Circadin (Tablets) Instructions for Use

Marketing Authorization Holder

RAD Neurim Pharmaceuticals EEC, Ltd. (United Kingdom)

Manufactured By

Catalent Germany Schorndorf, GmbH (Germany)

Or

SwissCo Servises AG (Switzerland)

ATC Code

N05CH01 (Melatonin)

Active Substance

Melatonin (BP British Pharmacopoeia)

Dosage Form

Circadin

Extended-release tablets 2 mg: 21 pcs.

Dosage Form, Packaging, and Composition

Extended-release tablets white or almost white, round, biconvex.

Excipients: copolymer of methyl methacrylate, trimethylammonioethyl methacrylate chloride and ethyl acrylate [1:2:0.1] – 40 mg, calcium hydrogen phosphate dihydrate – 40 mg, lactose monohydrate – 80 mg, colloidal silicon dioxide – 2 mg, talc – 4 mg, magnesium stearate – 2 mg.

21 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Hypnotic drug

Pharmacotherapeutic Group

Hypnotic agent

Pharmacological Action

Hypnotic drug. Melatonin is a synthetic analogue of the hormone produced by the pineal gland and is chemically similar to serotonin. Under physiological conditions, melatonin secretion increases shortly after the onset of darkness, reaches maximum values at 2-4 a.m., and decreases during the second half of the night. It is believed that Melatonin controls circadian rhythms and the perception of the day-night cycle. It has a hypnotic effect and improves sleep onset.

It is assumed that the effect of melatonin on MT1, MT2, and MT3 receptors enhances the hypnotic action, as 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 sleep quality in primary insomnia, especially in patients over 55 years of age.

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

Pharmacokinetics

Absorption

Melatonin after oral administration in adults is rapidly absorbed from the gastrointestinal tract; in the elderly, the absorption rate may be reduced by 50%. When taking melatonin in the dose range of 2-8 mg, the kinetic parameters have a linear dynamic character. Bioavailability is 15%. There is a significant first-pass effect through the liver with an estimated primary metabolism of 85%. T_max – 3 h when taking the drug after a meal. Food intake affects the absorption of melatonin and its C_max in plasma when taking Circadin at a dose of 2 mg orally. Concomitant food intake slowed the absorption of melatonin, leading to a longer T_max (T_max= 3 h compared to T_max = 0.75 h) and a lower C_max (1020 pg/ml compared to 1176 pg/ml).

Distribution

In in vitro studies, the binding of melatonin to plasma proteins is 60%. Melatonin mainly binds to albumin, alpha₁-acid glycoprotein and HDL.

No accumulation of the drug was noted during long-term treatment. These data are consistent with the short T_1/2 of melatonin in humans.

Metabolism

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

Excretion

T_1/2 is 3.5-4 h. Excretion is 89% renal, in the form of sulfate and glucuronide conjugates of 6-hydroxymelatonin, and 2% of the drug is excreted unchanged.

Pharmacokinetics in special clinical cases

Women have a 3-4 times higher C_max value compared to men. A five-fold interindividual variability in C_max within the same sex was also noted. However, no other differences in pharmacodynamic parameters between men and women, except for differences in plasma drug concentration, were noted.

The metabolism process 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 metabolism in patients of this group. While C_max in adults (18-45 years) was 500 pg/ml, in the elderly (55-69 years) it was 1200 pg/ml; AUC in adults was 3000 pg × h/ml and 5000 pg × h/ml in the elderly.

Patients with impaired renal function: after 1 and 3 weeks of course treatment with Circadin at a dose of 2 mg, blood was drawn at 23:00, 2 hours after oral administration of the drug, the concentration was 411.4±56.5 and 432±83.2 pg, respectively, and is similar to that after a single dose of 2 mg of Circadin in healthy volunteers.

Patients with impaired liver function: the liver is the main organ involved in the metabolism of melatonin, so liver diseases lead to an increase in the concentration of endogenous melatonin. Plasma melatonin concentration increased significantly during the daytime in patients with liver cirrhosis. A significant decrease in the total excretion of 6-sulfatoxymelatonin compared to the control group was noted.

Indications

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

ICD codes

Dosage Regimen

Orally, 2 mg once/day, after a meal, in the evening, 1-2 hours before bedtime.

Tablets should be swallowed whole to maintain the delayed release. Do not break or chew the tablet to facilitate the swallowing process.

The course of treatment can be up to 13 weeks.

The effect of renal failure (any severity) on the pharmacokinetics of melatonin has not been studied. The drug should be prescribed with caution to this category of patients.

Adverse Reactions

In clinical studies, adverse reactions were reported in 48.8% of patients receiving Circadin, compared with 37.8% in the placebo group. Comparing the ratio of patients with adverse reactions per 100 patient-weeks, the rate in the placebo group was higher than in the group receiving Circadin (5.743 – placebo vs. 3.013 – Circadin). The most frequent adverse reactions in both groups were headache, nasopharyngitis, back pain, joint pain.

