This information is intended for use by health professionals

1. Name of the medicinal product

Melatonin 1mg/ml oral solution

2. Qualitative and quantitative composition

Each 1 ml of solution contains 1 mg of melatonin.

Excipients with known effect:

Sorbitol: 140 mg per 1 ml dose.

Propylene glycol: 150.37 mg per 1 ml dose.

Ethanol: 0.00045 mg per 1 ml dose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral Solution

Clear, colourless to yellowish solution with characteristic strawberry odour.

4. Clinical particulars
4.1 Therapeutic indications

Melatonin 1mg/ml oral solution is indicated for short-term treatment of jet-lag in adults.

4.2 Posology and method of administration

Posology

The standard dose is 3 mg daily for a maximum of 5 days. The dose may be increased to 6 mg if the standard 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 1mg/ml oral solution should not be taken before 20:00 hr or after 04:00 hr at destination.

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 1mg/ml oral solution.

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 1mg/ml oral solution.

Melatonin 1mg/ml oral solution may be taken for a maximum of 16 treatment periods per year.

Elderly

As the pharmacokinetics of 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 1mg/ml oral solution in patients with renal impairment. Caution should be exercised if melatonin is used by patients with renal impairment. Melatonin 1mg/ml oral solution is not recommended for patients with severe renal impairment (see Section 5.2).

Hepatic impairment

There is no experience regarding the use of Melatonin 1mg/ml oral solution in patients with hepatic impairment. Limited data indicate that plasma clearance of melatonin is significantly reduced in patients with liver cirrhosis. Melatonin 1mg/ml oral solution is not recommended in patients with moderate or severe hepatic impairment (see Section 5.2).

Paediatric population

The safety and efficacy of Melatonin 1mg/ml oral solution in children and adolescents aged 0 – 18 years have not been established. Melatonin 1mg/ml oral solution should not be used in children and adolescents due to safety and efficacy concerns (see Sections 4.4 and 5.1).

Method of administration

Melatonin 1mg/ml oral solution is for oral use only.

A 10 ml graduated oral syringe with intermediate graduations of 0.5 ml and a “Press-In” Bottle Adapter (PIBA) are provided with the product.

1. Open the bottle and at first use insert the “Press-In” Bottle Adapter (PIBA).

2. Insert the syringe into the PIBA and draw out the required volume from the inverted bottle.

3. Remove the filled syringe from the bottle in the upright position

4. Discharge the syringe contents into the mouth.

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

Melatonin may cause drowsiness. Melatonin 1mg/ml oral solution should be used with caution if the effects of drowsiness are likely to be associated with a risk to patient safety.

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 1mg/ml oral solution. Melatonin may promote or increase the incidence of seizures in children and adolescents with multiple neurological defects.

Occasional case reports have described exacerbation of an autoimmune disease in patients taking melatonin. There are no data regarding use of Melatonin 1mg/ml oral solution in patients with autoimmune diseases. Melatonin 1mg/ml oral solution is not recommended in patients with autoimmune diseases.

Limited data suggest that melatonin taken in close proximity to ingestion of carbohydrate-rich meals may impair blood glucose control for several hours. Melatonin 1mg/ml 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.

Only limited data are available on the safety and efficiency of melatonin in patients with renal impairment or hepatic impairment. Melatonin 1mg/ml oral solution is not recommended for use in patients suffering from severe renal impairment or moderate or severe hepatic impairment.

Paediatric population

The safety and efficacy of Melatonin 1mg/ml oral solution in children and adolescents aged 0 – 18 years have not been established. Melatonin 1mg/ml oral solution should not be used in children and adolescents due to safety and efficacy concerns (see Section 5.1).

Melatonin 1mg/ml oral solution contains sorbitol, ethanol and propylene glycol.

This medicine contains 140 mg sorbitol and 150.37 mg propylene glycol in each ml.

This medicinal product contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 6ml dose. This statement is to provide reassurance to patients concerning the low levels of alcohol in the product.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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.

• 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.

•Melatonin may affect the anticoagulation activity of warfarin.

