Circadian - instructions for use, dose, side effects, contraindications

Composition:1 tablet of prolonged action contains:
active substance: melatonin 2.0 mg
Excipients: methyl methacrylate, trimethylammonioethyl methacrylate chloride and ethyl acrylate copolymer [1: 2: 0.1] 40.0 mg, calcium hydrophosphate dihydrate 40.0 mg, lactose monohydrate 80.0 mg, silicon dioxide colloid 2.0 mg, talc 4.0 mg, magnesium stearate 2.0 mg.

Description:Round biconvex tablets white or almost white.

Pharmacotherapeutic group:hypnotic.

ATX: & nbsp

N.05.C.H.01 Melatonin

N.05.C.H Melatonin receptor agonists

Pharmacodynamics:Melatonin is a synthetic analogue of the hormone produced by the epiphysis, is close to serotonin by its chemical structure.Under physiological conditions, the secretion of melatonin rises soon after the onset of the dark time of the day, reaches its maximum values at 2-4 hours of the night, and decreases during the second half of the night. It is believed that melatonin controls circadian rhythms and perception of the day-night cycle. Has a hypnotic effect and improves falling asleep.
It is assumed that the influence of melatonin on the receptors of MT1, MT2 and MTZ 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 older than 55 years.
Circadian in a dose of 2 mg / day in the evening hours increases the duration and improves sleep quality, and also improves activity during wakefulness, without worsening of psychomotor reactions during the day.
Pharmacokinetics Absorption:
Melatonin after ingestion in adults is quickly absorbed in the gastrointestinal tract, in the elderly, the rate of absorption can be reduced by 50%. The kinetics of melatonin in the range 2-8 mg is linear. Bioavailability is 15%.There is a significant effect of "primary transmission" through the liver with a primary metabolism value of 85%. The time to reach the maximum concentration (Tmax) is 3 h in the full state. Food intake affects the absorption of melatonin and its maximum plasma concentration (Stach) with the admission of circadian in a dose of 2 mg. Concomitant food intake slowed the absorption of melatonin, which
led to a later Tmax (Tmax = 3 hr compared with Tmax = 0.75 h) and a lower Stax (Stax = 1020 pg / ml compared to Stax = 1176 pc / ml). Distribution: In in vitro studies, the bond of melatonin to plasma proteins is 60%. Basically melatonin binds to albumin, aglyklym glycoprotein and high-density lipoprotein.
Biotransformation:
Experimental studies suggest that the isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism. The main metabolite of melatonin is 6-sulfatoxymelatonin, is inactive. The process of presystemic metabolism occurs in the liver. Excretion of the metabolite is completed within 12 hours after ingestion.
Excretion:
The half-life (T1 / 2) is 3.5-4 hours.Excretion is performed on 89% by kidneys, in the form of sulfated and glucuronated conjugates of 6-hydroxymelatonin, and 2% is excreted unchanged.
Floor:
Women are observed 3-4 times, in comparison with men, an increase. There was also a fivefold interindividual variability of the Stach within the same sex.
Nevertheless, despite differences in plasma concentrations, no pharmacodynamic differences between men and women have been identified.
Elderly patients:
Metabolism of melatonin, as is known, slows down with age. At different doses of melatonin, higher values of area under the concentration-time curve (AUC) and Stach were obtained in the elderly, which reflects a reduced melatonin metabolism in this group of patients. While the Stach in adults (18-45 years) is 500 pg / ml, in the elderly (55-69 years) - 1200 pg / ml; AUC in adults is 3000 pg / hr and 5000 pg / h in the elderly. Patients with impaired renal function:
With prolonged treatment, cumulation of melatonin was not observed. These data are consistent with a short half-life of melatonin in humans. After 1 and 3 weeks of treatment with circadian 2 mg dose, blood was taken at 23:00 (2 hours after ingestion),the concentration was 411.4 ± 56.5 and 432.0 ± 83.2 pg, respectively, and is similar to that of a single admission of 2 mg of circadian healthy volunteers.
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 cirrhosis of the liver, the plasma concentration of melatonin increased significantly during the day. Compared to 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 older than 55 years (as a monotherapy).

