Melatonin Mylan is indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.

Posology

The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food. This dosage may be continued for up to thirteen weeks.

Paediatric population

The safety and efficacy of Melatonin Mylan in children aged 0 to 18 years has not yet been established. No data are available.

Renal impairment

The effect of any stage of renal impairment on melatonin pharmacokinetics has not been studied. Caution should be used when melatonin is administered to such patients.

Hepatic impairment

There is no experience of the use of Melatonin Mylan in patients with liver impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, Melatonin Mylan is not recommended for use in patients with hepatic impairment.

Method of Administration

Oral use. Tablets should be swallowed whole to maintain prolonged release properties. Crushing or chewing should not be used to facilitate swallowing.

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

Melatonin Mylan 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.

No clinical data exist concerning the use of Melatonin Mylan in individuals with autoimmune diseases. Therefore, Melatonin Mylan is not recommended for use in patients with autoimmune diseases.

Melatonin Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction studies have only been performed in adults.

Pharmacokinetic interactions

• Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations. The clinical relevance of the finding is unknown. If induction occurs, this can give rise to reduced plasma concentrations of concomitantly administered medicinal products.

• Melatonin does not induce CYP1A enzymes in vitro at supra-therapeutic concentrations. Therefore, interactions between melatonin and other active substances as a consequence of melatonin's effect on CYP1A enzymes are not likely to be significant.

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

• Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum C_max) 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.

• Caution should be exercised in patients on cimetidine a CYP2D inhibitor, which increases plasma melatonin levels, by inhibiting its metabolism.

• Cigarette smoking may decrease melatonin levels due to induction of CYP1A2.

• 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 give rise to reduced 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 medicinal products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion. Whether or not these active substances interfere with the dynamic or kinetic effects of Melatonin Mylan or vice versa has not been studied.

Pharmacodynamic interactions

• Alcohol should not be taken with Melatonin, because it reduces the effectiveness of Melatonin Mylan on sleep.

• Melatonin Mylan may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Melatonin Mylan and zolpidem one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone.

• Melatonin Mylan 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 Mylan 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

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, parturition or postnatal development (see section 5.3). In view of the lack of clinical data, use in pregnant women and by women intending to become pregnant is not recommended.

Breastfeeding

Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probably 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, breast-feeding is not recommended in women under treatment with melatonin.

Melatonin Mylan has moderate influence on the ability to drive and use machines. Melatonin Mylan 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.

Summary of the safety profile

In clinical trials (in which a total of 1,931 patients were taking Melatonin Mylan and 1,642 patients were taking placebo), 48.8% of patients receiving Melatonin Mylan reported an adverse reaction compared with 37.8% taking placebo. Comparing the rate of patients with adverse reactions per 100 patient weeks, the rate was higher for placebo than Melatonin Mylan (5.743– placebo vs. 3.013– Melatonin Mylan). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia, which were common, by MedDRA definition, in both the Melatonin Mylan and placebo treated groups.

Tabulated list of adverse reactions

The following adverse reactions were reported in clinical trials and from post-marketing spontaneous reporting.

In clinical trials a total of 9.5% of patients receiving Melatonin Mylan reported an adverse reaction compared with 7.4% of patients taking placebo. Only those adverse reactions reported during clinical trials occurring in patients at an equivalent or greater rate than placebo have been included below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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 established from the available data).

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.

Several cases of overdose have been reported post-marketing. Somnolence was the most reported adverse event. Most were mild to moderate in severity. Melatonin Mylan has been administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported.

Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions 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.

Pharmacotherapeutic group: Psycholeptics, melatonin receptor agonists, ATC code: N05CH01

Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin. Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night. Melatonin is associated with the control of circadian rhythms and entrainment to the light-dark cycle. It is also associated with a hypnotic effect and increased propensity for sleep.

Mechanism of action

The activity of melatonin at the MT1, MT2 and MT3 receptors is believed to contribute to its sleep-promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep regulation.

Rationale for use

Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.

Clinical efficacy and safety

In clinical trials, where patients suffering from primary insomnia received Melatonin Mylan 2 mg every evening for 3 weeks, benefits were shown in treated patients compared to placebo in sleep latency (as measured by objective and subjective means) and in subjective quality of sleep and daytime functioning (restorative sleep) with no impairment of vigilance during the day.

In a polysomnographic (PSG) study with a run-in of 2 weeks (single-blind with placebo treatment), followed by a treatment period of 3 weeks (double-blind, placebo-controlled, parallel group design) and a 3-week withdrawal period, sleep latency (SL) was shortened by 9 minutes compared to placebo. There were no modifications of sleep architecture and no effect on REM sleep duration by Melatonin Mylan. Modifications in diurnal functioning did not occur with Melatonin Mylan 2 mg.

