4.1. Therapeutic indications

Slenyto is indicated for:

- treatment of insomnia in children and adolescents aged 2-18 years with Autism Spectrum Disorder (ASD), and / or neurogenetic disorders with aberrant diurnal melatonin secretion and /or nocturnal awakenings, where sleep hygiene measures have been insufficient.

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

4.2. Posology and method of administration

Posology

Insomnia in children and adolescents aged 2-18 years with Autism Spectrum Disorder (ASD) and / or neurogenetic disorders with aberrant diurnal melatonin secretion and /or nocturnal awakenings

The recommended starting dose is 2 mg of Slenyto. If an inadequate response has been observed, the dose should be increased to 5 mg, with a maximal dose of 10 mg.

Slenyto should be taken once daily, 0.5-1 hour before bedtime and with or after food.

Data are available for up to 2 years' treatment. The patient should be monitored at regular intervals (at least every 6 months) to check that Slenyto is still the most appropriate treatment. 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. 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.

If a tablet is forgotten, it could be taken before the patient goes to sleep that night, but after this time, no other tablet should be given before the next scheduled dose.

Insomnia in children and adolescents aged 6-17 years with ADHD

The recommended starting dose is 1-2 mg. The dose may be adjusted on an individual basis to 5 mg per day regardless of age of the child. If clinically needed, the maximum daily dose may be increased to 10 mg. The lowest effective dose should be taken for the shortest period.

Slenyto should be taken once daily, 0.5-1 hour before bedtime and with or after food.

After approximately 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 regularly (at least every 6 months) to check that Slenyto 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 a year.

If a tablet is forgotten, it could be taken before the patient goes to sleep that night, but after this time, no other tablet should be given before the next scheduled dose.

Special populations

Renal impairment

The effect of any stage of renal impairment on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to patients with renal impairment.

Hepatic impairment

There is no experience of the use of melatonin in patients with liver impairment. Therefore, melatonin is not recommended for use in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Slenyto have not been established for children under 6 years of age with ADHD.

There is no relevant use of melatonin in children aged 0 to 2 years for the treatment of insomnia.

Method of administration

Oral use. Tablets should be swallowed whole. The tablet should not be broken, crushed or chewed because it will lose the prolonged release properties.

Tablets can be put into food such as yoghurt, orange juice or ice-cream to facilitate swallowing and improve compliance. If the tablets are mixed with food or drink, they should be taken immediately and the mixture not stored.

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

Drowsiness

Melatonin may cause drowsiness and residual effects such as daytime fatigue may occur. These effects should be considered, particularly in children and adolescents with ADHD, as they may exacerbate daytime symptoms like inattention, hyperactivity, or behavioural disturbances. Caregivers and healthcare professionals should monitor patients for signs of daytime fatigue and adjust the dosing schedule or discontinue treatment if such effects impair daily functioning. Therefore, the medicinal product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety (see section 4.7).

Autoimmune diseases

No clinical data exist concerning the use of melatonin in individuals with autoimmune diseases. Therefore, melatonin is not recommended for use in patients with autoimmune diseases.

Interactions with other medicines and alcohol

Concomitant use with fluvoxamine, alcohol, benzodiazepines/non-benzodiazepines hypnotics, thioridazine and imipramine is not recommended (see section 4.5).

Lactose

Slenyto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Interaction studies have only been performed in adults. In the absence of specific studies in children, the drug interactions with melatonin are those known in adults.

Melatonin's metabolism is mainly mediated by CYP1A enzymes. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes is possible.

Concomitant use not recommended

Concomitant use of the following medicinal products and alcohol is not recommended (see section 4.4):

Fluvoxamine

Fluvoxamine increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided.

Alcohol

Alcohol should not be taken with melatonin, because it reduces the effectiveness of melatonin on sleep.

Benzodiazepines/non-benzodiazepine hypnotics

Melatonin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone. Combination with benzodiazepines and non-benzodiazepine hypnotics should be avoided.

Thioridazine and imipramine

Melatonin has been co-administered in studies with thioridazine and imipramine, active substances which affect the central nervous system. No clinically significant pharmacokinetic interactions were found in each case. However, melatonin co-administration resulted in increased feelings of tranquility and difficulty in performing tasks compared to imipramine alone, and increased feelings of “muzzy-headedness” compared to thioridazine alone. Combination with thioridazine and imipramine should be avoided.

Concomitant use to be considered with caution

Concomitant use of the following medicinal products should be considered with caution:

5- or 8-methoxypsoralen

Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 or 8-MOP), which increases melatonin levels by inhibiting its metabolism.

Cimetidine

Caution should be exercised in patients on cimetidine which is a potent inhibitor of certain cytochrome P450 (CYP450) enzymes, mainly CYP1A2 and thereby increases plasma melatonin levels, by inhibiting its metabolism.

Oestrogens

Caution should be exercised in patients on oestrogens (e.g. contraceptive or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2.

CYP1A2 inhibitors

CYP1A2 inhibitors such as quinolones (ciprofloxacin and norfloxacin) may give rise to increased melatonin exposure.

CYP1A2 inducers

CYP1A2 inducers such as carbamazepine and rifampicin may reduce plasma concentrations of melatonin. Therefore, when CYP1A2 inducers and melatonin are both given, dose adjustment may be required.

Smoking

Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with melatonin, dose adjustment may be required.

NSAIDs

Prostaglandin synthesis inhibitors (NSAIDs) such as acetylsalicylic acid and ibuprofen, given in the evening may suppress endogenous melatonin levels in the early part of the night by up to 75%. If possible, administration of NSAIDs should be avoided in the evening.

Beta-blockers

Beta-blockers may supress the night-time release of endogenous melatonin and thus should be administered in the morning.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of melatonin in pregnant women. Animal studies do not indicate reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of melatonin during pregnancy.

Breastfeeding

Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probably secreted into human milk. Data in animals indicate maternal transfer of melatonin to the foetus via the placenta or in the milk. The effect of melatonin on newborns/infants is unknown.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from melatonin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

In studies performed in both adult and juvenile animals, melatonin had no effect on male or female fertility (see section 5.3).

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

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions with Slenyto in clinical studies were somnolence, fatigue, mood swings, headache, irritability, aggression and hangover occurring in 1:100-1:10 children.

Tabulated list of adverse reactions

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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 estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class

Common

Psychiatric disorders

Mood swings, Aggression, Irritability

Nervous system disorders

Somnolence, Headache, Sudden onset of sleep

Respiratory, thoracic and mediastinal disorders

Sinusitis

General disorders and administration site conditions

Fatigue, Hangover

The following adverse reactions (frequency unknown) have been reported with off-label use of the adult formulation, 2 mg prolonged-release melatonin tablets: epilepsy, visual impairment, dyspnoea, epistaxis, constipation, decreased appetite, swelling face, skin lesion, feeling abnormal, abnormal behaviour and neutropenia.

Furthermore, in ASD and neurogenetic children treated with 2-6 mg of the adult formulation under a Temporary Recommendation for Use (RTU) program in France (N=926), the following additional adverse reactions (frequency uncommon) have been reported: depression, nightmares, agitation and abdominal pain.

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

If overdose occurs, drowsiness is to be expected. Clearance of the active substance is expected within 12 hours after ingestion. No special treatment is required.