Melatonin Evalar, 3 mg 40 pcs.

Pharmacotherapeutic group: adaptogenic agent.

ATH code: N05CH01.

Pharmacological action

Pharmacodynamics

Melatonin is a synthetic analog of the pineal body hormone (epiphysis); synthesized from amino acids of plant origin. It has adaptogenic, sedative and hypnotic effect. Normalizes circadian rhythms. Increases the concentration of gamma-aminobutyric acid (GABA) and serotonin in the midbrain and hypothalamus, changes the activity of pyridoxal kinase, involved in the synthesis of GABA, dopamine and serotonin.

Regulates the sleep-wake cycle, daily changes in locomotor activity and body temperature, has a positive effect on mental and intellectual functions of the brain, on the emotional and personality sphere.

Contributes to the organization of the biological rhythm and normalization of night sleep, has a sedative effect. It improves the quality of sleep, accelerates falling asleep, reduces the number of night awakenings, improves the sense of well-being after the morning awakening, does not cause a feeling of dullness, weariness and fatigue upon awakening. Makes dreams more vivid and emotionally rich.

Adapts the body to rapid change of time zones, reduces stress reactions, regulates neuroendocrine functions. Adapts the body of people sensitive to changes in weather conditions. Exhibits immunostimulatory and antioxidant properties. It is not addictive and not dependent.

Pharmacokinetics

Absorption

Melatonin after oral administration is quickly absorbed in the gastro-intestinal tract. Absorption rate may be reduced by 50% in the elderly. The kinetics of melatonin in the 2-8 mg range are linear. When administered orally at a dose of 3 mg, Cmax in plasma and saliva is reached after 20 minutes and 60 minutes, respectively. Time to reach maximum serum Tmax concentration is 60 minutes (normal range 20-90 minutes).

After administration of 3-6 mg melatonin, maximum serum Cmax concentration is typically 10 times higher than endogenous melatonin at night. Accompanying food intake delays absorption of melatonin.

bioavailability

Bioavailability of melatonin when taken orally ranges from 9 to 33 % (approximately 15 %).

In in vitro studies melatonin binding to plasma proteins is 60 %. Melatonin binds mainly to albumin, α1 – acidic glycoprotein and high density lipoproteins. Vd distribution volume is about 35 liters. Rapidly distributed in saliva and passes through the blood-brain barrier, determined in the placenta. Concentration in cerebrospinal fluid is 2.5 times lower than in plasma.

Biotransformation

Melatonin is metabolized primarily in the liver. After ingestion melatonin undergoes significant transformation during primary passage through the liver where it is hydroxylated and conjugated to sulfate and glucuronide to form 6-sulfatoxymelatonin; presystemic metabolism can reach 85%. Experimental studies suggest that CYP1A1, CYP1A2 isoenzymes and possibly CYP2C19 of the cytochrome P450 system are involved in the metabolism of melatonin. The main metabolite of melatonin, 6-sulfatoxymelatonin, is inactive.

Melatonin is excreted from the body by the kidneys. The average elimination half-life (T½) of melatonin is 45 minutes. Excretion is with the urine, about 90% as sulfate and glucuron conjugates of 6-hydroxymelatonin, and about 2-10% is excreted unchanged.

Pharmacokinetic parameters are affected by age, caffeine intake, smoking, taking oral contraceptives. Patients in critical condition have accelerated absorption and impaired elimination.

Elderly patients

Melatonin metabolism is known to slow with age. At different doses of melatonin higher values of area under the concentration-time curve (AUC) and Cmax were obtained in elderly patients, which reflects the reduced metabolism of melatonin in this group of patients.

Patients with impaired renal function

No cumulation of melatonin was noted with long-term treatment. These data are consistent with the short elimination half-life of melatonin in humans.

Indications

For sleep disorders, incl. caused by a disturbance in the sleep-wake rhythm, such as desynchronosis (sudden change of time zones).

Pharmacological effect

Pharmacotherapeutic group: adaptogenic agent.

ATX code: N05CH01.

