Glycine + Melatonin Evalar (Tablets) Instructions for Use

Marketing Authorization Holder

Evalar, CJSC (Russia)

Contact Information

Evalar, CJSC (Russia)

ATC Code

N05CX (Hypnotic and sedative drugs, excluding barbiturates, in combination with other drugs)

Active Substances

Glycine (Rec.INN registered by WHO)

Melatonin (BP British Pharmacopoeia)

Dosage Form

Glycine + Melatonin Evalar

Sublingual tablets 100 mg+3 mg: 20 pcs.

Dosage Form, Packaging, and Composition

Sublingual tablets round, biconvex, from white to grayish-white in color; marbling is allowed.

Excipients: sorbitol – 113.7 mg, mannitol – 22.05 mg, croscarmellose sodium – 6.25 mg, magnesium stearate – 2.5 mg, colloidal silicon dioxide – 1.25 mg, stearic acid – 1.25 mg.

20 pcs. – blister packs (1) – cardboard packs.

Clinical-Pharmacological Group

Hypnotic drug

Pharmacotherapeutic Group

Hypnotic agent

Pharmacological Action

A combined drug containing Glycine and Melatonin, the action of which is due to the pharmacological effects caused by glycine and melatonin, respectively.

Glycine

An essential amino acid, a central inhibitory neurotransmitter.

It improves metabolic processes in brain tissues and has an antidepressant and sedative effect.

It has glycinergic and GABA-ergic, alpha₁-adrenergic blocking, antioxidant, and antitoxic effects; it regulates the activity of glutamate (NMDA) receptors, thereby facilitating falling asleep and normalizing sleep, reducing psycho-emotional stress, aggressiveness, and conflict; it improves social adaptation and mood; it increases mental performance; it reduces the severity of vegetative-vascular disorders (including during menopause) and general cerebral disorders in ischemic stroke and traumatic brain injury, and reduces the toxic effect of ethanol on the central nervous system.

Melatonin

A synthetic analogue of the pineal gland hormone melatonin; it has adaptogenic, sedative, and hypnotic effects.

It normalizes circadian rhythms.

It increases the concentration of 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, and has a positive effect on the intellectual and mnestic functions of the brain and on the emotional and personal sphere.

It contributes to the organization of the biological rhythm and normalization of night sleep.

It improves sleep quality, accelerates falling asleep, reduces the number of nighttime awakenings, improves well-being after morning awakening, and does not cause feelings of lethargy, fatigue, or exhaustion upon awakening.

It makes dreams more vivid and emotionally rich.

It adapts the body to rapid time zone changes, reduces stress reactions, and regulates neuroendocrine functions.

It adapts the body of weather-sensitive people to changes in weather conditions.

It exhibits immunostimulating and antioxidant properties.

It inhibits the secretion of gonadotropins and, to a lesser extent, other hormones of the adenohypophysis (corticotropin, TSH, GH).

It does not cause habituation or dependence.

The combination of glycine and melatonin potentiates the effects of both substances in sleep disorders, reduces the time to fall asleep, subjectively improves sleep quality (without affecting sleep architecture), reduces drowsiness and fatigue during the day in patients suffering from insomnia or with reduced sleep duration (including against the background of somatic diseases), reduces anxiety levels, and increases performance.

Since both Glycine and Melatonin are endogenous compounds, the combined drug is characterized by low systemic toxicity and does not cause dependence or withdrawal syndrome.

Pharmacokinetics

Glycine

It easily penetrates into most biological fluids and body tissues, including the brain, and does not accumulate.

It is quickly destroyed in the liver by glycine oxidase to water and carbon dioxide.

Melatonin

Absorption

After sublingual administration, it is rapidly and completely absorbed, bypassing the “first-pass” effect through the liver, where up to 85% of melatonin is converted into an inactive metabolite, thereby achieving a high level of drug bioavailability.

The average C_max of melatonin in blood plasma is achieved within (T_max) 0.57 hours after sublingual administration of the drug at a dose of 3 mg and is 6.2 ng/ml.

AUC 9.2 ng×h/ml.

Distribution

In in vitro studies, the binding of melatonin to plasma proteins is 60%.

Melatonin mainly binds to albumin, α₁-acid glycoprotein, and HDL.

V_d is about 35 L.

It is rapidly distributed into saliva and passes through the blood-brain barrier, and is detected in the placenta.

The concentration in the cerebrospinal fluid is 2.5 times lower than in plasma.

Metabolism

It undergoes metabolism mainly in the liver, where it is hydroxylated and conjugated with sulfate and glucuronide to form 6-sulfatoxymelatonin; the level of presystemic metabolism can reach 85%.

Experimental studies suggest that the 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.

Excretion

T_1/2 is 0.7 hours.

Melatonin is excreted from the body by the kidneys.

Excretion is carried out in the urine, about 90% as sulfate and glucuronic conjugates of 6-hydroxymelatonin, and about 2-10% is excreted unchanged.

Indications

• Sleep disorders;
• Disturbance of the circadian rhythm of sleep and wakefulness associated with a change in time zones; in case of violation of the light regime, including in people engaged in shift or rotational work.

ICD codes

Dosage Regimen

Sublingually (under the tongue).

The tablet must be held under the tongue until completely dissolved. Do not drink the tablet with liquid.

For sleep disorders, 1 tablet under the tongue until completely dissolved 20 minutes before sleep or immediately before sleep.

For disturbance of the circadian rhythm of sleep and wakefulness, 1 day before the flight and for the next 2-5 days, 1 tablet 20 minutes before sleep or immediately before sleep.

Adverse Reactions

During the first week of taking the drug allergic reactions, edema.

From the nervous system headache, drowsiness.

From the digestive system nausea, vomiting, diarrhea.

Contraindications

• Hypersensitivity to the components of the drug;
• Severe liver dysfunction;
• Chronic renal failure;
• Autoimmune diseases;
• Hereditary fructose intolerance (contains sorbitol);
• Pregnancy;
• Breastfeeding period;
• Age under 18 years.

Use in Pregnancy and Lactation

The drug is not recommended for use during pregnancy and breastfeeding due to the lack of sufficient data on the safety of the drug during this period.

Women wishing to become pregnant should be informed about the weak contraceptive effect of the drug.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

Use in Renal Impairment

Contraindicated in chronic renal failure.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

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

Effect on the ability to drive vehicles and mechanisms

When using the drug, it is necessary to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

There is no information on overdose with the combination of Glycine + Melatonin.

Treatment in case of overdose requires gastric lavage and symptomatic therapy.

Drug Interactions

Glycine reduces the severity of side effects of antipsychotic drugs (neuroleptics), anxiolytics, antidepressants, hypnotics, and anticonvulsants.

Melatonin is incompatible with MAO inhibitors, corticosteroids, cyclosporine.

It enhances the effect of drugs that depress the central nervous system and beta-blockers.

It is not recommended to take it together with hormonal drugs.

Storage Conditions

The drug should be stored out of the reach of children, at a temperature not exceeding 25°C (77°F), in the original packaging (carton).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is available without a prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.