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.

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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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'.

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.

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.

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.

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).

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.

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.

Pharmacotherapeutic group: Psycholeptics, Melatonin receptor agonists, ATC code: N05CH01.

Melatonin is a hormone produced by the pineal gland. It is structurally related to serotonin.

Melatonin secretion increases shortly after dark, reaching its peak between 2 am and 4 am and decreases during the latter half of the night. Melatonin is involved in controlling the circadian rhythm and adaptation to the light-dark cycle. Melatonin is also associated with a sedative effect and an increased propensity for sleep.

Mechanism of action

Melatonin activity on MT1, MT2 and MT3 receptors is considered to contribute to its sleep promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythm and sleep regulation.

Pharmacodynamic effects

Melatonin has a hypnotic/sedative effect and increases propensity for sleep. Melatonin administered earlier or later than the nocturnal peak in melatonin secretion can, respectively, advance or delay the circadian rhythmicity of melatonin secretion. Administration of melatonin at bedtime (between 22:00 and 24:00 hr) at destination following rapid transmeridian travel (aircraft flight) hastens resynchronisation of circadian rhythmicity from 'departure time' to 'destination time', and ameliorates the collection of symptoms known as jet lag that are a consequence of such de-synchronisation.

Clinical efficacy and safety

Typical symptoms of jet lag are sleep disturbances and daytime tiredness and fatigue, though mild cognitive impairment, irritability, and gastrointestinal disturbances may also occur.

Jet lag is worse the more time-zones crossed, and is typically worse following eastward travel. Melatonin taken close to the target bedtime at the destination (10 pm to midnight), decreased jet lag from flights crossing five or more time zones. The benefit is likely to be greater the more time zones are crossed, and less for westward flights. Daily doses of melatonin between 0.5 and 5 mg are similarly effective, except that people fall asleep faster and sleep better after 5 mg than 0.5 mg.

Clinical trials have found melatonin to reduce patient-assessed overall symptoms of jet lag, and to shorten the duration of jet lag. Due to the potential for incorrectly timed intake of melatonin to have no effect, or to cause an adverse effect, on re-synchronisation of circadian rhythmicity/jet lag, melatonin should not be taken before 20:00 hr or after 04:00 hr at destination.

Adverse reactions reported in jet lag studies involving melatonin doses of 0.5 to 8 mg were typically mild, and often difficult to distinguish from symptoms of jet lag.

Paediatric population

Melatonin treatment has been studied in a 4-week randomized, double-blind, placebo-controlled study conducted in 105 children between 6– 12 years of age, with ADHD and chronic sleep onset insomnia (van der Heijden KB et al. 2007). Participants received melatonin (3 mg when body weight < 40 kg [n=44]; or 6 mg when body weight > 40 kg [n=9]) in fast-release tablets or placebo.

Mean actigraphic estimate of sleep onset advanced by 26.9 ± 47.8 minutes with melatonin, whereas there was a delay of 10.5 ± 37.4 minutes with placebo (p < 0.0001). 48.8% of children who received melatonin showed an advance of sleep onset > 30 minutes compared to 12.8% with placebo (p=0.001). There was an increase in mean total time asleep of 19.8 ± 61.9 minutes with melatonin and a decrease of 13.6 ± 50.6 minutes with placebo (p=0.01). As compared with placebo, the melatonin group showed a decrease in sleep latency (p=0.001) and increase in sleep efficiency (p=0.01).

There was no significant effect on behaviour, cognition, and quality of life.

There were no discontinuations or withdrawals caused by adverse events.

There is very little long-term safety data on immediate-release melatonin products specifically in children and adolescents with ADHD.

Absorption

The absorption of orally ingested melatonin is complete in adults. Absolute bioavailability of melatonin has been estimated to average 15% of the given dose. There is a signifigant first pass effect with an estimated first pass metabolism of 80-90%. The T_max occurs usually approximately 50 minutes (normal range 15 to 90 minutes) after administration.

Maximum concentration and exposure of melatonin after oral dosing of tablets increases proportionally to the dose from 0.1 up to 5 mg.

