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

Sleep disorders, including those caused by sleep-wake rhythm disturbances, such as desynchronosis (sudden change of time zones).

Active ingredient

Melatonin

Composition

Ingredients per tablet:

Active ingredient: melatonin – 3.00 mg.

Excipients: microcrystalline cellulose – 172.72 mg, calcium hydrophosphate dihydrate – 54.68 mg, croscarmellose sodium – 7.20 mg, colloidal silica – 1.20 mg, magnesium stearate – 1.20 mg.

Excipients in the capsule: 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.

Interaction

Pharmacokinetic interaction

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

• In concentrations significantly higher 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.

• Metabolism of melatonin is mainly mediated by CYP1A isoenzymes. Therefore, melatonin may interact with other medicinal products due to the effect of melatonin on CYP1A isoenzymes.

• Paution is necessary in patients receiving fluvoxamine which increases melatonin concentrations (17-fold AUC and 12-fold Cmax) due to inhibition of its metabolism by cytochrome P450 (CYP4AE↩P) isoenzymes: CYP1A2 and CYP2C19. This combination should be avoided.

• Patients taking 5- and
  8-methoxypsoralen, which increases melatonin concentrations due to inhibition of its metabolism, should be treated with caution.

• Patients who are taking cimetidine (a CYP2D isoenzyme inhibitor) should be treated with caution because it increases melatonin plasma levels by inhibiting the latter.

• smoking may decrease melatonin concentration due to induction of CYP1A2 isoenzyme.

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

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

• Inducers of CYP1A2 isoenzyme, such as carbamazepine and rifampicin, can decrease the plasma concentration of melatonin.

• Modern literature is full of data regarding the effects of adrenergic and opioid receptor agonists/antagonists, antidepressants, prostaglandin 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 decreases 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. Combined use may lead to progressive impairment of attention, memory and coordination compared with zolpidem monotherapy.

• In studies, melatonin has been co-administered with thioridazine and imipramine, drugs that affect the central nervous system. No clinically significant pharmacokinetic interactions were found in any of the cases. However, concomitant use with melatonin resulted 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.

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Directions for use

Orally.

In case of sleep disorders – 3 mg once a day 30-40 minutes before sleep. In desynchronosis as an adaptogen when changing the time zones 1 day before the flight and during the next 2-5 days 3 mg once 30-40 minutes before sleeping. Maximal daily dose is 6 mg.

Elderly patients

With age melatonin metabolism decreases that is necessary to consider while choosing the dosage regimen for elderly patients. Taking this into account in elderly patients, it is possible to take the drug 60-90 minutes before sleep.

Renal failure

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

Special Instructions

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

Women who want to get pregnant should be informed about the weak contraceptive effect of the drug.

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

Synopsis

Sleep better, dream better, live better!

The quality of sleep depends on melatonin levels in the body. Few people realize that melatonin production decreases rapidly as early as the age of 30 and therefore sleep problems may become more frequent. If you have insomnia and regular sleeping pills do not give results, try Melatonin Evalar.

• It has adaptogenic, sedative, sleeping pills;
• Assists in organizing the biological rhythm and normalization of night sleep, has a sleeping effect;
• It improves the quality of sleep, accelerates falling asleep, reduces the number of night awakenings, does not cause a feeling of lethargy, frazzled and tiredness upon awakening. Makes dreams more vivid and emotionally rich.
• Accelerates sleep-wake cycle, has a positive effect on the emotional-personal sphere.
• Adapt the body to rapid change of time zones, reduces stress reactions.
• Adapts the body of people sensitive to changes in weather conditions.
• Does not cause addiction and dependence.

Melatonin and COVID-19

Paul Maric, MD, chief of pulmonology from Virginia, suggests taking melatonin for prevention and relief of symptoms in patients with COVID-19 in an intensive care protocol. In conjunction with vitamin C, D3 and zinc, it may play a role in improving the course of the disease. And according to Rospotrebnadzor, melatonin provides protection against the most severe lung damage because of its ability to affect inflammation. With this, melatonin is attracting the attention of scientists as a means to potentially reduce the severity of a new coronavirus infection.

Contraindications

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

With caution

The effect of varying degrees of renal failure on the pharmacokinetics of melatonin has not been studied, so such patients should use melatonin with caution.

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), infrequent (≥1/1000 to < 1/100), rare
(≥1/10000 to < 1/1000), very rare (< 1/10000), including individual reports; frequency is unknown (it is not possible to determine the frequency of occurrence from the available data).

Infectious and parasitic diseases:

Rarely: herpes zoster.

Disorders of the blood and lymphatic system:

rarely: leukopenia, thrombocytopenia.

Disorders of the immune system:

frequency unknown: hypersensitivity reactions.

Disorders of the metabolism and nutrition:

rare: 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, drowsiness;

rarely: fainting, memory disturbance, impaired concentration, delirium, restless legs syndrome, dreaming state, poor sleep quality, paresthesias.

Visual disorders:

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

Hearing organ disorders and labyrinth disorders:

rarely: vertigo, positional vertigo.

Cardiovascular system disorders:

infrequent: arterial hypertension;

rare: angina pectoris, palpitations, hot flashes.

Gastrointestinal disorders:

infrequent: abdominal pain, upper abdominal pain, dyspepsia, ulcerative stomatitis, dry mouth, nausea;

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

Liver and biliary tract disorders:

infrequent: hyperbilirubinemia.

Skin and subcutaneous tissue disorders:

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

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

frequency unknown: Quincke’s edema, oral mucosal edema, tongue edema.

Muscular and connective tissue disorders:

infrequent: pain in the extremities.

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

Renal and urinary tract disorders:

infrequent: glucosuria, proteinuria;

rare: polyuria, hematuria, nicturia.

Genital and breast disorders:

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 findings:

infrequent: abnormal laboratory measures of liver function, increased body weight;

rare: increased activity of “hepatic” transaminases, abnormal blood electrolytes, abnormal laboratory test results.

Overdose

According to the available literature, the use of melatonin in daily doses of up to 300 mg did not cause clinically significant adverse reactions. Melatonin doses of 3000 mg to 6600 mg over several weeks have resulted in symptoms such as hyperemia, abdominal cramps, diarrhea, headache, and scotoma. When using very high doses of melatonin (up to 1 g), involuntary loss of consciousness has been observed. In case of overdose somnolence may occur.

Treatment – gastric lavage and activated charcoal, symptomatic therapy. Clearance of the active substance is assumed within 12 hours after ingestion.

Pregnancy use

The drug is contraindicated in pregnancy and during breast-feeding.

Similarities

Melaxen, Sonnovan, Melarena, Melatonin, Wellson, Strengthen Your Immunity by Evalar