Circadin sustained release pills 2mg, 21pcs

Composition

1 tablet of prolonged action contains:

Active ingredient:

melatonin 2 mg,

excipients:

methyl methacrylate,

trimethylammonioethyl methacrylate chloride and ethyl acrylate copolymer [1: 2: 0.1] – 40 mg;

calcium hydrophosphate dihydrate-40 mg;

lactose monohydrate-80 mg;

colloidal silicon dioxide-2 mg;

talc-4 mg;

magnesium stearate-2 mg

Pharmacological action

Pharmacodynamics

Melatonin is a synthetic analog of the hormone produced by the pineal gland, and its chemical structure is similar to serotonin. Under physiological conditions, melatonin secretion increases shortly after dark, reaches maximum values at 2-4 o’clock in the morning, and decreases during the second half of the night. Melatonin is thought to control circadian rhythms and the perception of the day-night cycle.

It has a hypnotic effect and improves falling asleep. It is suggested that the effect of melatonin on MT1, MT2, and MT3 receptors enhances the hypnotic effect, since these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep. The content of endogenous melatonin decreases with age, so the drug can significantly improve the quality of sleep in primary insomnia, especially in patients over 55 years of age.

Circadin at a dose of 2 mg / day in the evening hours increases the duration and improves the quality of sleep, as well as improves activity during wakefulness, without worsening psychomotor reactions during the day.

Pharmacokinetics

Absorption. Melatonin after oral use in adults is rapidly absorbed into the gastrointestinal tract, in the elderly, the absorption rate can be reduced by 50%. The kinetics of melatonin in the range of 2-8 mg is linear. Bioavailability is 15%. There is a significant effect of primary passage through the liver with a primary metabolism value of 85%. T_max — 3 hours when full. Food intake affects melatonin absorption and its_cmax when taking Circadine at a dose of 2 mg. Concomitant food intake slowed melatonin absorption, resulting in a later tmax (tmax = 3 h compared to tmax = 0.75 h) and a lower_cmax (_cmax = 1020 pg/ml compared to_cmax = 1176 pg/ml).

Distribution. In vitro studies showed a 60% association of melatonin with plasma proteins. Melatonin mainly binds to albumin, _α1-acid glycoprotein, and HDL.

Biotransformation. Experimental studies suggest that the cytochrome P450 isoenzymes CYP1A1, CYP1A2, and possibly CYP2C19 are involved in melatonin metabolism. The main metabolite of melatonin,6-sulfatoxymelatonin, is inactive. Presystemic metabolism occurs in the liver. Excretion of the metabolite is completed within 12 hours after oral use.

Output. T_1/2 is 3.5 h. Excretion is carried out by 89% of the kidneys in the form of sulfated and glucuronated conjugates of 6-hydroxymelatonin, and 2% is excreted unchanged.

Gender. Women have a 3-4-fold increase in cmax compared to men.

There was also a five-fold interindividual variability of_cmax within the same sex.

However, despite the differences in plasma concentrations, no pharmacodynamic differences were found between men and women.

Elderly patients. Melatonin metabolism is known to slow down with age. At different doses of melatonin, higher AUC and_cmax values were obtained in the elderly, which reflects a reduced melatonin metabolism in this group of patients. While_cmax in adults (18-45 years) 500 pg/ml, in the elderly (55-69 years) – 1200 pg / ml; AUC in adults-3000 pg * h / ml and 5000 pg·h/ml in the elderly.

Patients with impaired renal function. Melatonin accumulation was not observed during long-term treatment. These findings are consistent with the short human melatonin half-life. After 1 and 3 weeks of treatment with Circadin at a dose of 2 mg, blood samples were taken at 23: 00 (2 hours after oral use), the concentration was (411.4±56.5) and (432±83.2) pg, respectively, and similar to that of a single dose of 2 mg of Circadin in healthy volunteers.

Patients with impaired liver function. The liver is the main organ involved in melatonin metabolism, so liver diseases lead to an increase in the concentration of endogenous melatonin.

In patients with cirrhosis of the liver, the plasma concentration of melatonin in the daytime significantly increased. Compared to the control group, there was a significant decrease in the total excretion of 6-sulfatoxymelatonin.