Contraindications:Hypersensitivity to the drug components (active substance and excipients), congenital galactose intolerance, glucose-galactose malabsorption syndrome, congenital lactase deficiency; autoimmune diseases, liver failure, age under 18 years (efficacy and safety of use not established).

Pregnancy and lactation:There are no clinical data on the effects of melatonin on the course of pregnancy. Pre-clinical data do not indicate adverse effects on pregnancy, fetal development, delivery, or postnatal neonatal development. Due to the lack of clinical data, the use of circadian during pregnancy and women planning a pregnancy is not recommended. Breastfeeding period
Due to the fact that endogenous melatonin is defined in breast milk, probably exogenous melatonin can also penetrate into breast milk. Data obtained for animals, including rodents, sheep, cattle and primates, indicate the transfer of melatonin through the placenta or milk from mother to fetus. Therefore, it is not recommended to take melatonin in the period of breastfeeding.

Dosing and Administration:Inside, 2 mg once a day, after meals, in the evening, 1-2 hours before bedtime. Tablets should be swallowed whole to support sustained release. Do not crush or chew the tablet to facilitate swallowing.
The course of treatment can be up to 13 weeks.
Renal insufficiency
The effect of renal failure (of any severity) on the pharmacokinetics of melatonin has not been studied. Care should be taken when administering melatonin to such patients.

Side effects:

System-Organic grade	Highly often	Often	Infrequently	Rarely	Frequency unknown a
			Insomnia Unusual dreaming Night nightmares Anxiety	Agitation Tearfulness Symptoms stress Disorientation Early morning awakening Increase libido Decreased mood Depression
Disturbances from the nervous system			Migraine Headache Lethargy Psychomotor Hyperactivity Dizziness Drowsiness	Fainting Violation memory Violation concentrations attention Dreamy state Syndrome "restless" legs Poor quality of Paresthesia sleep
Disturbances on the part of the organ of sight				Decrease visual acuity Unclear view Increased lacrimation
Hearing disorders and labyrinthine disorders				Vertigo Positional vertigo
Heart Disease				Angina pectoris stresses Feeling palpitation
Vascular disorders			Arterial hypertension	"Tides"
Disorders from the gastrointestinal tract			Abdominal pain Abdominal pain in the upper abdomen Dyspepsia	Gastroesophageal reflux disease Gastrointestinal disturbance or

System-Organic grade	Highly often	Often	Infrequently	Rarely	Frequency unknown a
			Ulcerative stomatitis Dry mouth Nausea	disorder Blistering on the oral mucosa Ulcerative glossitis Vomiting Abnormal intestinal noise Abdominal swelling Hyper secretion of saliva Unpleasant odor from the mouth Abdominal discomfort Indigestion Gastritis
Disturbances from the liver and bile ducts			G yperbilirubinemiya
Disturbances from the skin and subcutaneous tissues			Dermatitis Perspiration at night Itching and generalized itching Rash Dryness of the skin	Eczema Erythema Hand dermatitis Psoriasis Generalized rash Itching rash Defeat nails	Edema Quincke Edema of the mouth Edema of the tongue
Disturbances from musculoskeletal and connective tissue			Pain in the limb	Arthritis Muscle spasm Neck pain Night cramps
Disorders from the kidneys and urinary tract			Glycosuria Proteinuria	Polyuria Gematuria Nicturia
Violations of the genitals and the breast			Menopausal symptoms	Priapism Prostatitis	Galactor I
General disorders and disorders in place			Asthenia Chest pain	Fatigability Pain

Overdose:There were no cases of overdose of the drug Circadian. The drug was used at a dose of 5 mg / day in clinical studies lasting more than 12 months, while there was no change in the nature of reported side effects.
There are published data on the use of circadian in a daily dose of 300 mg without clinically significant side effects.
Overdose suggests the development of drowsiness. The clearance of the active substance is expected within 12 hours after ingestion. Special treatment is not required.

