Welson, 3 mg 30 pcs.

Pharmacotherapeutic group: adaptogenic agent. ATX code: N05CH01 Pharmacological properties

Pharmacodynamics

A synthetic analog of the pineal body hormone (epiphysis); has adaptogenic, sedative, sedative 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 regulates the sleep-wake cycle, daily changes in locomotor activity and body temperature, has a positive effect on the intellectual and mental functions of the brain and on the emotional-personal sphere.

It helps to organize the biological rhythm and normalize night sleep. Improves the quality of sleep, speeds up falling asleep and regulates neuroendocrine functions. It adapts the body of people sensitive to changes in weather conditions.

Pharmacokinetics

Absorption

Melatonin is rapidly absorbed in the gastrointestinal tract after oral administration. In elderly patients 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, the maximum concentration (Cmax) in plasma and saliva is reached after 20 min and 60 min, respectively. Time to reach maximum concentration (TCmax) in blood serum is 60 min (normal range 20-90 min). After taking 3-6 mg of melatonin, serum Cmax is usually 10 times higher than endogenous melatonin in serum 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 mainly binds to albumin, α1-acid glycoprotein and high density lipoproteins. The volume of distribution is about 35 liters. It is rapidly distributed in saliva and passes through the blood-brain barrier and is 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 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.

The excretion

Melatonin is excreted from the body by the kidneys. The average elimination half-life (T1/2) 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, and 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 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 T1/2 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 liver cirrhosis, plasma concentrations of melatonin were significantly increased during the daytime.

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 properties

Pharmacodynamics

A synthetic analogue of the pineal gland hormone (epiphysis); has an adaptogenic, sedative, 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.

Helps organize biological rhythm and normalize night sleep. Improves sleep quality, speeds up falling asleep, regulates neuroendocrine functions. Adapts the body of weather-sensitive people to changes in weather conditions.

Pharmacokinetics

Absorption

Melatonin after oral administration is quickly absorbed from the gastrointestinal tract. In elderly patients, the rate of absorption may be reduced by 50%. The kinetics of melatonin in the range of 2-8 mg is linear. When taken orally at a dose of 3 mg, the maximum concentration (Cmax) in blood plasma and saliva is achieved after 20 minutes and 60 minutes, respectively. Time to reach maximum concentration (TCmax) in blood serum is 60 minutes (normal range 20-90 minutes). After taking 3-6 mg of melatonin, serum Cmax is typically 10 times the endogenous serum melatonin at night. Concomitant meals delay the absorption of melatonin.

Bioavailability

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

In in vitro studies, the binding of melatonin to plasma proteins is 60%. Melatonin binds mainly to albumin, α1-acid glycoprotein and high-density lipoproteins. Distribution volume approx. 35 l. 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, 6-sulfatoxymelatonin, is inactive.

Selection

Melatonin is excreted from the body by the kidneys. The average half-life (T1/2) 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% was excreted unchanged.

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

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 elderly patients, which reflects the 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 T1/2 of melatonin in humans.

Patients with liver dysfunction

The liver is the main organ involved in melatonin metabolism, so liver diseases lead to increased concentrations of endogenous melatonin. In patients with liver cirrhosis, plasma melatonin concentrations increased significantly during the daytime.

Special instructions

During the period of use of the drug Velson®, 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.

Impact on the ability to drive vehicles and machinery

The drug Velson® causes drowsiness; therefore, during the treatment period, you should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Melatonin

Composition

One film-coated tablet contains:

Active ingredient:

melatonin – 3 mg.

Excipients:

calcium hydrogen phosphate dihydrate – 64.67 mg,

microcrystalline cellulose – 25.00 mg,

povidone K 25 – 3.33 mg,

croscarmellose sodium – 2.00 mg,

talc – 1.00 mg,

colloidal silicon dioxide – 0.50 mg,

calcium stearate – 0.50 mg.

Shell composition:

opadry white (03A280002) – 3.00 mg [hypromellose (hydroxypropyl methylcellulose) – 40%, microcrystalline cellulose – 32%, titanium dioxide – 20%, macrogol (polyethylene glycol) – 8%].

Pregnancy

Velson® is contraindicated for use during pregnancy and breastfeeding.

Contraindications

Velson® should be used with caution in patients with varying degrees of renal failure.

Side Effects

Classification of adverse reactions by organs and systems, indicating the frequency of their occurrence: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/1000), very rarely (<1/10000), incl. isolated reports, frequency unknown (frequency cannot be estimated from 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 disorders: uncommon – irritability, nervousness, anxiety, 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; rarely – fainting, memory impairment, impaired concentration, delirium, restless legs syndrome, poor quality of sleep, paresthesia.

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

Hearing disorders and labyrinthine disorders: rarely – vertigo, positional vertigo.

Cardiac disorders: rarely – angina pectoris, palpitations.

Vascular disorders: uncommon – arterial hypertension; rarely – “hot flashes”.

Gastrointestinal disorders: uncommon – abdominal pain, abdominal pain in the upper abdomen, dyspepsia, ulcerative stomatitis, dry mouth, nausea; rarely – 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.

Disorders of the skin and subcutaneous tissues: infrequently – 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 extremities; 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 mammary glands: uncommon – menopausal symptoms; rarely – priapism, prostatitis; frequency unknown – galactorrhea.

General disorders and disorders at the injection site: infrequently – asthenia, chest pain; rarely – fatigue, pain, thirst.

Impact on the results of laboratory and instrumental studies: infrequently – deviation from the norm in laboratory parameters of liver function, increase in body weight; rarely – increased activity of “liver” transaminases, deviation from the norm in the content of electrolytes in the blood, deviation from the norm in the results of laboratory tests.

If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

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 the concentration of melatonin (increase in AUC by 17 times and Cmax by 12 times) due to inhibition of its metabolism by cytochrome P450 isoenzymes (CYP): CYP1A2 and CYP2C19. This combination should be avoided.

Caution should be exercised in patients taking 5- and 8-methoxy-psoralen, 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 dose of up to 300 mg did not cause clinically significant adverse reactions. Flushing, abdominal cramps, diarrhea, headache and scotoma have been observed when melatonin was used in doses of 3000-6600 mg for several weeks. When very high doses of melatonin (up to 1 g) were used, involuntary loss of consciousness was observed.

Symptoms: in case of overdose, drowsiness may develop.

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

Storage conditions

In a place protected from light at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

4 years.

Do not use after the expiration date stated on the package.

Manufacturer

Pharmproject, Russia