Indications

Short-term treatment of primary insomnia characterized by poor sleep quality in patients over 55 years of age (as monotherapy).

Use during pregnancy and lactation

There are no clinical data on the effects of melatonin on pregnancy. Data from preclinical studies do not indicate an adverse effect on the course of pregnancy, fetal development, delivery process, or postnatal development of newborns. Due to the lack of clinical data, the use of Circadine during pregnancy in women planning pregnancy is not recommended.

Due to the fact that endogenous melatonin is detected in breast milk, it is likely that exogenous melatonin can also enter breast milk. Data from animals including rodents, sheep, cattle, and primates indicate that melatonin is transmitted through the placenta or milk from the mother to the fetus. Therefore, it is not recommended to take melatonin during breastfeeding.

Contraindications

• hypersensitivity to the components of the drug Circadin (active and auxiliary substances);
• congenital galactose intolerance, glucose-galactose malabsorption syndrome, congenital lactase deficiency;
• autoimmune diseases;
• liver failure;
• age up to 18 years (efficacy and safety of use have not been established).

Side effects

In clinical trials,48.8% of patients treated with Circadin reported adverse reactions, compared to 37.8% in the placebo group. Comparing the ratio of patients with adverse reactions per 100 weeks-patients, the rate in the placebo group was higher than in the Circadine group (5,743-placebo vs. 3,013-Circadine). The most common adverse reactions were headache, nasopharyngitis, back pain, and joint pain, which were common in both groups. The list below includes only those adverse reactions from clinical trials that were observed in patients with the same or greater frequency than in the placebo group.

The frequency of adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to

Infectious and parasitic diseases: rarely-herpes zoster.

From the blood and lymphatic system: rarely-leukopenia, thrombocytopenia.

Immune system disorders: frequency unknown-hypersensitivity reactions.

From the side of metabolism and nutrition: rarely-hypertriglyceridemia, hypokalemia, hyponatremia.

Mental disorders: infrequently-irritability, nervousness, restlessness, insomnia, unusual dreams, nightmares, anxiety; rarely-mood swings, aggression, agitation, tearfulness, stress symptoms, disorientation, early morning awakening, increased libido, low mood, depression.

From the nervous system: infrequently-migraine, headache, lethargy, psychomotor hyperactivity, dizziness, drowsiness; rarely-fainting, memory impairment, impaired concentration, dream state, restless legs syndrome, poor sleep quality, paresthesia.

From the side of the organ of vision: rarely-decreased visual acuity, blurred vision, increased lacrimation.

From the side of the organ of hearing and labyrinth disorders: rarely-vertigo, positional vertigo.

From the heart: rarely-angina pectoris of tension, palpitation.

Vascular disorders: infrequently-arterial hypertension, rarely-hot flashes.

From the gastrointestinal tract: infrequently — abdominal pain, abdominal pain in the upper abdomen, dyspepsia, ulcerative stomatitis, dry mouth, nausea; rarely — gastroesophageal reflux disease, gastrointestinal disorder or disorder, blistering of the oral mucosa, ulcerative glossitis, vomiting, abnormal intestinal noise, bloating, hypersecretion of saliva, bad breath, abdominal discomfort, upset stomach, gastritis.

From the liver and biliary tract: infrequently-hyperbilirubinemia.

From the skin and subcutaneous tissues: infrequently-dermatitis, night sweating, itching and generalized itching, rash, dry skin; rarely-eczema, erythema, dermatitis of the hands, psoriasis, generalized rash, itchy rash, nail damage; frequency unknown-Quincke’s edema, mouth edema, tongue edema.

Musculoskeletal and connective tissue disorders: infrequently-pain in the extremity; rarely-arthritis; muscle spasm, neck pain, night cramps.

From the kidneys and urinary tract: infrequently-glucosuria, proteinuria; rarely-polyuria, hematuria, nocturia.

From the genitals and breast: infrequently-menopausal symptoms; rarely-priapism, prostatitis; frequency unknown-galactorrhea.

