Melatonin-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

N05CH01 (Melatonin)

Active Substance

Melatonin (BP British Pharmacopoeia)

Dosage Form

Melatonin-SZ

Film-coated tablets, 3 mg: 10, 20, 30, 60, 90, or 120 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with a score on one side; the core of the tablet on the cross-section is white or almost white.

Excipients: microcrystalline cellulose 102, sodium carboxymethyl starch, calcium hydrogen phosphate dihydrate, magnesium stearate.

Coating composition: hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171).

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – contour cell packs (4) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Adaptogenic agent

Pharmacotherapeutic Group

Adaptogenic agent

Pharmacological Action

Synthetic analogue of the pineal gland hormone; has adaptogenic, sedative, 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.

Regulates the sleep-wake cycle, daily changes in locomotor activity and body temperature, positively affects the intellectual and mnestic functions of the brain, and the emotional-personal sphere. Promotes the organization of the biological rhythm and normalization of night sleep. Improves sleep quality, accelerates falling asleep, regulates neuroendocrine functions.

Adapts the body of weather-sensitive people to changes in weather conditions. Does not cause habituation or dependence.

Pharmacokinetics

Absorption

Melatonin after oral administration is rapidly absorbed from the gastrointestinal tract. In elderly people, the absorption rate may be reduced by 50%. The pharmacokinetics of melatonin in the range of 2-8 mg is linear. When taken orally at a dose of 3 mg, C_max in plasma and saliva is reached after 20 min and 60 min, respectively. The time to reach maximum concentration T_max in serum is 60 min (normal range 20-90 min). After taking 3-6 mg of melatonin, C_max in serum 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 after oral administration 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 LDL. V_d is about 35 L. It is rapidly distributed into saliva, penetrates 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

Melatonin is metabolized mainly in the liver. After oral administration, Melatonin undergoes significant transformation during the “first pass” through 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 is 6-sulfatoxymelatonin, which is inactive.

Excretion

Melatonin is excreted from the body by the kidneys. The average T_1/2 of melatonin is 45 min. Excretion is carried out in the urine, about 90% as sulfate and glucuronide conjugates of 6-hydroxymelatonin, and about 2-10% is excreted unchanged.

Pharmacokinetics in special patient groups

Pharmacokinetic parameters are influenced by age, caffeine intake, smoking, and oral contraceptive use.

In critically ill patients, accelerated absorption and impaired elimination are observed.

Elderly patients. The metabolism of melatonin is known to slow down with age. At different doses of melatonin, higher values of AUC and C_max were obtained in the elderly, reflecting the reduced metabolism of melatonin in this patient group.

Patients with impaired renal function. No accumulation of melatonin was noted during long-term treatment. These data are consistent with the short T_1/2 of melatonin in humans.

Patients with impaired hepatic function. The liver is the main organ involved in the metabolism of melatonin, so liver disease leads to an increase in the concentration of endogenous melatonin. In patients with liver cirrhosis, the plasma concentration of melatonin during the daytime was significantly increased.

Indications

• For sleep disorders, including those caused by disruption of the sleep-wake rhythm, such as desynchronosis (rapid change of time zones).

ICD codes

Dosage Regimen

Orally.

For sleep disorders – 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 for the next 2-5 days – 3 mg 30-40 minutes before bedtime.

Maximum daily dose – 6 mg.

Elderly patients

With age, the metabolism of melatonin decreases, which must be taken into account when choosing a dosing regimen for elderly patients. Taking this into account, in elderly patients, the drug can be taken 60-90 minutes before bedtime.

Patients with impaired renal function

The effect of varying degrees of renal impairment on the pharmacokinetics of melatonin has not been studied, therefore the drug Melatonin-SZ should be used with caution in patients with mild to moderate renal failure. The use of the drug in patients with severe renal failure (CrCl <30 ml/min) is contraindicated (see section “Contraindications”).

Children

The safety and efficacy of the drug Melatonin-SZ in children aged 0 to 18 years have not been established to date. The drug Melatonin-SZ is contraindicated for use in children under 18 years of age (see section “Contraindications”).

Adverse Reactions

Classification of the frequency of side effects according to WHO recommendations: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), including isolated reports; frequency unknown (cannot be estimated from the available data).

Infections and infestations rarely – herpes zoster.

Blood and lymphatic system disorders rarely – leukopenia, thrombocytopenia.

Immune system disorders frequency unknown – hypersensitivity reactions.

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

Psychiatric disorders uncommon – irritability, nervousness, restlessness, insomnia, unusual dreams, nightmares, anxiety; rarely – mood changes, aggression, agitation, tearfulness, stress symptoms, disorientation, early morning awakening, increased libido, depressed mood, depression.

Nervous system disorders uncommon – migraine, headache, lethargy, psychomotor hyperactivity, dizziness, drowsiness; rarely – syncope, memory impairment, attention disturbance, delirium, restless legs syndrome, poor sleep quality, paresthesia.

Eye disorders rarely – reduced visual acuity, blurred vision, increased lacrimation.

Ear and labyrinth disorders rarely – vertigo, positional vertigo.

Cardiac disorders uncommon – arterial hypertension; rarely – angina pectoris, palpitations, hot flush.