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 1mg/ml 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 1mg/ml 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 1mg/ml 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 1mg/ml 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.

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)

Blood and lymphatic system disorders

leucopenia, thrombocytopenia

Immune system disorders

hypersensitivity reaction

Metabolism and nutrition disorders

hypertriglyceridaemia

hyperglycaemia

Psychiatric disorders

irritability, nervousness, restlessness, abnormal dreams, anxiety

mood altered, aggressive behaviour, disorientation, libido increased

Nervous system disorders

headache, somno-lence

dizziness

syncope (fainting), memory impairment, restless legs syndrome, paraesthesia

Eye disorders

visual acuity reduced, vision blurred, lacrimation increased

Cardiac disorders

palpitations

Vascular disorders

hypertension

hot flushes

Gastrointestinal disorders

abdominal pain, upper abdominal pain, dyspepsia, oral ulcers, dry mouth, nausea

vomiting, flatulence, salivary hypersecretion, halitosis, gastritis

Skin and subcutaneous tissue disorders

pruritus, rash, dry skin

nail disorder

tongue edema, edema of the oral mucosa

Musculoskeletal and connective tissue disorders

arthritis, muscle spasms

Renal and urinary disorders

glycosuria, proteinuria

polyuria, haematuria

Reproductive system and breast disorders

priapism, prostatitis

galactorrhoea

General disorders and administration site conditions

chest pain, malaise

thirst

Laboratory and other examinations

weight increased

blood electrolytes abnormal

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

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: Melatonin,

ATC code: N05CH01

Melatonin is a hormone and antioxidant. Melatonin secreted by the pineal gland 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 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 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 re-synchronisation 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.

Paediatric population

The safety and efficacy of melatonin in children and adolescents aged 0 – 18 years have not been established. Melatonin 1mg/ml oral solution should not be used in children and adolescents aged 0 – 18 years due to safety concerns. Specifically, this is due to the fact that interference with the function of endogenous melatonin on the development of the hypothalamic-pituitary-gonadal axis cannot be excluded.

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 Tmax is ~ 50 minutes. A 3 mg dose of immediate- release melatonin raises plasma melatonin Cmax to ~ 3400 pg/mL, which is ~ 60-times the nocturnal (endogenous) plasma melatonin Cmax, though both endogenous- and exogenous Cmax 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 Tmax for immediate-release melatonin. This is not expected to affect the efficacy or safety of Melatonin 1mg/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 (T½) is ~ 45 minutes (normal range ~ 30 – 60 minutes) in healthy adults. 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 Cmax and AUC increase in a directly proportional, linear manner for oral doses of immediate-release melatonin in the range 3 – 6 mg whereas Tmax and plasma T½ remain constant.

Gender

Limited data suggest that Cmax 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

Older people

Night-time endogenous melatonin plasma concentration is lower in the elderly compared to young adults. Limited data for plasma- Tmax, Cmax, elimination half-life (T½), 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 T½ 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 post-partum. 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

Propylene Glycol (E1520)

Sorbitol liquid (non crystallising) (E420)

Sucralose (E955)

Strawberry Flavour (including ethanol (E1510) and propylene glycol (E1520))

Hydrochloric acid, concentrated (E507)

Purified Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

18 months

After first opening do not store above 25°C and use within 2 months.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

Amber, type III glass bottle of 150 ml nominal capacity, safely closed with an HDPE child-resistant, tamper-evident screw cap with an LDPE liner. An LDPE, CE marked 10 ml graduated oral syringe with intermediate graduations of 0.5 ml and an LDPE, CE marked “press-in” syringe/bottle adaptor are also provided.

6.6 Special precautions for disposal and other handling

None.

7. Marketing authorisation holder

Colonis Pharma Ltd

Quantum House,

Hobson Industrial Estate,

County Durham,

Burnopfield,

NE16 6EA,

United Kingdom

8. Marketing authorisation number(s)

PL 41344/0050

9. Date of first authorisation/renewal of the authorisation

10/06/2019

10. Date of revision of the text

10/06/2019