Several cases of overdose have been reported post-marketing. Somnolence was the most reported adverse event. Most were mild to moderate in severity. Melatonina LEK-AM 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.
Not applicable.
Summary of the safety profile
In clinical trials (in which a total of 1,931 patients were taking Melatonina LEK-AM and 1,642 patients were taking placebo), 48.8% of patients receiving Melatonina LEK-AM 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 Melatonina LEK-AM (5.743- placebo vs. 3.013- Melatonina LEK-AM). The most common adverse reactions were headache, nasopharyngitis, back pain, and arthralgia , which were common, by MedDRA definition, in both the Melatonina LEK-AM 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 Melatonina LEK-AM 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).
| System Organ Class | Very Common | Common | Uncommon | Rare | Not known: (Cannot be established from the available data) |
| Infections and infestations | Herpes zoster | ||||
| Blood and lymphatic system disorders | Leukopenia, thrombocytopenia | ||||
| Immune system disorders | Hypersensitivity reaction | ||||
| Metabolism and nutrition disorders | Hypertriglyceridaemia, hypocalcaemia, hyponatraemia | ||||
| 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 | Migraine, headache, lethargy, psychomotor hyperactivity, dizziness, somnolence | 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 | Hyperbilirubinaemia | ||||
| 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 electrolyes abnormal, laboratory test 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 the national reporting system listed in Appendix V.
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.
Melatonina LEK-AM 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.
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 Melatonina LEK-AM 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 Melatonina LEK-AM. Modifications in diurnal functioning did not occur with Melatonina LEK-AM 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 Melatonina LEK-AM group as compared to 27% in the placebo group. In addition, quality of sleep and morning alertness significantly improved with Melatonina LEK-AM 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 Melatonina LEK-AM group as compared to 15% in the placebo group. Melatonina LEK-AM 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 Melatonina LEK-AM compared to placebo. Quality of life was improved significantly with Melatonina LEK-AM 2 mg compared to placebo.
An additional randomised clinical trial (n=600) compared the effects of Melatonina LEK-AM 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 Melatonina LEK-AM 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%. Tmax occurs after 3 hours in a fed state. The rate of melatonin absorption and Cmax following Melatonina LEK-AM 2 mg oral administration is affected by food. The presence of food delayed the absorption of the melatonin resulting in a later (Tmax=3.0 h versus Tmax=0.75 h) and lower peak plasma concentration in the fed state (Cmax=1020pg/ml versus Cmax=1176 pg/ml).
Distribution
The in vitro plasma protein binding of melatonin is approximately 60%. Melatonina LEK-AM 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 (t½) 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 Cmax is apparent for women compared to men. A five-fold variability in Cmax 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 Cmax levels have been reported in older patients compared to younger patients, reflecting the lower metabolism of melatonin in the elderly. Cmax 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 Melatonina LEK-AM 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.
Melatonina LEK-AM 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 Melatonina LEK-AM in individuals with autoimmune diseases. Therefore, Melatonina LEK-AM is not recommended for use in patients with autoimmune diseases.
Melatonina LEK-AM contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Melatonina LEK-AM has moderate influence on the ability to drive and use machines. Melatonina LEK-AM 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.
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 Melatonina LEK-AM 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 Melatonina LEK-AM 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, Melatonina LEK-AM 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.
No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