Gastrointestinal disorders uncommon – abdominal pain, upper abdominal pain, dyspepsia, ulcerative stomatitis, dry mouth, nausea; rarely – gastroesophageal reflux disease, gastrointestinal disorder, bullous stomatitis, ulcerative glossitis, vomiting, increased intestinal motility, abdominal distension, hypersalivation, halitosis, abdominal discomfort, stomach dyskinesia, gastritis.

Hepatobiliary disorders uncommon – hyperbilirubinemia.

Skin and subcutaneous tissue disorders: uncommon – dermatitis, night sweats, pruritus and generalized pruritus, rash, dry skin; rarely – eczema, erythema, hand dermatitis, psoriasis, generalized rash, pruritic rash, nail disorder; frequency unknown – angioedema, oral mucosal edema, tongue edema.

Musculoskeletal and connective tissue disorders uncommon – pain in extremity; rarely – arthritis, muscle spasm, neck pain, night cramps.

Renal and urinary disorders uncommon – glucosuria, proteinuria; rarely – polyuria, hematuria, nocturia.

Reproductive system and breast disorders uncommon – menopausal symptoms; rarely – priapism, prostatitis; frequency unknown – galactorrhea.

General disorders and administration site conditions uncommon – asthenia, chest pain; rarely – fatigue, pain, thirst.

Investigations uncommon – abnormal liver function tests, weight increased; rarely – increased hepatic enzyme levels, abnormal blood electrolytes, abnormal laboratory test results.

If the adverse reactions mentioned in the instructions occur, or they worsen, or any other adverse reactions not mentioned in the instructions occur, the patient should inform the doctor.

Contraindications

• Hypersensitivity to melatonin or to any of the excipients of the drug;
• Severe renal impairment (CrCl <30 ml/min);
• Autoimmune diseases (no clinical data);
• Hepatic failure;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (efficacy and safety in patients of this age group have not been established).

With caution: renal failure (CrCl >30 ml/min), elderly age.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and in women planning pregnancy. Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

Contraindicated in hepatic failure.

Use in Renal Impairment

Contraindicated in severe renal failure.

The drug should be used with caution in patients with varying degrees of renal impairment.

Pediatric Use

Contraindicated for use under 18 years of age.

Geriatric Use

With age, the metabolism of melatonin decreases, which must be taken into account when choosing a dosing regimen for elderly patients.

Special Precautions

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

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

There are no clinical data on the use of melatonin in patients with autoimmune diseases, therefore, use in this category of patients is contraindicated (see section “Contraindications”).

When using the drug Melatonin-SZ, alcohol should not be consumed (see section “Drug Interactions”).

With age, the metabolism of melatonin decreases, which must be taken into account when choosing a dosing regimen in elderly patients (see section “Dosage Regimen”).

Effect on the ability to drive vehicles and operate machinery

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 (risk of drowsiness).

Overdose

Symptoms: according to published 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 were observed when melatonin was used at doses of 3000-6600 mg for several weeks. When using very high doses of melatonin (up to 1 g), involuntary loss of consciousness was observed.

Overdose may cause drowsiness.

Treatment: gastric lavage and administration of activated charcoal, symptomatic therapy.

Elimination of the active substance is expected within 12 hours after oral administration.

Drug Interactions

Pharmacokinetic interaction

It is known that in concentrations significantly exceeding therapeutic ones, Melatonin induces the CYP3A isoenzyme in vitro. The clinical significance of this phenomenon has not been fully elucidated. If signs of induction develop, a dose reduction of concomitantly used drugs should be considered.

In concentrations significantly exceeding therapeutic ones, Melatonin does not induce CYP1A group isoenzymes in vitro. Therefore, the interaction of melatonin with other drugs due to the effect of melatonin on CYP1A group isoenzymes is apparently insignificant.

The metabolism of melatonin is mainly mediated by CYP1A isoenzymes. Therefore, interaction of melatonin with other drugs is possible due to the effect of melatonin on CYP1A group isoenzymes.

Caution should be exercised in patients taking fluvoxamine, which increases the concentration of melatonin (increase in AUC by 17 times and C_max by 12 times) by inhibiting its metabolism by cytochrome P450 isoenzymes: CYP1A2 and CYP2C19. This combination should be avoided.

Caution should be exercised in patients taking 5- and 8-methoxypsoralen, which increases the concentration of melatonin by inhibiting its metabolism.

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

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

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

Inhibitors of CYPA2 isoenzymes, for example, quinolones, can increase the exposure of melatonin.

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

There is a lot of data in the modern literature concerning the influence of adrenergic and opioid receptor agonists/antagonists, antidepressants, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol on the secretion of endogenous melatonin. Studies of the mutual influence of these drugs on the dynamics or kinetics of melatonin have not been conducted.

Pharmacodynamic interaction

Alcohol should not be consumed while taking melatonin, as it reduces the effectiveness of the drug.

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

In studies, Melatonin was administered concomitantly with thioridazine and imipramine, drugs that affect the CNS. In none of the cases was a clinically significant pharmacokinetic interaction detected. However, concomitant use with melatonin led to an increased feeling of calmness and difficulty in performing certain tasks compared to imipramine monotherapy, as well as to an increased feeling of “fogginess in the head” compared to thioridazine monotherapy.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date stated on the packaging.

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.