Sliponia

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SLIPONIYA (SLIPONIYA)

Composition:

Active substance: melatonin;

1 tablet contains 2 mg, 3 mg, or 5 mg of melatonin;

Excipients: microcrystalline cellulose (type 101), microcrystalline cellulose (type 102), sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Sliponiya, 2 mg: white or almost white, round, biconvex tablets, with circular embossing on one side.

Sliponiya, 3 mg: white or almost white, round, biconvex tablets.

Sliponiya, 5 mg: white or almost white, round, biconvex tablets, with a score line on one side.

Pharmacotherapeutic group. Hypnotics and sedatives. Melatonin receptor agonists. ATC code N05C H01.

Pharmacological Properties.

Pharmacodynamics.

Melatonin is a natural neurohormone produced in the human body by the pineal gland in the central nervous system. Melatonin synthesis from the amino acid tryptophan also occurs in other cells and organs, such as the retina of the eye, lacrimal glands, gastrointestinal tract, skin, and lymphocytes. High concentrations of melatonin are also observed in bone marrow cells and in mammalian bile. The hormone plays an important role in regulating the biological circadian rhythm. Melatonin regulates sleep and wakefulness periods throughout the day. Endogenous melatonin exhibits a characteristic daily rhythm of synthesis and secretion: during daytime, hormone concentration is low, while at night it reaches its peak. In addition to the daily secretion profile of melatonin, there is also a seasonal rhythm caused by changes in the duration of daylight throughout the year. Melatonin has two main mechanisms of action in the treatment of sleep disorders. First, it exerts a direct hypnotic effect, which is likely related to its interaction with the central GABA-ergic system. Second, it demonstrates chronobiological activity by adapting the sleep-wake cycle to changes in light exposure and day-night duration. This effect occurs primarily via specific central melatonin receptors MT1 and MT2. In addition to its positive effects on sleep processes, regulation of sleep phases and duration, melatonin also exhibits anti-inflammatory and antioxidant activity, immunostimulatory, antitumor, hypotensive, and thermoregulatory effects, and possesses cytoprotective properties. Experimental studies have shown that the aforementioned pharmacodynamic effects are also induced by exogenous administration of melatonin.

Pharmacokinetics.

The bioavailability of melatonin ranges from 3% to 76%. Up to 60% of the absorbed dose undergoes the first-pass effect. Food intake enhances melatonin absorption. The active substance of the medicinal product is metabolized into 6-hydroxymelatonin and N-acetylserotonin, after which the formed metabolites are excreted in urine as glucuronides or sulfates. Melatonin rapidly penetrates into body fluids such as saliva, cerebrospinal fluid, and amniotic fluid. After oral administration, maximum drug concentration in blood is reached within 0.5–2 hours. The elimination half-life of melatonin after oral administration ranges from 30 to 50 minutes.

Clinical characteristics.

Indications.

Melatonin is indicated as an adjunctive treatment for sleep-wake rhythm disorders, such as those associated with jet lag or shift work. The medicinal product also facilitates regulation of circadian sleep-wake disorders in patients with visual impairment.

Contraindications.

Hypersensitivity to the components of the medicinal product.

Renal and hepatic dysfunction; the medicinal product must not be used after alcohol consumption.

Pregnancy or breastfeeding period.

Age under 18 years.

Depression.

Interaction with other medicinal products and other types of interactions.

Medicinal products that block β-adrenergic receptors, clonidine, dexamethasone, antidepressants (e.g., fluvoxamine), and certain other drugs may alter the secretion of endogenous melatonin. Melatonin may affect the efficacy of hormonal medicinal products (estrogens, androgens, etc.) and may enhance benzodiazepine binding to specific receptors; therefore, their concomitant use requires medical supervision. Melatonin may potentiate the sedative properties of benzodiazepines and non-benzodiazepine hypnotics such as zaleplon, zolpidem, and zopiclone. Clear evidence of a pharmacodynamic interaction between melatonin and zolpidem has been obtained one hour after co-administration. Concomitant use leads to greater impairment of attention, memory, and coordination compared to use of zolpidem alone.

Melatonin may potentiate the antitumor effect of tamoxifen.

Dopaminergic and serotonergic effects of methamphetamine may be enhanced when administered concurrently with melatonin.

Melatonin may enhance the antibacterial effect of isoniazid.

Melatonin may be used in combination with lisinopril as part of concomitant antihypertensive therapy in patients with pineal gland functional insufficiency, enhancing its effect.

According to existing observations, melatonin induces CYP3A in vitro at concentrations exceeding therapeutic levels. The clinical significance of this finding is unknown. Induction, if it occurs, may lead to decreased plasma concentrations of concurrently administered medicinal products.

Fluvoxamine increases melatonin levels by inhibiting its metabolism via hepatic cytochrome P450 isoenzymes CYP1A2 and CYP2C19. Such a combination should be avoided.