In an outpatient study with 2 week run-in baseline period with placebo, a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks and 2 week withdrawal period with placebo, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 47% in the Melatonin Mylan group as compared to 27% in the placebo group. In addition, quality of sleep and morning alertness significantly improved with Melatonin Mylan compared to placebo. Sleep variables gradually returned to baseline with no rebound, no increase in adverse reactions and no increase in withdrawal symptoms.

In a second outpatient study with two week run in baseline period with placebo and a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 26% in the Melatonin Mylan group as compared to 15% in the placebo group. Melatonin Mylan shortened patients' reported sleep latency by 24.3 minutes vs 12.9 minutes with placebo. In addition, patients' self-reported quality of sleep, number of awakenings and morning alertness significantly improved with Melatonin Mylan compared to placebo. Quality of life was improved significantly with Melatonin Mylan 2 mg compared to placebo.

An additional randomised clinical trial (n=600) compared the effects of Melatonin Mylan and placebo for up to six months. Patients were re-randomised at 3 weeks. The study demonstrated improvements in sleep latency, quality of sleep and morning alertness, with no withdrawal symptoms and rebound insomnia. The study showed that the benefit observed after 3 weeks is maintained for up to 3 months but failed the primary analysis set at 6 months. At 3 months, about an extra 10% of responders were seen in the Melatonin Mylan treated group.

Absorption

The absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly. The kinetics of melatonin are linear over the range of 2-8 mg.

Bioavailability is in the order of 15%. There is a significant first pass effect with an estimated first pass metabolism of 85%. T_max occurs after 3 hours in a fed state. The rate of melatonin absorption and C_max following Melatonin Mylan 2 mg oral administration is affected by food. The presence of food delayed the absorption of the melatonin resulting in a later (T_max=3.0 h versus T_max=0.75 h) and lower peak plasma concentration in the fed state (C_max=1020pg/ml versus C_max=1176 pg/ml).

Distribution

The in vitro plasma protein binding of melatonin is approximately 60%. Melatonin Mylan is mainly bound to albumin, alpha₁-acid glycoprotein and high density lipoprotein.

Biotransformation

Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. The site of biotransformation is the liver. The excretion of the metabolite is completed within 12 hours after ingestion.

Elimination

Terminal half life (t_½ ) is 3.5-4 hours. Elimination is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as melatonin (unchanged active substance).

Gender

A 3-4-fold increase in C_max is apparent for women compared to men. A five-fold variability in C_max between different members of the same sex has also been observed. However, no pharmacodynamic differences between males and females were found despite differences in blood levels.

Special populations

Older People

Melatonin metabolism is known to decline with age. Across a range of doses, higher AUC and C_max levels have been reported in older patients compared to younger patients, reflecting the lower metabolism of melatonin in the elderly. C_max levels around 500 pg/ml in adults (18-45) versus 1200 pg/ml in elderly (55-69); AUC levels around 3,000 pg*h/mL in adults versus 5,000 pg*h/mL in the elderly.

Renal impairment

Company data indicates that there is no accumulation of melatonin after repeated dosing. This finding is compatible with the short half-life of melatonin in humans.

The levels assessed in the blood of the patients at 23:00 (2 hours after administration) following 1 and 3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ml respectively, and are similar to those found in in healthy volunteers following a single dose of Melatonin Mylan 2 mg.

Hepatic impairment

The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels.

Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

The carcinogenicity study in the rat did not reveal any effect which may be relevant for humans.

In reproductive toxicology, oral administration of melatonin in pregnant female mice, rats or rabbits did not result in adverse effects on their offspring, measured in terms of foetal viability, skeletal and visceral abnormalities, sex ratio, birthweight and subsequent physical, functional and sexual development. A slight effect on post-natal growth and viability was found in rats only at very high doses, equivalent to approximately 2000 mg/day in humans.

Lactose Monohydrate

Calcium hydrogen phosphate dihydrate

Ammonio methacrylate copolymer

Talc

Silica, colloidal anhydrous

Magnesium stearate

Not applicable.

3 years

This medicinal product does not require any special storage conditions. Store in the original package in order to protect from light.

The tablets are packed in PVC/PVDC opaque Aluminium blister strips or Aluminium/Aluminium blister pack. The pack consists of 7, 20, 21 or 30 tablets. The blisters are then packed in cardboard boxes.

Not all pack sizes may be marketed.

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.