Melatonin-SZ, 3 mg 30 pcs.

Pharmacodynamics

A synthetic analog of the pineal body hormone (epiphysis); it has adaptogenic, sedative and hypnotic effects. 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.

It improves the quality of sleep, speeds up falling asleep and regulates neuroendocrine functions. Adapts the body of weather-sensitive people to changes in weather conditions. Pharmacokinetics Absorption

Melatonin after oral administration is rapidly absorbed in the gastrointestinal tract. In the elderly, the absorption rate may be reduced by 50%. The kinetics of melatonin in the 2 – 8 mg range are linear. When administered orally at a dose of 3 mg, St> in plasma and saliva is reached in 20 minutes and 60 minutes, respectively.

The time to reach maximum serum Tta> concentration is 60 minutes (normal range 20-90 minutes). After ingestion of 3-6 mg of melatonin, the maximum serum Tt> concentration is typically 10 times the endogenous serum melatonin concentration at night. Concomitant food intake delays the absorption of melatonin.

Bioavailability

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

Distribution

In in vitro studies, the binding of melatonin to plasma proteins is 60%. Melatonin primarily binds to albumin, α-acid 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 conversion during primary passage through the liver, where it is hydroxylated and conjugated to sulfate and glucuronide to form 6-sulfatoxymelatonin; presystemic metabolism can be as high as 85%.

Experimental studies suggest that the CYP1A1, CYP1A2 and possibly CYP2C19 cytochrome P450 isoenzymes are involved in the metabolism of melatonin. The main metabolite of melatonin, 6-sulfatoxymelatonin, is inactive.

The excretion

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

Pharmacokinetic parameters are affected by age, caffeine intake, smoking, taking oral contraceptives. In critical patients accelerated absorption and impaired elimination are observed.

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 Stach were obtained in the elderly, which reflects the reduced metabolism of melatonin in this group of patients.

Patients with impaired renal function No cumulation of melatonin was noted during long-term treatment. These data are consistent with the short half-life of melatonin in humans.

Patients with impaired liver function The liver is the main organ involved in melatonin metabolism, so liver disease leads to increased concentrations of endogenous melatonin. In patients with cirrhosis, plasma concentrations of melatonin were significantly increased during the day.

Indications

Active ingredient

Composition

1 tablet contains:

the active ingredient:

melatonin -Z mg;

excipients:

microcrystalline cellulose – 48.5 mg:

sodium carboxymethyl starch – 6.5 mg;

calcium hydrophosphate dihydrate – 41.0 mg;

magnesium stearate – 1.0 mg

coating composition:

hypromellose, 1.53 mg;

polysorbate-80 (tween-80), 0.64 mg;

talk, 0.51 mg;

titanium dioxide E 171-0.32 mg.

Interaction

Pharmacokinetic interaction

Melatonin is known to induce the CYP3A isoenzyme in vitro at concentrations significantly greater than therapeutic. The clinical significance of this phenomenon is not fully understood. In case of signs of induction, a dose reduction of concomitantly administered drugs should be considered;

In concentrations significantly greater than therapeutic, 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 appears to be insignificant;

Melatonin metabolism is primarily mediated by CYP1A isoenzymes. Therefore, melatonin may interact with other drugs due to the effect of melatonin on CYP1A isoenzymes. – Caution should be used in patients receiving fluvoxamine, which increases melatonin concentrations (17-fold AUC and 12-fold Cmax increase) due to inhibition of its metabolism by cytochrome P450 isoenzymes: CYP1A2 and CYP2C19. This combination should be avoided.

Patients taking 5- and 8-methoxypsoralen, which increases melatonin concentrations by inhibiting its metabolism, should be treated with caution. – Caution should be used with patients taking cimetidine (a CYP2D isoenzyme inhibitor), because it increases plasma melatonin concentrations by inhibiting the latter;

smoking may decrease melatonin concentrations through 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 isoenzymes;

The CYPA2 isoenzyme inhibitors, such as quinolones, can increase melatonin exposure;

– CYP1A2 isoenzyme inducers, such as carbamazepine and rifampicin, can decrease plasma concentrations of melatonin. – current literature is replete with data regarding the effects of adrenergic and opioid receptor agonists/antagonists, antidepressants, GH inhibitors, benzodiazepines, tryptophan and alcohol on endogenous melatonin secretion. No studies of the reciprocal effects of these drugs on melatonin dynamics or kinetics have been performed.

Pharmacodynamic interaction

– Alcohol should not be consumed while taking melatonin because it reduces the effectiveness of the drug;

Melatonin potentiates the sedative effects of benzodiazepine and non-benzodiazepine sleeping pills such as zaleplon, zolpidem and zopiclone.

In a clinical study, there were clear signs of transient pharmacodynamic interaction between melatonin and zolpidem one hour after their administration.

The combined use may lead to progressive impairment of attention, memory and coordination compared to zolpidem monotherapy;

In studies, melatonin was co-administered with thioridazine and imipramine, drugs that affect the CNS. No clinically significant pharmacokinetic interactions were observed in any of the cases.

