Melatonin 1 mg/ml oral solution – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Melatonin 1 mg/ml oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 1 mg of melatonin.

Excipients with known effect:

Sodium Methyl Parahydroxybenzoate (E219) 1.4 mg per 1 ml Sodium Ethyl Parahydroxybenzoate (E215) 0.7 mg per 1 ml Propylene glycol (E1520): 150 mg per 1 ml

Ethanol: Less than 0.3 micrograms per 1 ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution.

Clear, colourless/yellowish solution with characteristic strawberry odour.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

• 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

Short-term treatment of jet lag in adults:

The recommended dose is 2 mg (2 ml) daily for a maximum of 5 days. The dose may be increased to 5 mg (5 ml) if the initial 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 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 oral solution.

Melatonin 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.

The 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 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

Caution should be exercised in the elderly population due to greater variability in plasma melatonin concentrations in this age group and potential for morning drowsiness. Elderly patients should be commenced on a low dose, with cautious dose increase or reduction as necessary (see section 5.2).

Renal impairment

There is limited experience of administered melatonin in patients with renal impairment. Caution should be exercised if melatonin is used by patients with renal impairment. Melatonin oral solution is not recommended for patients with severe renal impairment (see section 5.2).

Hepatic impairment

There is limited data regarding the use of administered melatonin in patients with hepatic impairment. Data indicate markedly elevated endogenous melatonin levels in patients with liver cirrhosis. Melatonin oral solution is not recommended in patients with moderate or severe hepatic impairment (see section 5.2).

Paediatric population (under 6 years of age)

Melatonin oral solution is not recommended for use in children aged under 6 years of age.

Method of administration

Melatonin may act more quickly when administered as an oral solution compared with tablet or capsule formulations. Care should be exercised when switching between tablet/capsule and solution formulations.

Food may increase the absorption of melatonin, leading to higher plasma melatonin concentrations (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 oral solution.

A 5 ml graduated oral syringe with intermediate graduations of 0.1 ml and a “Press-In” Bottle Adapter (PIBA) are provided with the product.

1. 1. Open the bottle and at first use insert the “Press-In” Bottle Adapter (PIBA).
2. 2. Insert the syringe into the PIBA and draw out the required volume from the inverted bottle.
3. 3. Remove the filled syringe from the bottle in the upright position
4. 4. Discharge the syringe contents into the mouth.
5. 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 oral solution in patients with autoimmune diseases. Melatonin 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 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 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 oral solution is not recommended for use in patients suffering from severe renal impairment or moderate or severe hepatic impairment.

Warfarin

Due to the potential for pharmacokinetic interaction between warfarin and melatonin, there is a risk of increased anti-coagulation effect, with bleeding, if melatonin is taken alongside warfarin (see section 4.5) The patient should be closely monitored or switched to an alternative anti-coagulant, during melatonin use.

Paediatric population (under 6 years of age)

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

Melatonin oral solution contains:

Sodium Methyl Parahydroxybenzoate (E219): This medicine contains 1.4 mg Sodium Methyl Parahydroxybenzoate per 1 ml. May cause allergic reactions (possibly delayed).

Sodium Ethyl Parahydroxybenzoate (E215): This medicine contains 0.7 mg Sodium Ethyl Parahydroxybenzoate per 1 ml. May cause allergic reactions (possibly delayed).

Propylene Glycol (E1520): This medicine contains 150 mg Propylene Glycol per 1 ml.

Sodium:

This medicine contains less than 1mmol sodium (23 mg) per ml, that is to say essential ‘sodium-free’.

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.
• Melatonin may increase the anticoagulation activity of warfarin due to metabolism by CYP2C19, CYP1A and CYP2C9 families (see section 4.4).
• 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.
• 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 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 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 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 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.

Paediatric population

In the paediatric population, a low frequency of generally mild side effects has 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 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

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and sedatives, melatonin receptor agonists ATC code: N05CH01

Melatonin is a hormone secreted by the pineal gland and is involved in the synchronisation of circadian rhythms to the diurnal light-dark cycle. Melatonin secretion/plasma melatonin level increases shortly after the onset of darkness, peaks around 02:00 – 04:00 hr and declines to the daytime nadir by dawn. Peak melatonin secretion is almost diametrically opposite peak daylight intensity, with daylight being the primary stimulus for maintaining the circadian rhythmicity of melatonin secretion.

Mechanism of action

The pharmacological mechanism of action in melatonin is believed to be based on its interaction with MT1-, MT2- and MT3 receptors, as these receptors (particularly MT1 and MT2) are involved in the regulation of sleep and circadian rhythms in general.

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 desynchronisation.

Clinical efficacy and safety

Jet-lag in adults

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 as people generally find it harder to advance their circadian (body clock) than to delay it, as required following westward travel. Clinical trials have found melatonin to reduce patient-assessed overall symptoms of jet-lag by ~44%, and to shorten the duration of jet-lag. In 2 studies of flights over 12 time zones melatonin effectively reduce the duration of jet-lag by ~ 33%. Due to the potential for incorrectly timed intake of melatonin to have no effect, or an adverse effect, on resynchronisation of circadian rhythmicity/jet-lag, melatonin should not be taken before 20:00 hr or after 04:00 hr at destination.