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

Laboratory and instrumental data: infrequently-deviation from the norm of laboratory parameters of liver function, weight gain; rarely-increased activity of hepatic transaminases, deviation from the norm of blood electrolyte content, deviations from the norm of laboratory test results.

Interaction

Pharmacokinetic interaction

Melatonin is known to induce the CYP3A isoenzyme in vitro at concentrations significantly higher than therapeutic levels. The clinical significance of this phenomenon is not fully understood. If signs of induction develop, consideration should be given to reducing the dose of concomitantly administered drugs. At concentrations significantly higher than therapeutic levels, melatonin does not induce CYP1A isoenzymes in vitro. Consequently, 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. Consequently, melatonin may interact with other drugs due to the effect of melatonin on CYP1A isoenzymes.

Caution should be exercised in patients taking fluvoxamine, which increases the concentration of melatonin (17-fold increase in_AUC and 12-fold increase in cmax) due to inhibition of its metabolism by cytochrome P450 (CYP) 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 due to inhibition of its metabolism. Caution should be exercised in patients taking cimetidine (an inhibitor of CYP2D isoenzymes), as it increases the content of melatonin in plasma by inhibiting the latter.

Smoking can reduce the concentration of melatonin by inducing the CYP1A2 isoenzyme.

Caution should be exercised in patients taking estrogens (such as contraceptives or hormone replacement therapy) that increase melatonin concentrations by inhibiting their metabolism by the CYP1A1 and CYP1A2 isoenzymes.

Inhibitors of CYP1A2 isoenzymes, such as quinolones, can increase melatonin exposure.

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

There is a wealth of data in the current literature regarding the effects of adrenergic and opioid receptor agonists/antagonists, antidepressants, PH inhibitors, benzodiazepines, tryptophan, and alcohol on endogenous melatonin secretion. Studies of the mutual effect of these drugs on the dynamics or kinetics of Circadine have not been conducted.

Pharmacodynamic interaction

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

Circadine potentiates the sedative effect of benzodiazepine and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. During the clinical study, clear signs of a transient pharmacodynamic interaction between Circadine and zolpidem were observed 1 h after their use. Combined use may result in progressive attention, memory, and coordination disorders compared to zolpidem monotherapy.

In studies, Circadine was co-administered with thioridazine and imipramine, drugs that affect the central nervous system. No clinically significant pharmacokinetic interaction was detected in any of the cases. However, concomitant use with Circadine resulted in an increased sense of calm and difficulty in performing certain tasks compared to imipramine monotherapy, as well as an increased feeling of blurring in the head compared to thioridazine monotherapy.

How to take, course of use and dosage

of Circadin is taken orally, after meals, in the evening,1-2 hours before bedtime. Tablets should be swallowed whole to support sustained release. Do not break or chew the tablet to make it easier to swallow. 2 mg once a day. The course of treatment can be up to 13 weeks.

Kidney failure. The effect of renal failure (of any severity) on the pharmacokinetics of melatonin has not been studied. Caution should be exercised when prescribing melatonin to such patients.

Overdose

There were no cases of overdose of the drug Circadin. The drug was used at a dose of 5 mg / day in clinical trials lasting more than 12 months, and there were no changes in the nature of reported side effects.

There are literature data on the use of Circadine in a daily dose of up to 300 mg without clinically significant side effects. In case of overdose, drowsiness is expected to develop. Clearance of the Active ingredient is expected within 12 hours after oral use. No special treatment is required.

Special instructions

Circadine may cause drowsiness. Therefore, the drug should be prescribed with caution if the drowsiness caused threatens the patient’s safety.

There are no clinical data on the use of Circadine in patients with autoimmune diseases, and therefore Circadine is not recommended for patients with autoimmune diseases. This medication should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Influence on the ability to drive vehicles and mechanisms. Circadine has a moderate effect on driving vehicles and working with mechanisms. Circadine may cause drowsiness, and therefore the drug should be used with caution if the effects of drowsiness may become a safety hazard.

Form of production

Long-acting tablets

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

5 years

Active ingredient

Melatonin

Conditions of release from pharmacies

By prescription

Dosage form

long-acting tablets

Purpose

For adults as directed by your doctor

Indications

Time Zone Change, Weather Sensitivity, Insomnia