Data on the effect of intake of food at or around the time of intake of melatonin on its pharmacokinetics are limited, though suggest that concomitant food intake may increase the absorption almost 2-fold. Food appears to have a limited effect on t_max for immediate-release melatonin. This is not expected to affect the efficacy or safety of Melatonin Orion, however, it is recommended that food is not consumed approximately 2 h before and 2 h after intake of melatonin.

Distribution

The plasma protein binding of melatonin in vitro is about 60%. Distribution volume during terminal elimination phase is proportional to body weight, averaging just over 1 L/kg.

Melatonin primarily binds to albumin, though also binds alpha1-acid glycoprotein; binding to other plasma proteins is limited. Melatonin rapidly distributes from the plasma into and out of most tissues and organ, and readily crosses the brain-blood barrier.

Biotransformation

Melatonin is mainly eliminated by hydroxylation to 6-hydroxymelatonin in the liver, primarily mediated by CYP1A2 (to a lesser extent by CYP1A1). Quantitatively less important O-demethylation to N-acetyl-5-hydroxytryptamine mediated by CYP2C19 occurs. Melatonin metabolites are mainly eliminated by the urine, ~ 90% as sulphate and glucuronide conjugates of 6-hydroxymelatonin. Less than ~ 1% of a melatonin dose is excreted unchanged in urine.

Elimination and accumulation

Plasma elimination half-life (T_1/2) is ~ 45 minutes (normal range ~ 30– 60 minutes) in healthy adults. The half-life, on average, is comparable or slightly shorter in children compared to adults. Administration once daily in combination with the short half-life means minimal accumulation of melatonin during regular treatment.

Special populations

Elderly

Metabolism of melatonin decreases with age. Night-time endogenous melatonin plasma concentration is lower in the elderly compared to young adults. Limited data for plasma/serum T_max, C_max, elimination half-life (T_½ ), and AUC following ingestion of immediate-release melatonin do not indicate significant differences between younger adults and elderly persons in general, though the range of values (inter-individual variability) for each parameter (particularly T_max and AUC) tend to be greater in the elderly.

Hepatic impairment

Limited data indicate that the daytime endogenous blood melatonin concentration is markedly elevated in patients with liver cirrhosis, probably due to reduced clearance (metabolism) of melatonin.

Serum t_1/2 for exogenous melatonin in cirrhosis patients was double that of controls in a small study. As the liver is the primary site of melatonin metabolism, hepatic impairment can be expected to result in increased exposure to exogenous melatonin.

Renal impairment

Published data indicate that there is no accumulation of melatonin after repeated dosing in patients on stable haemodialysis. As melatonin is primarily excreted as metabolites in the urine, serum/plasma levels of melatonin metabolites can be expected increase in patients with more advanced renal impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, mutagenicity, genotoxicity and carcinogenic potential. Effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

After intra-peritoneal administration of a single, high dose of melatonin to pregnant mice, fetal body-weight and length tended to be lower, possibly due to maternal toxicity. Delay in sexual maturation in male and female offspring of the rat and ground squirrel occurred upon exposure to melatonin during pregnancy and post-partum. These data indicate that melatonin crosses the placenta and is secreted in milk, and that it may influence the ontogeny and activation of the hypothalamic-pituitary-gonadal axis. As the rat and ground squirrel are seasonal breeders, the relevance of these findings for humans is uncertain.

There are no safety studies in juvenile animals.

Magnesium stearate (E470b)

Silica colloidal anhydrous (E551)

Cellulose microcrystalline (E460)

Croscarmellose sodium (E468)

Not applicable.

3 years

This medicinal product does not require any special temperature storage conditions.

Blister: Keep the blister in the outer carton in order to protect from light.

Bottle: Store in the original package in order to protect from light.

Melatonin Orion 3 mg tablets are available in a carton containing PVC/PE/PVDC/AL blister packs of 10, 30, 50 and 60 tablets.

Melatonin Orion 3 mg tablets are available in HDPE bottles closed with HDPE closures.

Pack sizes:

100 tablets

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.