Expiration date: 10/2025

Active substance: Melatonin

Pharmachologic effect: a sleeping pill

Pharmacodynamics

Melatonin is a synthetic analogue of the hormone produced by the pineal gland, in the chemical structure similar to serotonin. Under physiological conditions, melatonin secretion increases soon after the onset of the dark time of the day, reaches a maximum in 2-4 hours of the night and decreases during the second half of the night. It is believed that the circadian rhythms of melatonin and controls perception of the day-night cycle.

It has a sedative effect and improves sleep. It is assumed that the effect of melatonin receptors MT1, MT2 and MT3 enhances the soporific effect, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep. The content of endogenous melatonin declines with age, so the drug can significantly improve the quality of sleep in primary insomnia, particularly in patients older than 55 years.

Circadin 2 mg / day in the evening prolongs and improves the quality of sleep and wakefulness improves activity period without deterioration psychomotor reactions during the day.

Pharmacokinetics

Absorption. Melatonin after oral administration in adults rapidly absorbed in the gastrointestinal tract, the rate of absorption in the elderly can be reduced by 50%. Kinetics of melatonin in the range of 2-8 mg is linear. Bioavailability is 15%. There is a significant effect of first pass through the liver to the value of the primary metabolism - 85%. Tmax - 3 h in a fed state. Ingestion of melatonin affects the absorption and Cmax when receiving Circadin 2 mg. Concomitant ingestion of melatonin absorption slowed, resulting in the later Tmax (Tmax = 3 h versus Tmax = 0,75 h) and a lower Cmax (Cmax = 1020 pg / ml versus Cmax = 1176 pg / ml).

Distribution. In in vitro studies of melatonin connection to plasma proteins is 60%. Basically melatonin binds to albumin, ?1-acid glycoprotein, and HDL.

Biotransformation. Experimental studies suggest that the metabolism of melatonin are involved isozymes CYP1A1, of CYP1A2, and possibly, of CYP2C19 of the cytochrome P450. The main metabolite of melatonin - 6 sulfatoximelatonin - inactive. The process of first-pass metabolism in the liver. The excretion of the metabolite is completed within 12 hours after ingestion.

Withdrawal. T1 / 2 is 3.5 hours. Excretion is carried out on 89% of the kidneys in the form of sulfated and 6-conjugates glyukuronirovannogo gidroksimelatonina, and 2% is excreted unchanged.

Floor. Women have 3-4-fold compared to men increase in Cmax.

Also marked interindividual variability of Cmax five times within the same sex.

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

Elderly patients. Metabolism melatonin is known to slow down with age. When different doses of melatonin higher AUC and Cmax values ??of parameters obtained in the elderly, which represents a decline of melatonin metabolism in this patient group. While Cmax in adults (18-45 years) is 500 pg / ml, in older (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. Long-term treatment accumulation of melatonin is not checked. These data are consistent with the short half-life of melatonin in humans. After 1 and 3 week course of treatment Circadin 2 mg blood sampling was carried out at 23:00 (2 hours after ingestion of the drug), the concentration was (411,4 ± 56,5) and (432 ± 83.2) pg, respectively, and is similar to that for single dose of 2 mg Circadin healthy volunteers.

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

In patients with liver cirrhosis plasma concentration of melatonin during the day significantly increased. Compared with the control group showed a significant decrease in the total excretion of 6-sulfatoximelatonin.

Testimony

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

Contraindications

• Hypersensitivity to the drug's components (active and excipients);
  
• congenital galactose intolerance, glucose-galactose syndrome malabsorption, congenital lactase deficiency;
  
• autoimmune diseases;
  
• liver failure;
  
• age of 18 years (effectiveness and safety have not been established).
  

Pregnancy and breast-feeding

There are no clinical data on the effects of melatonin on the course of pregnancy. These preclinical studies do not indicate an adverse effect on pregnancy, fetal development, the process of delivery or postnatal development of the newborns. In the absence of clinical data, use Circadin during pregnancy in women who are planning a pregnancy, it is not recommended.

Due to the fact that determined the endogenous melatonin in human milk, probably exogenous melatonin may also penetrate into breast milk. The data obtained for animals including rodents, sheep, cattle, and primates, indicate the transfer of melatonin through the placenta or the milk from mother to fetus. Therefore, it is not recommended to take melatonin during breastfeeding.

