Circadin, 2 mg 21 pcs

Pharmacodynamics

Melatonin is a synthetic analog of the hormone produced by the epiphysis, its chemical structure is similar to serotonin. Under physiological conditions, melatonin secretion increases shortly after dark, peaks at 2-4am 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 sleep. The effects of melatonin on the MT1, MT2 and MT3 receptors are thought to increase the sleeping effect, since these receptors (predominantly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep. Endogenous melatonin content decreases with age, so the drug may significantly improve the quality of sleep in primary insomnia, especially in patients older than 55 years.

Cirkadine at a dose of 2 mg/day in the evening improves sleep duration and quality, and also improves activity during waking hours, without worsening psychomotor reactions during the day.

Pharmacokinetics

Absorption. Melatonin after oral administration in adults is rapidly absorbed in the gastrointestinal tract, in the elderly the absorption rate may 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 is 3 h in the saturated state. Food intake affects the absorption of melatonin and its C_max when taking Circadin at a dose of 2 mg. Concomitant food intake slowed melatonin absorption, resulting in a later T_max (T_max = 3 h versus T_max = 0.75 h) and lower C_max (C_max = 1020 pg/mL versus C_max = 1176 pg/mL).

Distribution. In in vitro studies, the binding of melatonin to plasma proteins is 60%. Melatonin primarily binds to albumin, α₁-acid glycoprotein and HDL.

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

Excretion. T_1/2 is 3.5 h. Excretion is 89% by the kidneys as sulfated and glucuronated 6-hydroxymelatonin conjugates, and 2% is excreted unchanged.

Gender. There is a 3-4-fold increase in C_max in women compared with men.

There is also a five-fold interindividual variability in C_max within the same sex.

However, despite differences in plasma concentrations, no pharmacodynamic differences were found between males and females.

Elderly patients. Melatonin metabolism is known to slow down with age. At different doses of melatonin, higher AUC and C_max values were obtained in the elderly, reflecting reduced melatonin metabolism in this group of patients. While C_max in adults (18-45 years) is 500 pg/mL, in the elderly (55-69 years) it is 1200 pg/mL; AUC in adults is 3000 pg-h/ml and 5000 pg-h/ml in the elderly.

Patients with impaired renal function. No cumulation of melatonin has been noted with long-term treatment. These data are consistent with the short half-life of melatonin in humans. 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 administration). Concentration was (411.4±56.5) and (432±83.2) pg, respectively, and similar to that in healthy volunteers taking 2 mg of Circadin once daily.

Patients with impaired liver function. The liver is the main organ involved in melatonin metabolism, so liver disease leads to increased concentrations of endogenous melatonin.

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

Indications

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

Active ingredient

Composition

1 sustained release tablet contains:

the 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

How to take, the dosage

Cirkadine is taken orally, after a meal, in the evening, 1-2 hours before going to bed. Tablets should be swallowed whole to support delayed release. The tablet should not be crushed or chewed to facilitate swallowing. Take 2 mg once daily. The course of treatment may be up to 13 weeks.

Renal insufficiency. The effect of renal failure (of any severity) on the pharmacokinetics of melatonin has not been studied. Caution should be exercised when prescribing melatonin in these patients.

Interaction

Pharmacokinetic interaction

Melatonin is known to induce the CYP3A isoenzyme in vitro at concentrations significantly greater than therapeutic. The clinical significance of this phenomenon is not fully understood. In the case of signs of induction, a dose reduction of concomitantly administered drugs should be considered. Melatonin does not induce CYP1A isoenzymes in vitro in concentrations significantly higher than therapeutic ones. Therefore, the interaction of melatonin with other drugs due to the effect of melatonin on CYP1A isoenzymes appears to be insignificant. The metabolism of melatonin is mainly mediated by CYP1A isoenzymes. Therefore, melatonin may interact with other drugs due to the effect of melatonin on CYP1A isoenzymes.

Patients should be cautious when taking fluvoxamine which increases melatonin concentrations (17-fold AUC and 12-fold Cmax increase) 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 (CYP2D isoenzyme inhibitor) because it increases plasma melatonin concentration by inhibiting the latter.

Smoking may decrease melatonin concentration due to induction of CYP1A2 isoenzyme.

Patients taking estrogens (e.g., contraceptives or hormone replacement therapy) which increase melatonin concentrations by inhibiting their metabolism by CYP1A1 and CYP1A2 isoenzymes should be treated with caution.