The concomitant use with melatonin did, however, result in increased feelings of calmness and difficulty performing certain tasks compared to imipramine monotherapy, and increased feelings of blurring in the head, compared to thioridazine monotherapy.

Directions for use

Ingestion, 30-40 min. In sleep disorders – 3 mg once a day.

In desynchronosis as an adaptogen when changing time zones – 1 day before the flight and in the next 2-5 days – 3 mg. The maximum daily dose is 6 mg.

Elderly patients. Melatonin metabolism decreases with age; this should be considered when choosing a dosing regimen for elderly patients. Taking this into consideration, in elderly patients it is possible to take the drug 60-90 minutes before sleep.

Renal insufficiency. The effect of varying degrees of renal impairment on the pharmacokinetics of melatonin has not been studied, so melatonin should be taken with caution in these patients. In patients with severe renal impairment, use of the drug is not recommended.

Special Instructions

During the use of Melatonin-SZ it is recommended to avoid being in bright light.

Women who want to get pregnant should be informed about the weak contraceptive effect of the drug. There is no clinical data about the use of melatonin in patients with autoimmune diseases; therefore, it is not recommended for this category of patients.

Impact on driving and operating ability. Melatonin-SZ causes somnolence, therefore during the treatment period it is necessary to refrain from driving vehicles and engaging in potentially dangerous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

WARNING

Melatonin-SZ should be used with caution in patients with various degrees of renal impairment.

Side effects

Classification of frequency of side effects according to WHO recommendations: very common (≥1/10); common (≥1/100 to < 1/10); infrequent (≥1/1000 to < 1/100); rare (≥1/10000 to < 1/1000); very rare (< 1/10000), including individual reports; frequency is unknown (according to available data it is impossible to determine the incidence).

Infectious and parasitic diseases: rarely herpes zoster.

Blood and lymphatic system disorders: rarely – leukopenia, thrombocytopenia.

Immune system disorders: frequency unknown – hypersensitivity reactions.

Metabolism and nutrition: rarely – hypertriglyceridemia, hypokalemia, hyponatremia.

Mental disorders: infrequent – irritability, nervousness, anxiety, insomnia, unusual dreams, nightmares, anxiety; rarely – mood swings, aggression, agitation, tearfulness, stress symptoms, disorientation, early morning awakening, increased libido, decreased mood, depression.

Nervous system disorders: infrequent – migraine, headache, lethargy, psychomotor hyperactivity, dizziness, somnolence; rarely – fainting, memory disturbance, concentration disorders, delirium, restless legs syndrome, poor sleep quality, paresthesias.

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

Hearing organ and labyrinth disorders: rare – vertigo, positional vertigo.

Systems: infrequent – arterial hypertension; rare – angina pectoris, palpitations, hot flashes.

Gastrointestinal disorders: infrequent – abdominal pain, upper abdominal pain, dyspepsia, ulcerative stomatitis, dry mouth, nausea; rare – GERD, gastrointestinal disturbance or disorder, bullous stomatitis, ulcerative glossitis, vomiting, increased peristalsis, abdominal bloating, hyper-secretion of saliva, bad breath, abdominal discomfort, gastric dyskinesia, gastritis.

Hepatic and biliary tract disorders: infrequent – hyperbilirubinemia.

Skin and subcutaneous tissue: infrequent – dermatitis, night sweats, itching and generalized itching, rash, dry skin; rarely – eczema, erythema, dermatitis of the hands, psoriasis, generalized rash, itching rash, nail damage; frequency unknown – Quincke’s edema, oral mucosa edema, tongue edema.

Skeletal-muscular system and connective tissue disorders: infrequent – pain in the extremities; rare – arthritis, muscle spasm, neck pain, night cramps.

Key kidneys and urinary tract: infrequent – glucosuria, proteinuria; rarely – polyuria, hematuria, nycturia.

Genital organs and the breast: infrequent – menopausal symptoms; rare – priapism, prostatitis; frequency unknown – galactorrhea.

General disorders and disorders at the site of administration: infrequent – asthenia, chest pain; rare – fatigue, pain, thirst.

Laboratory and instrumental data: infrequent – abnormal liver function tests, weight gain; rare – increased liver transaminase activity, abnormal blood electrolyte levels, abnormal laboratory test results.

Overdose

Symptoms: According to the available literature, the use of melatonin in daily doses up to 300 mg has not caused clinically significant adverse reactions. Hyperemia, abdominal cramps, diarrhea, headache, and scotoma have been observed when melatonin doses of 3000-6600 mg have been used for several weeks. In very high doses of melatonin (up to 1 g), involuntary loss of consciousness has been observed. In overdose, drowsiness may develop.

The treatment: gastric lavage and activated charcoal use, symptomatic therapy. Clearance of the active substance is assumed within 12 hours after oral administration.

Pregnancy use

Similarities