Adverse effects 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. Transient drowsiness/sedation, headache, and dizziness/disorientation were reported; these same adverse effects, plus nausea, are those typically associated with short-term use of melatonin in reviews of the safety of melatonin in humans.

Sleep onset insomnia in children and adolescents aged 6-17 years with ADHD Published clinical studies support the effectiveness and safety of melatonin before bedtime to phase shift the circadian rhythm and improve sleep disturbance in paediatric patients with ADHD, by shortening the time to sleep onset and increasing the total sleep time.

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). The mean score on sleep log item difficulty falling asleep decreased by 1.2 ± 1.3 points (35.3% of baseline) with melatonin and by 0.1 ± 0.8 points (4.3% of baseline) with placebo (p < 0.0001).

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

5.2 Pharmacokinetic properties

Melatonin is a small, amphiphilic molecule (molecular weight 232 g/mol) active in its parent form. Melatonin is synthesised in the human body from tryptophan via serotonin. Small quantities are obtained via diet. Data summarised below are from studies that generally involved healthy men and women, primarily young and middle-aged adults.

Absorption

Orally administered melatonin is almost completely absorbed. Oral bioavailability is ~ 15%, owing to first-pass metabolism of ~ 85%. Plasma T_max is ~ 50 minutes. A 3 mg dose of immediate- release melatonin raises plasma melatonin C_max to ~ 3400 pg/mL, which is ~ 60-times the nocturnal (endogenous) plasma melatonin C_max, though both endogenous- and exogenous C_max show considerable inter-individual variation.

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 bioavailability 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 1 mg/ml oral solution, however, it is recommended that food is not consumed approximately 2 h before and 2 h after intake of melatonin.

Distribution

The protein binding of melatonin is approximately 50 – 60%. 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. Melatonin readily crosses the placenta. The level in umbilical blood of full-term babies closely correlates with and is only slightly lower (~ 15 – 35%) than that of their mother following ingestion of a 3 mg dose.

Biotransformation

Melatonin is mainly metabolised by the liver. Experimental data suggest that the cytochrome P450 enzymes CYP1A1 and CYP1A2 are primarily responsible for melatonin metabolism, with CYP2C19 of minor importance. Melatonin is primarily metabolised to 6-hydroxymelatonin (constituting ~ 80 – 90% of melatonin metabolites recovered in the urine). N-acetylserotonin appears to be the primary minor metabolite (constituting ~ 10% of melatonin metabolites recovered in the urine). Melatonin metabolism is very rapid, with plasma 6-hydroxymelatonin level rising within minutes of exogenous melatonin entering the systemic circulation. 6-hydroxymelatonin undergoes sulphate conjugation (~ 70%) and glucuronide conjugation (~ 30%) prior to excretion.

Elimination

Plasma elimination half-life (T_½) 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. Dosage once daily in combination with the short half-life means minimal accumulation of melatonin during regular treatment. 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.

Linearity

Plasma melatonin C_max and AUC increase in a directly proportional, linear manner for oral doses of immediate-release melatonin in the range 1 – 6 mg whereas Tmax and plasma T_½ remain constant.

Gender

Limited data suggest that C_max and AUC following ingestion of immediate-release melatonin may be higher (potentially roughly double) in women compared to men, however a large variability in the pharmacokinetics is observed. Plasma melatonin half-life does not appear to be significantly different in men and women.

Special populations

Elderly

Night-time endogenous melatonin plasma concentration is lower in the elderly compared to young adults. Limited data for plasma- 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 tend to be greater in the elderly.

Hepatic impairment

Limited data indicate that daytime endogenous blood melatonin concentration is markedly elevated in patients with liver cirrhosis, probably due to reduced clearance (metabolism) of melatonin. Serum T_½ 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

Literature data indicate that there is no accumulation of melatonin after repeated dosing (3 mg for 5 – 11 weeks) in patients on stable haemodialysis. However, as melatonin is primarily excreted as metabolites in the urine, plasma levels of melatonin metabolites can be expected increase in patients with more advanced renal impairment.

5.3 Preclinical safety data

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, large 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 postpartum. These data indicate that exogenous 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 implications of these findings for humans uncertain.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium methyl parahydroxybenzoate (E219) Sodium ethyl parahydroxybenzoate (E215)

Glycerol (E422)

Propylene glycol (E1520)

Citric acid monohydrate

Sodium citrate

Sucralose

Strawberry flavour (containing propylene glycol (E1520), lactic acid (E270), triacetin (E1518) and ethanol)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months (unopened).

After first opening, use within 4 months.

6.4 Special precautions for storage

Store in the original container in order to protect from light.

6.5 Nature and contents of container

Melatonin oral solution is supplied in 150ml, Type III, amber glass bottles sealed with a polypropylene/HDPE, child resistant and tamper evident cap. A 5 ml polypropylene/HDPE dosing syringe with 0.1 ml graduations and LDPE adaptor are also included in the carton.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Aristo Pharma GmbH

Wallenroder Strasse 8-10

13435 Berlin

Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 40546/0258

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

12/08/2026

10 DATE OF REVISION OF THE TEXT

12/08/2026