Melatonin 1 mg/ ml oral solution 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 (1.0-2.0 ml) 30-60 minutes before bedtime.

The dose of melatonin can be increased by 1 mg (1.0 ml) every week until effect up to a maximum 5 mg (5 ml) per day, independent of age. The lowest effective dose that controls symptoms should be given.

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 1 mg/ ml oral solution 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.

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

Hepatic impairment

There is no experience regarding the use of Melatonin 1 mg/ 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 1 mg/ ml oral solution is not recommended in patients with moderate or severe hepatic impairment (see Section 5.2).

Paediatric population (under 6 years of age)

The safety and efficacy of Melatonin 1 mg/ ml oral solution in children aged 0-6 years have not been established.

Method of administration

Melatonin 1 mg/ ml oral solution is for oral use only.

Once titrated to an effective dose of Melatonin oral solution, patients may remain on their treatment and care should be exercised when changing between different formulations.

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 1 mg/ ml oral solution.

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. 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

Auto-immune diseases

Occasional case reports have described exacerbation of an autoimmune disease in patients taking melatonin. There are no data regarding use of Melatonin 1 mg/ ml oral solution in patients with autoimmune diseases. Melatonin 1 mg/ ml oral solution is not recommended in patients with autoimmune diseases.

Epilepsy

Melatonin has been reported to both increase and decrease 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.

Drowsiness

Melatonin may cause drowsiness. Melatonin 1 mg/ ml oral solution should be used with caution if the effects of drowsiness are likely to be associated with a risk to patient safety.

Food interaction

Limited data suggest that melatonin taken in close proximity to ingestion of carbohydrate-rich meals may impair blood glucose control for several hours. Melatonin 1 mg/ ml oral solution 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.

Renal and hepatic impairment

Only limited data are available on the safety and efficiency of melatonin in patients with renal impairment or hepatic impairment. Melatonin 1 mg/ ml oral solution is not recommended for use in patients suffering from severe renal impairment or moderate or severe hepatic impairment.

Switching between formulations

Caution may be taken when switching between melatonin products as the mean Cmax on single dose administration for the suspension may be higher than that observed with tablet formulations.

Paediatric population (under 6 years of age)

Melatonin 1 mg/ ml oral solution is not recommended for use in children younger than 6 years of age.

Melatonin 1 mg/ ml oral solution contains sorbitol and propylene glycol.

This medicine contains 140 mg sorbitol and 150.50 mg propylene glycol in each ml.

This medicinal product contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

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

Interaction studies have only been performed in adults. Melatonin is metabolized mainly via the enzyme CYP1A2. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes are possible.

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.

• Alcohol should not be taken with melatonin as it may reduce the effect of melatonin on sleep.

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 1 mg/ ml oral solution 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 1 mg/ ml oral solution 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 1 mg/ 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 1 mg/ 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 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)

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

Skin and subcutaneous tissue disorders

dermatitis, night sweats, pruritus, rash, dry skin

eczema, erythema, hand dermatitis, psoriasis, rash generalised, rash pruritic, nail disorder

tongue edema, edema of the oral mucosa

Musculoskeletal and connective tissue disorders

pain in extremity

arthritis, muscle spasms, neck pain, night cramps

Renal and urinary disorders

glycosuria, proteinuria

polyuria, haematuria

Reproductive system and breast disorders

menopausal symptoms

priapism, prostatitis

galactorrhoea

General disorders and administration site conditions

chest pain, malaise

fatigue, pain, thirst

Laboratory and other examinations

liver function test abnormal, weight increased

hepatic enzyme increased, blood electrolytes abnormal, laboratory test

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.