The table includes only those adverse reactions from clinical studies that were observed in patients with the same or greater frequency than in the placebo group.

Definition of adverse reaction frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), frequency unknown (cannot be estimated from the available data).

Contraindications

• Congenital galactose intolerance, glucose-galactose malabsorption syndrome, congenital lactase deficiency;
• Autoimmune diseases;
• Hepatic insufficiency;
• Childhood and adolescence under 18 years of age (efficacy and safety of use have not been established);
• Hypersensitivity to the components of the drug (active substance and excipients).

Use in Pregnancy and Lactation

There are no clinical data on the effect of melatonin on the course of pregnancy. Due to the lack of clinical data, the use of Circadin during pregnancy and in women planning pregnancy is not recommended.

Since endogenous Melatonin is detected in breast milk, exogenous Melatonin is also likely to pass into breast milk. It is not recommended to use Circadin during breastfeeding.

Preclinical study data do not indicate adverse effects on the course of pregnancy, fetal development, the process of childbirth, or postnatal development of newborns. Data obtained for animals, including rodents, sheep, cattle, and primates, indicate that Melatonin crosses the placental barrier and is excreted in breast milk.

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency.

Pediatric Use

Contraindicated for children and adolescents under 18 years of age (efficacy and safety of use have not been established).

Special Precautions

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

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 syndrome.

Effect on ability to drive vehicles and operate machinery

Circadin causes drowsiness, therefore, during the treatment period, one should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

No cases of Circadin overdose have been reported. The drug was used at a dose of 5 mg/day in clinical studies lasting more than 12 months, with no change in the nature of the reported side effects. There are literature data on the use of Circadin at a daily dose of up to 300 mg without clinically significant side effects.

In case of overdose, drowsiness is expected to develop. The active substance is expected to be eliminated from the body within 12 hours after oral administration. No specific treatment is required.

Drug Interactions

Pharmacokinetic interaction

It is known that in concentrations significantly exceeding therapeutic ones, Melatonin induces CYP3A in vitro. The clinical significance of this fact is not fully understood. If signs of induction develop, a dose reduction of concomitantly used drugs should be considered.

In concentrations significantly exceeding therapeutic ones, Melatonin does not induce CYP1A group enzymes in vitro. Therefore, the interaction of melatonin with other active substances due to the effect of melatonin on CYP1A group isoenzymes is apparently insignificant.

The metabolism of melatonin is mainly mediated by CYP1A enzymes. Therefore, interaction of melatonin with other drugs due to the effect of melatonin on CYP1A group isoenzymes is possible.

Caution should be exercised regarding patients taking fluvoxamine, which increases the concentration of melatonin (increase in AUC by 17 times and C_max in blood by 12 times) by inhibiting its metabolism by cytochrome P450 isoenzymes – CYP1A2 and CYP2C19. Such a combination should be avoided.

Caution should be exercised regarding patients taking 5- or 8-methoxypsoralen, which increases the concentration of melatonin by inhibiting its metabolism.

Caution should be exercised regarding patients taking cimetidine (a CYP2D inhibitor), which increases plasma melatonin levels by inhibiting its metabolism.

Smoking can reduce the concentration of melatonin by stimulating CYP1A2.

Caution should be exercised regarding patients taking estrogens (e.g., contraceptives or hormone replacement therapy), which can increase the concentration of melatonin by inhibiting its metabolism by CYP1A1 and CYP1A2 isoenzymes.

CYP1A2 inhibitors, such as quinolones, can increase melatonin exposure.

CYP1A2 inducers, such as carbamazepine and rifampicin, can reduce plasma melatonin concentration.

There is a lot of data in the modern literature concerning the influence of adrenergic and opioid receptor agonists/antagonists, antidepressants, prostaglandin inhibitors, benzodiazepines, tryptophan, and ethanol on the secretion of endogenous melatonin. Studies of the mutual influence of these drugs on the dynamics or kinetics of Circadin have not been conducted.

Pharmacodynamic interaction

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

Circadin potentiates the sedative effect of benzodiazepine and non-benzodiazepine hypnotics, such as zaleplon, zolpidem, and zopiclone. During a clinical study, clear signs of transient pharmacodynamic interaction between Circadin and zolpidem were observed within one hour after their administration. Combined use may lead to progressive impairment of attention, memory, and coordination compared to zolpidem monotherapy.

During studies, Circadin was administered together with thioridazine and imipramine, drugs that affect the CNS. In no case was a clinically significant pharmacokinetic interaction detected. However, simultaneous use with Circadin led to an increased feeling of calmness and difficulties in performing certain tasks compared to imipramine monotherapy, as well as an increased feeling of “fogginess in the head” compared to thioridazine monotherapy.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 5 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.