Interaction:Pharmacokinetic interaction
- It is known that in concentrations significantly exceeding therapeutic, melatonin induces CYP3A in vitro. The clinical significance of this fact has not been fully clarified. In case of development of signs of induction, consideration should be given to reducing the dose of concomitant medications.
- In concentrations significantly exceeding therapeutic, melatonin does not induce the enzymes of the CYP1A group in vitro. Consequently, the interaction of melatonin with other active substances due to the influence of melatonin on the isozymes of the CYP1A group can hardly be significant.
- Metabolism of melatonin, mainly, is mediated by CYP1A enzymes. Consequently, the possibility of interaction of melatonin with other active substances due to the influence of melatonin on the enzymes of the CYP1A group is quite probable.
- Care should be taken in patients receiving fluvoxamine, which increases the concentration of melatonin (17-fold increase in AUC and 12-fold in blood) due to inhibition of its metabolism by cytochrome P450 (CYP) -CYP1A2 and CYP2C19 isoenzymes. Such a combination should be avoided.
Caution should be exercised in patients taking 5- or 8-methoxypsoralen, which increases the concentration of melatonin due to inhibition of its metabolism.
- Care should be taken in patients receiving cimetidine (inhibitor of CYP2D), which increases the level of melatonin in the blood plasma by inhibiting its metabolism.
- Smoking can reduce the concentration of melatonin by stimulating CYP 1A2:
Caution should be exercised in patients taking estrogens (eg, contraceptives or hormone replacement therapy) that are able to increase melatonin concentration by inhibiting its metabolism with CYP1A1 and CYPI A2 isoenzymes.
- CYP1A2 inhibitors, such as quinolones, can increase the exposure of melatonin.
- Inductors CYP1A2, such as carbamazepine and rifampicin, are able to reduce the concentration of melatonin in the blood plasma.
- In the modern literature there is a lot of data concerning the effect of agonists / antagonists of adrenergic and opiate receptors, antidepressants, inhibitors of prostaglandins, benzodiazepines, tryptophan and alcohol on the secretion of endogenous melatonin. Studies of the mutual influence of these drugs on the dynamics or kinetics of circadian were not carried out.

Pharmacodynamic interaction
- During the reception of Circadian, you should not drink alcohol, as it reduces the effectiveness of the drug.
- Circadian potentiates the sedative effect of benzodiazepine and non-benzodiazepine hypnotics, such as zaleplon, zolpidem and zopiclone. In the course of the clinical study, there were clear signs of transient pharmacodynamic interaction between circadian and zolpidem within one hour after administration. Combined use can lead to progressive attention, memory and coordination disorder compared to zolpidem monotherapy.
- In the course of research, circadian was administered together with thioridazine and imipramine, drugs that affect the central nervous system. In none of the cases was there a clinically significant pharmacokinetic interaction. However, a combined appointment with Circadian resulted in an increased sense of calm and difficulty in performing certain tasks in comparison with imipramine monotherapy, as well as an increase in the feeling of "clouding in the head", in comparison with monotherapy with thioridazine.
- Joint use with non-steroidal anti-inflammatory drugs (NSAIDs) is not recommended.

Special instructions:Circadian may cause drowsiness. Therefore, the drug should be administered with caution, if the induced drowsiness threatens the safety of the patient.
Clinical data on the use Tsikardina in patients with autoimmune diseases are absent, in this regard, Tsirkadin not recommended for patients with autoimmune diseases.
This drug should not be given to patients with a rare hereditary intolerance to galactose, deficiency of Lappa lactase or malabsorption of glucose-galactose.

Effect on the ability to drive transp. cf. and fur:Tsirkadin causes sleepiness, in this regard, the period of treatment should refrain from driving motor vehicles and activities potentially hazardous activities that require high concentration and psychomotor speed reactions.

Form release / dosage:Long-acting tablets 2.0 mg. For 21 tablets in a blister of PVC / PVDC / AL foil. For 1 blister together with instructions for use in a pack of cardboard.

Packaging:(21) - packings of cellular contour (1) - packs cardboard.

Storage conditions:At a temperature of no higher than 25 ° C.
KEEP OUT OF THE REACH OF CHILDREN.

Shelf life:2 years.
Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002400/10

Date of registration:24.03.2010

The owner of the registration certificate:RAD Newim Pharmaceuticals EEC LtdRAD Newim Pharmaceuticals EEC Ltd United Kingdom

Representation: & nbspNycomed Distribution Ltd.Nycomed Distribution Ltd.

Information update date: & nbsp06.08.2015

Illustrated instructions

Instructions

Circadian (Circadine)