Medicinal products metabolized by the CYP2C19 isoenzyme (e.g., citalopram, omeprazole, lansoprazole) slow the metabolism of exogenously administered melatonin and increase its bioavailability, likely by inhibiting the conversion of the hormone to N-acetylserotonin.

Patients receiving 5- or 8-methoxypsoralen, which increases melatonin levels by inhibiting its metabolism, should be closely monitored.

Patients receiving cimetidine—an inhibitor of CYP2D that increases melatonin plasma levels by suppressing its metabolism—should be closely monitored. Smoking may reduce melatonin levels by inducing CYP1A2.

Patients receiving estrogens (e.g., contraceptives or hormone replacement therapy) should be closely monitored, as melatonin levels increase due to inhibition of its metabolism by CYP1A1 and CYP1A2.

CYP1A2 inhibitors, such as quinolones, may enhance the effects of melatonin. CYP1A2 inducers, such as carbamazepine and rifampicin, may reduce melatonin plasma concentrations.

Concomitant administration of melatonin with thioridazine results in greater impairment of attention, memory, and coordination compared to administration of thioridazine alone.

An increased risk of adverse effects on the central nervous system may occur when melatonin is used concomitantly with imipramine and thioridazine.

Special precautions for use

Do not use in women planning pregnancy due to melatonin's potential contraceptive effect.

When using melatonin, bright light exposure should be avoided.

Melatonin metabolism is reduced in patients with liver cirrhosis; therefore, the use of this medicinal product is contraindicated in such patients.

This medicinal product may be used in patients with elevated arterial pressure (especially systolic) and hypercholesterolemia. With prolonged use, melatonin reduces cholesterol levels in patients with hypercholesterolemia, but does not affect cholesterol levels when they are within the normal range in blood serum. The drug reduces insulin and plasma glucose levels; therefore, it may be used in patients with hypertension and hypercholesterolemia associated with insulin resistance (HOMA index above 3 units).

Melatonin is contraindicated in patients with hepatic impairment due to the lack of data on its use in such patients and because melatonin is metabolized in the liver, in patients with depression, immune dysfunction, endocrine disorders or epilepsy, as well as in patients receiving anticoagulant therapy and those with renal function impairment.

Use with caution in patients with hormonal disorders and/or undergoing hormonal therapy, as well as in patients with allergic diseases.

Melatonin may cause drowsiness. The medicinal product should be used cautiously when drowsiness may pose a risk or danger to the patient's health. Its use is not recommended in individuals with autoimmune diseases.

Patients with hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose/galactose malabsorption should not use this medicinal product.

Concomitant alcohol intake reduces melatonin's effectiveness.

Use during pregnancy or breastfeeding

The medicinal product should not be used during pregnancy or breastfeeding due to the absence of clinical data.

Ability to influence reaction rate while driving or operating machinery

Due to the fact that the medicinal product may cause drowsiness, patients should refrain from driving vehicles or performing other tasks requiring concentration during treatment.

Method of Administration and Dosage

Dosing

The lowest effective dose of melatonin should be used, and if necessary, another melatonin-containing medicinal product providing a different (e.g., lower) dose. Well-established medical use of melatonin includes doses starting from 0.5 mg.

Adult Patients

For sleep disorders associated with time zone changes: 2 mg to 3 mg of melatonin once daily after dark, starting on the first day of travel. Treatment should be continued for the next 2–3 days after completion of travel.

For sleep-wake cycle disorders, such as those associated with shift work: 1 mg to 5 mg once daily, taken one hour before bedtime.

For circadian rhythm sleep-wake disorders in patients with visual impairment: 0.5 mg to 5 mg once daily approximately between 9:00 PM and 10:00 PM.

The duration of treatment by the patient should be taken into account.

The effect of the medicinal product in long-term use for circadian rhythm sleep-wake disorders may sometimes only become apparent after 2 weeks of melatonin administration.

Hepatic Impairment

The medicinal product is contraindicated in patients with hepatic impairment.

Renal Impairment

The medicinal product is contraindicated in patients with renal impairment.

Elderly Patients

Dose adjustment in elderly patients is not required.

Method of Administration

Oral administration.

The tablet should be swallowed with a small amount of water.

Children. Experience with use of the medicinal product in patients under 18 years of age is lacking.

Overdose.

Symptoms. Several cases of melatonin overdose have been reported (single intake of 24–30 mg of melatonin). Somnolence, headache, dizziness, and nausea are the most common signs and symptoms of oral melatonin overdose. In cases of overdose, disorientation, prolonged sleep, and anterograde amnesia may occur.

Treatment. Symptomatic therapy.

Adverse reactions

The adverse reactions listed below were reported during clinical trials and from spontaneous post-marketing reports regarding the use of melatonin.

Within each frequency grouping: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data) – adverse effects are listed in order of decreasing severity.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging. 10 tablets in a blister, 3 blisters in a cardboard box, or 30 tablets in a blister, 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Biopharm Sp. z o.o.

Manufacturer's location and address of its business premises.

Walbrzyska 13, Poznan, 60-198, Poland