4.1. Therapeutic indications

Melatonin Orion 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

Adults with jet lag

The standard dose is one 3 mg tablet at local time to go to bed starting on arrival at destination for a maximum of 4 days. One 5 mg tablet may be taken instead of 3 mg at local time to go to bed if the standard dose of 3 mg does not adequately alleviate symptoms. The 5 mg tablet should not be taken in addition to the 3 mg tablet, but a higher dose may be taken on the following days. The maximum daily dose is 5 mg once daily and the complete duration of treatment is 4 days.

The dose should be taken at the time of destination bedtime for journeys of 5 time zones or longer, especially when traveling in an easterly direction.

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.

Paediatric population

The safety and efficacy of Melatonin Orion in children and adolescents less than 18 years of age in jet lag have not been established.

Insomnia in children and adolescents with ADHD

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

Melatonin treatment should be titrated up to the lowest effective dose. Melatonin Orion can be used when the lowest effective dose has been established to be 3 or 5 mg taken 30-60 minutes before bedtime.

Maximum daily dose is 5 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

Melatonin Orion tablets are not recommended for children below 6 years with ADHD.

Special populations

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 liver cirrhosis. Melatonin is not recommended in patients with moderate or severe hepatic impairment (see section 4.4 and 5.2).

Method of administration

Oral use.

The tablet can be crushed and mixed with cold water directly before the administration.

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 Orion tablets.

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

Autoimmune diseases

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. Therefore, Melatonin is not recommended for use in patients with autoimmune diseases.

Epilepsy

Melatonin has been reported to increase, decrease and have no effect on seizure frequency. Because of the uncertainty of the effect of melatonin on epileptic seizures, some caution should be exercised for use in people with epilepsy.

Diabetes

Limited data suggest that melatonin taken in close proximity to ingestion of carbohydrate-rich meals may impair blood glucose control for several hours. Melatonin tablets 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.

Unnecessary long-term use of melatonin should be avoided due to its effects on glucose metabolism and increased risk for type 2 diabetes.

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).

Long-term use in children and adolescents

There is limited data on long-term safety of melatonin in the paediatric population. Effects of long-term use on glucose homeostasis, pubertal development and sexual maturation are currently unknown.

Excipients

This medicinal product contains less than 1 mmol (23 mg) sodium per tablet, that is to say essentially 'sodium-free'.

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

Pharmacokinetic interactions

Melatonin is mainly metabolised by CYP1A enzymes. Interactions between melatonin and other active substances that affect CYP1A enzymes are therefore possible.

CYP1A2 inhibitors

CYP1A2 inhibitors may increase the plasma concentrations of melatonin considerably. Concomitant treatment with melatonin and the CYP1A2 inhibitor fluvoxamine (also a CYP2C19 inhibitor) should be avoided. Caution should be exercised when melatonin is used concomitantly with the CYP1A2 inhibitors, such as ciprofloxacin.

Caution should be exercised in patients on combined oral contraceptives or hormone replacement therapy, as melatonin levels might increase by inhibition of its metabolism by CYP1A1 and CYP1A2.

Through interaction with moderately pronounced inhibitors of CYP1A2, increase of the plasma concentration of melatonin is expected. Caution is therefore indicated in patients taking 5- or 8-methoxypsoralen (5 or 8-MOP), cimetidine or caffeine.

CYP1A2 inducers

CYP1A2 inducers may decrease the plasma concentrations of melatonin.

Dose adjustment of melatonin may be needed if given concomitantly with the following CYP1A2 inducers: carbamazepine, phenytoin, rifampicin, omeprazole and cigarette smoking (halved exposure compared to after 7 days of smoking abstinence).

Pharmacodynamic interactions

Adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressants, prostaglandin inhibitors, tryptophan and alcohol affect the endogenous secretion of melatonin in the epiphysis, but do not affect the metabolism of melatonin. It is not known if these interactions are of clinical significance.

Alcohol

Alcohol should not be used concomitantly with melatonin since it may reduce the effect of melatonin on sleep. Alcohol can impair sleep and potentially worsen certain symptoms of jet lag (e.g. headache, morning fatigue, impaired concentration).