Pharmacological action

Pharmacodynamics

Melatonin is a synthetic analogue of the pineal gland hormone; synthesized from amino acids of plant origin. It has an adaptogenic, sedative and hypnotic effect. Normalizes circadian rhythms. Increases the concentration of gamma-aminobutyric acid (GABA) and serotonin in the midbrain and hypothalamus, changes the activity of pyridoxal kinase, which is involved in the synthesis of GABA, dopamine and serotonin.

Regulates the sleep-wake cycle, daily changes in locomotor activity and body temperature, has a positive effect on the intellectual and mnestic functions of the brain, on the emotional and personal sphere.

Promotes the organization of biological rhythm and normalization of night sleep, has a hypnotic effect. Improves sleep quality, speeds up falling asleep, reduces the number of night awakenings, improves well-being after waking up in the morning, and does not cause a feeling of lethargy, weakness and fatigue when waking up. Makes dreams more vivid and emotionally rich.

Adapts the body to rapid changes in time zones, reduces stress reactions, and regulates neuroendocrine functions. Adapts the body of weather-sensitive people to changes in weather conditions. Shows immunostimulating and antioxidant properties. Does not cause addiction or dependence.

Pharmacokinetics

Absorption

Melatonin after oral administration is quickly absorbed from the gastrointestinal tract. In elderly people, the rate of absorption may be reduced by 50%. The kinetics of melatonin in the range of 2-8 mg is linear. When administered orally at a dose of 3 mg, Cmax in blood plasma and saliva is achieved after 20 minutes and 60 minutes, respectively. The time to reach the maximum Tmax concentration in the blood serum is 60 minutes (normal range 20-90 minutes).

After taking 3-6 mg of melatonin, the maximum concentration of Cmax in the blood serum is usually 10 times higher than the endogenous melatonin in the blood serum at night. Concomitant meals delay the absorption of melatonin.

Bioavailability

Oral bioavailability of melatonin ranges from 9 to 33% (approximately 15%).

In in vitro studies, the binding of melatonin to plasma proteins is 60%. Melatonin mainly binds to albumin, α1 acid glycoprotein and high-density lipoproteins. The distribution volume Vd is about 35 liters. It is quickly distributed into saliva and passes through the blood-brain barrier and is detected in the placenta. The concentration in cerebrospinal fluid is 2.5 times lower than in plasma.

Biotransformation

Melatonin is metabolized primarily in the liver. After oral administration, melatonin undergoes significant transformation during its initial passage through the liver, where it is hydroxylated and conjugated with sulfate and glucuronide to form 6-sulfatoxymelatonin; the level of first-pass metabolism can reach 85%. Experimental studies suggest that isoenzymes CYP1A1, CYP1A2 and, possibly, CYP2C19 of the cytochrome P450 system are involved in the metabolism of melatonin. The main metabolite of melatonin is 6-sulfatoxymelatonin, inactive.

Melatonin is excreted from the body by the kidneys. The average half-life (T½) of melatonin is 45 minutes. Excretion is carried out in the urine, about 90% in the form of sulfate and glucuronic conjugates of 6-hydroxymelatonin, and about 2-10% is excreted unchanged.

Pharmacokinetic parameters are affected by age, caffeine intake, smoking, and oral contraceptives. In critically ill patients, there is accelerated absorption and impaired elimination.

Elderly patients

Melatonin metabolism is known to slow down with age. At different doses of melatonin, higher values ​​of the area under the concentration-time curve (AUC) and Cmax were obtained in the elderly, which reflects a reduced metabolism of melatonin in this group of patients.

Patients with impaired renal function

With long-term treatment, no accumulation of melatonin was observed. These data are consistent with the short half-life of melatonin in humans.

Special instructions

During the period of use of the drug Melatonin Evalar, it is recommended to avoid exposure to bright light.

It is necessary to inform women who want to become pregnant that the drug has a weak contraceptive effect.

There are no clinical data on the use of melatonin in patients with autoimmune diseases, and therefore, use in this category of patients is not recommended.

Active ingredient

Melatonin

Composition

Composition per 1 tablet:

Active ingredient: melatonin – 3.00 mg.

Excipients: microcrystalline cellulose – 172.72 mg, calcium hydrogen phosphate dihydrate – 54.68 mg, croscarmellose sodium – 7.20 mg, colloidal silicon dioxide – 1.20 mg, magnesium stearate – 1.20 mg.

