4.1. Therapeutic indications

Ceyesto is indicated for:

• Short-term treatment of jet-lag in adults.

• Insomnia in children and adolescents aged 6-17 years with ADHD, where sleep hygiene measures have been insufficient.

4.2. Posology and method of administration

Posology

Jet-lag in adults:

The standard dose is one 3 mg tablet daily at local time to go to bed starting on arrival at destination for a maximum of 4 days. Other dosages from other manufacturers are available to achieve higher than 3 mg dose if required.

The dose that adequately alleviates symptoms should be taken for the shortest period. Due to the potential for incorrectly timed intake of melatonin to have no effect, or to cause 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.

Paediatric population

The safety and efficacy of melatonin in children and adolescents less than 18 years in jet lag has not been established.

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

Melatonin 3 mg dose is taken 30-60 minutes before bedtime. Ceyesto is suitable only when the lowest effective dose has been established to be 3 mg. Maximum dose: 3 mg.

Limited data are available for up to 3 months of treatment. The physician should evaluate the treatment effect at regular intervals and consider stopping treatment if no clinically relevant treatment effect is seen.

If the sleep disorder has started during treatment with medicinal products for ADHD, dose adjustment or switching to another product should be considered.

Children below 6 years of age

Ceyesto tablets are not recommended for children below 6 years with ADHD. The safety and efficacy of melatonin in children less than 6 years has not been established.

Elderly

As the pharmacokinetics of exogenous 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 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 sections 4.4 and 5.2).

Hepatic impairment

There is no 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 cirrhosis. Melatonin is not recommended for patients with hepatic impairment (see sections 4.4 and 5.2).

Method of administration

Oral use. Tablets should be swallowed with a glass of water. Intake of food at or around the time of intake of melatonin is not expected to affect the efficacy or safety of melatonin, however, it is recommended that food is not consumed approximately 2 h before or 2 h after intake of melatonin (see section 5.2).

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

Seizures

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.

Drowsiness

Melatonin may cause drowsiness. Therefore the 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.

Hepatic and renal impairment

There is only limited experience of safety and efficacy regarding the use of melatonin in patients with hepatic or renal impairment. Melatonin is not recommended for patients with hepatic impairment or severe renal impairment (see sections 4.2 and 5.2).

Cardiovascular conditions

There is limited data that melatonin may cause adverse effects on blood pressure and heart rate in populations with cardiovascular conditions and concurrent antihypertensive medications. It is unclear whether these adverse effects are attributable to melatonin itself or to melatonin-drug interactions. Melatonin is not recommended for use in patients with cardiovascular conditions and concurrent antihypertensive medication.

Concomitant use of anticoagulants

Caution is advised when using melatonin together with anticoagulant drugs, including warfarin and novel direct-acting anticoagulants, as melatonin may enhance the effect of these drugs resulting in increased risk of bleeding (see section 4.5).

Children and adolescents

Currently the safety profile of melatonin in children and adolescents is not fully established, especially in long-term use. Long-term melatonin use may negatively affect blood glucose control, pubertal development and sexual maturation.

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

Interaction studies have only been performed in adults.

Pharmacokinetic interactions

• Melatonin's metabolism is mainly mediated by CYP1A enzymes. Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP 1A enzymes are possible.

• Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (by 17-fold higher AUC and 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19. The combination should be avoided.

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

• Cigarette smoking may decrease melatonin levels due to induction of CYP 1A2.

• Caution is advised in patients taking cimetidine, since this agent increases plasma melatonin levels by inhibiting its metabolism by CYP1A2.

• Caffeine increases the concentrations of both endogenous and orally administered melatonin by inhibiting CYP1A2 catalysed melatonin metabolism.

• 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 such as quinolones may give rise to increased melatonin exposure.

• CYP1A2 inducers such as carbamazepine and rifampicin may reduce plasma concentrations of melatonin.

• There is a large amount of data in the literature regarding the effect of adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressant medical products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion. Whether or not these active substances interfere with dynamic or kinetic effects of melatonin or vice versa has not been studied.