Nifedipine

Melatonin may reduce the hypotensive effect of nifedipine. Caution must be taken during concomitant use of melatonin and adjustment of the nifedipine dose may be needed. As it is not known if this is a class effect, caution should be exercised when combining melatonin and other calcium antagonists.

Anticoagulants

It has been reported in case reports that concomitant use of melatonin and vitamin K antagonists such as warfarin can lead to enhanced anticoagulation. The combination of warfarin and direct-acting anticoagulants (e.g. dabigatran, rivaroxaban, apixaban, edoxaban) with melatonin may require dose adjustment of the anticoagulant drugs and should be avoided.

Benzodiazepine-related hypnotics

Melatonin may enhance the sedative properties of benzodiazepine-related hypnotics, e.g. zolpidem. Concomitant treatment with melatonin should be avoided.

NSAIDs

Prostaglandin synthesis inhibitors (NSAIDs) such as acetylsalicylic acid and ibuprofen, taken in the evening, may suppress endogenous melatonin levels. If possible, administration of NSAIDs should be avoided in the evening.

Beta-blockers

Beta-blockers may suppress the endogenous melatonin and should therefore be administered in the morning.

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of melatonin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, childbirth and postnatal development (see section 5.3). Exogenous melatonin readily crosses the human placenta. Considering the lack of clinical data, treatment with melatonin is not recommended during pregnancy or in women of childbearing potential not using contraceptives.

Breast-feeding

Data from animal studies indicate maternal transfer of melatonin to the foetus via the placenta or in the milk. Endogenous melatonin has also been measured in breast milk from breast-feeding women, and therefore exogenous melatonin is most likely also excreted in human milk. Melatonin is therefore not recommended to breast-feeding women.

Fertility

No adequate data on the effect of melatonin on human fertility are available. Animal studies are incomplete in terms of effects on fertility. High doses of melatonin and use for longer periods than indicated may compromise fertility in humans.

4.7. Effects on ability to drive and use machines

Melatonin has moderate effect on the ability to drive and use machines. Melatonin may cause drowsiness and impair alertness for hours; therefore melatonin should be used with caution if the effects of drowsiness are likely to be associated with a safety risk.

4.8. Undesirable effects

Summary of the safety profile

Melatonin causes few adverse reactions in the short term, up to three months.

Long term effects are poorly studied. Reported adverse reactions to melatonin are mainly headache, nausea and fatigue in both adults and children.

Adverse reactions in adults are listed according to MedDRA system organ class and presented within each frequency category according to the following: 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).

System organ class

Very

common

Common

Uncommon

Rare

Not Known

Infections and infestations

Herpes zoster

Blood and lymphatic system disorders

Leukopenia, Thrombocytopenia

Immune system disorders

Hypersensitivity reaction

Metabolism and nutrition disorders

Hypertriglyceridemia, Hypocalcaemia, Hyponatraemia

Hyperglycaemia

Psychiatric disorders

Irritability, Nervousness, Restlessness, Insomnia, Abnormal dreams, Nightmares, Anxiety

Mood altered, Aggression, Agitation, Crying, Stress symptoms, Disorientation, Early morning awakening, Libido increased, Depressed mood, Depression

Nervous system disorders

Headache, Somnolence

Migraine, Lethargy, Psychomotor Hyperactivity, Dizziness

Syncope, Memory impairment, Disturbance in attention, Dreamy state, Restless legs syndrome, Poor quality sleep, Paraesthesia

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 flush

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

Hyperbilirubinemia

Skin and subcutaneous tissue disorders

Dermatitis, night sweats, Pruritus, Rash, Pruritus generalised, Dry skin

Eczema, Erythema, Hand dermatitis, Psoriasis, Rash generalised, Rash pruritic, 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 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 headache, hyperactivity, dizziness, and abdominal pain. No serious adverse reactions 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 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 of overdose with oral melatonin.

Daily doses up to 300 mg of melatonin have been reported in the literature without any clinically significant adverse reactions.

If overdose occurs, drowsiness is to be expected.

Clearance of the active substance is expected within 12 hours of ingestion. A physician should assess if conventional overdose measures should be taken.