Excipients of the shell: hypromellose (hydroxypropyl methylcellulose) – 4.00 mg, titanium dioxide – 2.90 mg, polysorbate 80 – 1.32 mg, macrogol 4000 (polyethylene glycol 4000) – 0.89 mg, talc – 0.89 mg.

Pregnancy

The drug is contraindicated for use during pregnancy and breastfeeding.

Contraindications

Hypersensitivity to the components of the drug, autoimmune diseases, liver failure, severe renal failure, children under 18 years of age, pregnancy, breastfeeding.

With caution

The effect of varying degrees of renal impairment on the pharmacokinetics of melatonin has not been studied, so melatonin should be used with caution in such patients.

Side Effects

Classification of the frequency of side effects according to the recommendations of the World Health Organization:

Very common (≥1/10), common (≥1/10 to <1/10), uncommon (≥1/1000 to <1/100), rare
(from ≥1/10000 to <1/1000), very rare (<1/10000), including isolated reports; frequency is unknown (it is not possible to determine the frequency of occurrence based on available data).

Infectious and parasitic diseases:

rarely: herpes zoster.

Blood and lymphatic system disorders:

rarely: leukopenia, thrombocytopenia.

Immune system disorders:

frequency unknown: hypersensitivity reactions.

Metabolic and nutritional disorders:

rarely: hypertriglyceridemia, hypokalemia, hyponatremia.

Mental disorder:

uncommon: irritability, nervousness, restlessness, insomnia, unusual dreams, nightmares, anxiety;

rarely: mood swings, aggression, agitation, tearfulness, symptoms of stress, disorientation, early morning awakening, increased libido, decreased mood, depression.

Nervous system disorders:

uncommon: migraine, headache, lethargy, psychomotor hyperactivity, dizziness, drowsiness;

rare: fainting, memory impairment, impaired concentration, delirium, restless legs syndrome, dreamlike state, poor quality of sleep, paresthesia.

Visual disorders:

rarely: decreased visual acuity, blurred vision, increased lacrimation.

Hearing and labyrinth disorders:

rarely: vertigo, positional vertigo.

Cardiovascular system disorders:

uncommon: arterial hypertension;

rarely: angina pectoris, palpitations, hot flashes.

Gastrointestinal disorders:

uncommon: abdominal pain, abdominal pain in the upper abdomen, dyspepsia, ulcerative stomatitis, dry mouth, nausea;

rare: gastroesophageal disease, gastrointestinal disorder or disorder, bullous stomatitis, ulcerative glossitis, vomiting, increased peristalsis, bloating, hypersecretion of saliva, bad breath, abdominal discomfort, gastric dyskinesia, gastritis.

Disorders of the liver and biliary tract:

uncommon: hyperbilirubinemia.

Skin and subcutaneous tissue disorders:

uncommon: dermatitis, night sweats, itching and generalized itching, rash, dry skin;

rarely: eczema, erythema, hand dermatitis, psoriasis, generalized rash, itchy rash, nail damage;

frequency unknown: Quincke’s edema, swelling of the oral mucosa, swelling of the tongue.

Musculoskeletal and connective tissue disorders:

uncommon: pain in the limbs.

rarely: arthritis, muscle spasms, neck pain, night cramps.

Renal and urinary tract disorders:

uncommon: glucosuria, proteinuria;

rarely: polyuria, hematuria, nocturia.

Disorders of the genital organs and breast:

uncommon: menopausal symptoms;

rarely: priapism, prostatitis;

frequency unknown: galactorrhea.

General disorders and disorders at the injection site:

uncommon: asthenia, chest pain;

rarely: fatigue, pain, thirst.

Laboratory and instrumental data:

uncommon: deviation from normal laboratory parameters of liver function, weight gain;

rarely: increased activity of liver transaminases, abnormal levels of electrolytes in the blood, abnormal results of laboratory tests.

Interaction

Pharmacokinetic interaction

It is known that at concentrations significantly higher than therapeutic levels, melatonin induces the CYP3A isoenzyme in vitro. The clinical significance of this phenomenon is not fully understood. If signs of induction develop, consider reducing the dose of concomitantly used drugs.