Side effects

In clinical trials, 48.8% of patients receiving Circadin reported adverse reactions as compared to 37.8% in the placebo group. Comparing the proportion of patients with adverse reactions per 100 patient-weeks, the rate in the placebo group was higher than in the group treated with Circadin (5.743 - placebo vs. 3.013 - Circadin). The most common adverse reactions were headache, nasopharyngitis, back pain and pain in the joints, which were frequent in both groups. The list disposed below includes only the side reactions of the clinical trials that have been observed in patients with the same or higher frequency than in the placebo group.

The incidence of adverse reactions are classified as follows: very common (?1 / 10); commonly (?1 / 100 to <1/10); uncommon (?1 / 1,000 to <1/100); rare (?1 / 10,000 to <1 / 1,000); Frequency not known (can not be installed on the available data).

Infectious and parasitic diseases: rare - herpes zoster.

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

On the part of the immune system: the frequency is unknown - hypersensitivity reactions.

On the part of metabolism and nutrition: rarely - hypertriglyceridemia, hypokalemia, hyponatremia.

Mental disorders: Infrequent - irritability, nervousness, restlessness, insomnia, abnormal dreams, nightmares, anxiety; rarely - mood swings, aggression, agitation, crying, stress symptoms, disorientation, early morning awakening, increased libido, depressed mood, depression.

From the nervous system: Infrequent - Migraine, headache, lethargy, psychomotor hyperactivity, dizziness, drowsiness; rarely - fainting, memory impairment, impaired concentration, snovidnoe state, restless legs syndrome, poor quality sleep, paraesthesia.

On the part of the organ of vision: rarely - blurred vision, blurred vision, increased lacrimation.

On the part of the organ of hearing and labyrinth disorders: rare - vertigo, positional vertigo.

With the side of the heart: rarely - angina, palpitations.

On the part of the vessels: seldom - hypertension, rarely - "hot flashes."

On the part of the digestive tract: rare - abdominal pain, abdominal pain in the upper abdomen, indigestion, ulcerative stomatitis, dry mouth, nausea; rarely - gastroesophageal reflux disease, gastrointestinal disorder or a disorder, blistering in the oral mucosa, ulcerative glossitis, vomiting, abnormal intestinal noise, bloating, hypersecretion of saliva, bad breath, abdominal discomfort, indigestion, gastritis.

On the part of the liver and biliary tract: rarely - hyperbilirubinemia.

Skin and subcutaneous tissue disorders: uncommon - dermatitis, night sweats, itching and generalized itching, rash, dry skin; rarely - eczema, erythema, dermatitis of hands, psoriasis, generalized rash, itchy rash, nail infections; the frequency is unknown - angioedema, swelling of the mouth, swelling of the tongue.

On the part of the musculoskeletal and connective tissue disorders: rarely - pain in the limbs; rarely - arthritis; muscle spasms, neck pain, night cramps.

On the part of the kidney and urinary tract: rarely - glycosuria, proteinuria; rarely - polyuria, hematuria, nocturia.

On the part of the genital organs and the breast: Infrequent - menopausal symptoms; rarely - priapism, prostatitis; the frequency is unknown - galactorrhea.

General disorders and administration site at: rarely - fatigue, chest pain; rarely - fatigue, pain, thirst.

Laboratory and instrumental data: Infrequent - abnormal laboratory values ??of liver function, weight gain; rare - increase in liver enzymes, abnormal blood electrolytes, abnormal laboratory test results.

Interaction

Pharmacokinetic interactions

It is known that in concentrations much higher than therapeutic, melatonin induces isoenzyme CYP3A in vitro. The clinical significance of this phenomenon is not fully elucidated. In the case of the induction of symptoms should consider lowering the dose of drugs used simultaneously. At concentrations much higher than therapeutic, melatonin does not induce isozymes group CYP1A in vitro. Therefore, melatonin interactions with other drugs due to the effect of melatonin on CYP1A isozymes group apparently insignificant. The metabolism of melatonin is mainly mediated by CYP1A isozymes. Consequently, the possible interaction of melatonin with other drugs because of the effect of melatonin on isozymes CYP1A group.