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

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

In the current literature, there are numerous data concerning the effects of adrenergic and opioid receptor agonists/antagonists, antidepressants, GH inhibitors, benzodiazepines, tryptophan and alcohol on endogenous melatonin secretion. Studies of the reciprocal effects of these drugs on the dynamics or kinetics of Circadian have not been conducted.

Pharmacodynamic interaction

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

Cirkadine 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 Circadian and zolpidem 1 h after their administration. Combined use may lead to progressive impairment of attention, memory and coordination compared to zolpidem monotherapy.

In studies, Circadian has been coadministered with thioridazine and imipramine, drugs that affect the CNS. No clinically significant pharmacokinetic interaction was observed in any of the cases. However, concomitant use with Circadian resulted in increased feelings of calm and difficulty performing certain tasks compared with imipramine monotherapy, and increased feelings of blurring in the head compared with thioridazine monotherapy.

Special Instructions

Circadian may cause drowsiness. Therefore, the drug should be administered with caution if the resulting drowsiness endangers the safety of the patient.

There are no clinical data on the use of Circadin in patients with autoimmune diseases; therefore, Circadin is not recommended for patients with autoimmune diseases. This drug should not be prescribed to patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

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

Contraindications

Side effects

In clinical trials, 48.8% of patients receiving Circadin reported adverse reactions compared with 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 group taking Circadin (5.743 for placebo versus 3.013 for Circadin). The most common adverse reactions were headache, nasopharyngitis, back pain, and joint pain, which were frequent in both groups. The list posted below includes only those adverse reactions from the clinical trials that were seen in patients with equal 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: rare – herpes zoster.

Blood and lymphatic system: rare – leukopenia, thrombocytopenia.

Immune system disorders: frequency unknown – hypersensitivity reactions.

Metabolism and nutrition: rarely – 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, somnolence; rarely – fainting, memory impairment, concentration disorders, dream state, restless legs syndrome, poor sleep quality, paresthesias.

An organ of vision: rarely – decreased visual acuity, blurred vision, increased lacrimation.

Hearing organ and labyrinth disorders: rare – vertigo, positional vertigo.

Cardiac disorders: rare – angina pectoris, palpitations.

Vascular disorders: infrequent – arterial hypertension, rare – “hot flashes”.

Gastrointestinal disorders: infrequent – abdominal pain, abdominal pain in the upper abdomen, dyspepsia, ulcerative stomatitis, dry mouth, nausea; rare – gastroesophageal reflux disease, gastrointestinal disturbance or disorder, oral mucosal blistering, ulcerative glossitis, vomiting, abnormal bowel murmur, abdominal bloating, salivary hypersecretion, bad breath, abdominal discomfort, stomach upset, gastritis.

Hepatic and biliary tract disorders: infrequent – hyperbilirubinemia.

Skin and subcutaneous tissue: infrequent – dermatitis, night sweats, itching and generalized itching, rash, dry skin; rarely – eczema, erythema, hand dermatitis, psoriasis, generalized rash, itching rash, nail lesions; frequency unknown – Quincke’s edema, edema of the mouth, swelling of the tongue.

Skeletal, muscular and connective tissue disorders: infrequent – limb pain; rare – arthritis; muscle spasm, neck pain, night cramps.

Key kidneys and urinary tract: infrequent – glucosuria, proteinuria; rarely – polyuria, hematuria, nycturia.

Genital organs and the breast: 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 data: infrequent – abnormal liver function tests, weight gain, rare – increased liver transaminases activity, abnormal blood electrolyte levels, abnormal results of laboratory tests.

Overdose

There have been no cases of overdose of Cirkadine. The drug has been used in a dose of 5 mg/day in clinical trials lasting more than 12 months, and no changes in the nature of reported side effects have been observed.

Literature data are available on the use of Circadin in daily doses of up to 300 mg with no clinically significant side effects. In case of overdose, the development of somnolence is expected. Clearance of the active substance is assumed to be within 12 hours after oral administration. No special treatment is required.

Pregnancy use

There are no clinical data on the effects of melatonin on pregnancy. Preclinical data indicate no adverse effects on pregnancy, fetal development, delivery, or postnatal development of newborns. Due to a lack of clinical data, the use of Circadin during pregnancy in women planning to become pregnant is not recommended.

Because endogenous melatonin is detected in breast milk, it is likely that exogenous melatonin can also pass into breast milk. Evidence for animals, including rodents, sheep, cattle, and primates, indicates that melatonin is transmitted through the placenta or milk from the mother to the fetus. Consequently, it is not recommended that melatonin be taken while breastfeeding.

Similarities