At concentrations significantly higher than therapeutic levels, melatonin does not induce CYP1A isoenzymes in vitro. Therefore, the interaction of melatonin with other drugs due to the effect of melatonin on CYP1A isoenzymes is apparently insignificant.

Melatonin metabolism is mainly mediated by CYP1A isoenzymes. Therefore, it is possible that melatonin may interact with other drugs due to the effect of melatonin on isoenzymes of the CYP1A group.

Caution should be exercised in patients taking fluvoxamine, which increases melatonin concentrations (17-fold increase in AUC and 12-fold increase in Cmax) due to inhibition of its metabolism by cytochrome P450 (CYP) isoenzymes: CYP1A2 and CYP2C19. This combination should be avoided.

Caution should be exercised in patients taking 5- and
8-methoxypsoralen, which increases melatonin concentrations due to inhibition of its metabolism.

Caution should be exercised in patients taking cimetidine (an inhibitor of CYP2D isoenzymes) as it increases plasma melatonin levels by inhibiting the latter.

Smoking can reduce melatonin concentrations due to the induction of the CYP1A2 isoenzyme.

Caution should be exercised in patients taking estrogens (e.g., contraceptives or hormone replacement therapy), which increase melatonin concentrations by inhibiting their metabolism by CYP1A1 and CYP1A2.

Inhibitors of CYPA2 isoenzymes, such as quinolones, can increase melatonin exposure.

Inducers of the CYP1A2 isoenzyme, such as carbamazepine and rifampicin, can reduce plasma concentrations of melatonin.

In modern literature there is a lot of data regarding the effect of agonists/antagonists of adrenergic and opioid receptors, antidepressants, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol on the secretion of endogenous melatonin. There have been no studies of the mutual influence of these drugs on the dynamics or kinetics of melatonin.

Pharmacodynamic interaction

You should not drink alcohol while taking melatonin, as it reduces the effectiveness of the drug.

Melatonin potentiates the sedative effects of benzodiazepine and non-benzodiazepine hypnotics such as zaleplon, zolpidem and zopiclone. In a clinical study, clear evidence of a transient pharmacodynamic interaction between melatonin and zolpidem was observed one hour after administration. Combined use may lead to progressive impairment of attention, memory and coordination compared to zolpidem monotherapy.

In the studies, melatonin was given together with thioridazine and imipramine, drugs that affect the central nervous system. In none of the cases was there a clinically significant pharmacokinetic interaction. However, concomitant use with melatonin resulted in increased feelings of calmness and difficulty performing certain tasks compared with imipramine monotherapy, as well as increased feelings of brain fog compared with thioridazine monotherapy.

Overdose

According to available literature data, the use of melatonin in a daily dosage of up to 300 mg did not cause clinically significant adverse reactions. When taking melatonin in doses from 3000 mg to 6600 mg for several weeks, symptoms such as flushing, abdominal cramps, diarrhea, headache, and scotoma were observed. When very high doses of melatonin (up to 1 g) were used, involuntary loss of consciousness was observed. In case of overdose, drowsiness may develop.

Treatment is gastric lavage and the use of activated carbon, symptomatic therapy. Clearance of the active substance is expected within 12 hours after oral administration.

Recommendations for use

Inside.

For sleep disturbances – 3 mg once a day 30-40 minutes before bedtime. For desynchronosis, as an adaptogen when changing time zones – 1 day before the flight and in the next 2-5 days – 3 mg 30-40 minutes before bedtime. The maximum daily dose is 6 mg.

Elderly patients

With age, melatonin metabolism decreases, which must be taken into account when choosing a dosage regimen for elderly patients. Taking this into account in elderly patients, it is possible to take the drug 60-90 minutes before bedtime.

Kidney failure

The effect of varying degrees of renal impairment on the pharmacokinetics of melatonin has not been studied, so melatonin should be used with caution in such patients. The use of the drug is not recommended for patients with severe renal failure.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of the reach of children.

Shelf life

2 years. Do not use after expiration date.

Manufacturer

Evalar CJSC, Russia