Caution in patients taking fluvoxamine, which increases the concentration of melatonin (increase in AUC and Cmax 17 times to 12 times) by inhibiting its metabolism cytochrome P450 (CYP): CYP1A2 and CYP2C19. such combinations should be avoided. Caution in patients taking 5- and 8-methoxypsoralen that increases the concentration of melatonin from inhibition of its metabolism. Caution in patients receiving cimetidine (an inhibitor of isozyme CYP2D), because it increases the concentration of melatonin in the plasma due to inhibition of the latter.

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

Caution must be exercised in patients receiving estrogens (eg contraceptive or hormone replacement therapy), which increase the concentration of melatonin by inhibiting their metabolism isozymes CYP1A1 and CYP1A2.

Inhibitors isozymes CYP1A2, such as quinolones, are capable of increasing the exposure of melatonin.

Isoenzyme CYP1A2 inducers such as carbamazepine and rifampicin may reduce the plasma concentration of melatonin.

In modern literature, there are a lot of data on the effect of agonists / antagonists of the adrenergic and opioid receptors, antidepressants, PG inhibitors, benzodiazepines, tryptophan and alcohol on the secretion of endogenous melatonin. Research mutual influence of these drugs on the dynamics or kinetics Circadin not conducted.

Pharmacodynamic interactions

During the reception Circadin should not drink alcohol because it reduces the effectiveness of the drug.

Circadin potentiates the sedative effects of benzodiazepine and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In the clinical study were clear signs of transitory pharmacodynamic interaction between zolpidem and Circadin after 1 h after administration. The combined use can lead to a progressive disorder of attention, memory and coordination zolpidem compared to monotherapy.

Studies Circadin administered together with thioridazine and imipramine, drugs that affect the central nervous system. In none of the cases did not reveal clinically significant pharmacokinetic interaction. However, the simultaneous application of Circadin resulted in increased feelings of tranquility and difficulty in performing certain tasks compared to imipramine monotherapy, as well as strengthening the sense of opacity in the head in comparison with thioridazine monotherapy.

Dosing and Administration

Inside, after ingestion in the evening, for 1-2 hours before bedtime. The tablets should be swallowed whole to support the sustained release. Do not crush or chew the tablet for ease of swallowing process. At 1 mg 2 times a day. The course of treatment can take up to 13 weeks.

Renal insufficiency. Effect of renal failure (of any severity) on the pharmacokinetics of melatonin has not been studied. In the appointment of melatonin in these patients should be careful.

Overdose

There were no cases of overdose Circadin drug. The drug is used at a dose of 5 mg / day in clinical trials lasting more than 12 months, with no change of character of reported side effects.

There are literature data on Circadin applied in a daily dose of 300 mg without causing clinically significant adverse effects. If overdose is supposed sleepiness development. The clearance of the active substance within the expected 12 hours after ingestion. Special treatment is required.

Special instructions

Circadin can cause drowsiness. Therefore, the drug should be used with caution if causes drowsiness threaten patient safety.

Clinical data for use Circadin in patients with autoimmune diseases are not available, therefore Circadin not recommended for patients with autoimmune diseases. This drug should not be administered to patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Effects on ability to drive and use machines. Circadin has a moderate effect on driving and using machinery. Circadin may cause drowsiness, therefore the drug should be used with caution if the effects of drowsiness can be a security threat.

Release Form

Prolonged action tablets and 2 mg. According to Table 21. in blister PVC / PVDC / AL foil. 1 blister in paper cartons.

Manufacturer

1. Swisscom Services AG. Bahnhofstrasse 14, CH-4334 sisseln, Switzerland

2. Katalent Germany Schorndorf GmbH. Shtaynbaysshtrasse 2, D-73614 Schorndorf, Germany.

The owner of the registration certificate: RAD Newry Pharmaceuticals EEC Ltd. Ouen Forbury Square, Forbury, Reading, Berkshire RG1 ZEV, United Kingdom.

Storage conditions

The temperature is not above 25 ° C.

Keep out of the reach of children.

The shelf life: 5 years.

Do not use beyond the expiration date printed on the package.