Pharmacodynamic interactions

• Alcohol should not be taken with melatonin, because it reduces the effectiveness of melatonin on sleep. Alcohol can impair sleep and potentially worsen certain symptoms of jet-lag (e.g. headache, morning fatigue, impaired concentration).

• Melatonin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a clinical trial, there has been 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.

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

• Caution is advised in patients taking nifedipine, since concurrent use of melatonin and nifedipine may increase blood pressure. Concomitant use of melatonin and warfarin may lead to enhanced anticoagulation – INR should be checked when used together. Melatonin may also enhance the effect of direct-acting anticoagulants (e.g. dabigatran, rivaroxaban, apixaban, edoxaban).

4.6. Fertility, pregnancy and lactation

Pregnancy

For melatonin, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, partitution or postnatal development (see section 5.3). Exogenous melatonin readily crosses the human placenta. In view of lack of clinical data, use in pregnant women and by women intending to become pregnant is not recommended.

Breast-feeding

Endogenous melatonin was measured in human breast milk thus exogenous melatonin is problably secreted into 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 in the milk. Therefore, melatonin should not be used during breast-feeding.

Fertility

There is no data about possible adverse effects of short-term use of melatonin on human fertility.

4.7. Effects on ability to drive and use machines

Ceyesto has moderate influence on the ability to drive and use machines. Melatonin may cause drowsiness and impair alertness for hours; therefore the product 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

Drowsiness / sleepiness, headache, and dizziness / disorientation are the most frequently reported adverse effects in adults when melatonin is taken on a short-term basis to treat jet-lag. Drowsiness, headache, dizziness, and nausea are the most frequently reported adverse effects when typical clinical doses of melatonin have been taken for periods of several days to several weeks by healthy persons and patients including children and adolescents.

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, hypocalcaemia, hyponatremia

Psychiatric disorders

irritability, nervousness, restlessness, insomnia, abnormal dreams, nightmares, anxiety

mood changes, aggression, agitation, crying, stress symptoms, disorientation, early morning awakening, increased libido, depressed mood, depression

Nervous system disorders

migraine, headache, lethargy, psychomotor hyperactivity, dizziness, somnolence

syncope, impaired memory, disturbance in attention, dreamy state, restless legs syndrome, poor quality sleep, paraesthesia

Eye disorders

acuity reduced, vision blurred, increased lacrimation

Ear and labyrinth disorders

positional vertigo, vertigo

Cardiac disorders

angina pectoris, palpitations

Vascular disorders

hypertension

hot flushes

Gastrointestinal disorders

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

gastro-oesophageal reflux disease, gastrointestinal disorder, oral mucosal blistering, tongue ulceration, gastrointestinal upset, vomiting, bowel sounds abnormal, flatulence, salivary hypersecretion, halitosis, abdominal discomfort, gastric disorder, gastritis

Hepatobiliary disorders

hyperbilirubinaemia

Skin and subcutaneous tissue disorders

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

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

angioedema, oedema of mouth, tongue oedema

Musculoskeletal and connective tissue disorders

pain in extremity

arthritis, muscle spasms, neck pain, night cramps

Renal and urinary disorders

glycosuria, proteinuria

polyuria, haematuria, nocturia

Reproductive system and breast disorders

menopausal symptoms

priapism, prostatitis

galactorrhoea

General disorders and administration site conditions

asthenia, chest pain

fatigue, pain, thirst

Investigations

liver function test abnormal, weight increased

hepatic enzyme increased, blood electrolytes abnormal, laboratory test abnormal

Paediatric population

A low frequency of in general mild adverse reactions have been reported in the literature and paediatric population in short-term use (up to 4 weeks). The number of adverse reactions has not differed significantly between children who have received placebo compared to melatonin. The most common adverse reactions were headache, hyperactivity, dizziness and abdominal pain. No serious adverse reactions have been observed. Long term effects are poorly studied (see section 5.1).

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

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

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.