Agnesti

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AGNESTI® (AGNESTI)

Composition:

Active substance: agomelatine;

One tablet contains co-crystal of agomelatine and citric acid – 44.739 mg (equivalent to 25 mg of agomelatine);

Excipients: silicified microcrystalline cellulose, mannitol (E 421), povidone 30, colloidal anhydrous silicon dioxide, crospovidone (type A), sodium stearyl fumarate, magnesium stearate, stearic acid 50, hypromellose (hydroxypropylmethylcellulose) 2910/5, polyethylene glycol (macrogol) 6000, titanium dioxide (E 171), talc, iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow-colored, elongated, biconvex film-coated tablets.

Pharmacotherapeutic group. Psychoanaleptics. Other antidepressants.

ATC code N06AX22.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Agomelatine is a melatonergic agonist at MT1 and MT2 receptors and a 5-HT2c receptor antagonist. Receptor binding studies have demonstrated that agomelatine does not affect monoamine reuptake and has no affinity for α- and β-adrenergic, histaminergic, cholinergic, dopaminergic, or benzodiazepine receptors.

In experimental animal studies involving circadian rhythm disorders, agomelatine has been shown to resynchronize circadian rhythms.

Agomelatine increases the release of dopamine and norepinephrine, particularly in the frontal cortex, and does not affect extracellular serotonin levels.

Pharmacodynamic effects

In experimental animal studies, agomelatine demonstrated antidepressant effects in validated models of depression (learned helplessness, chronic mild stress), as well as in models involving circadian rhythm desynchronization and stress- and anxiety-related models.

In humans, agomelatine resynchronizes circadian rhythms, restores sleep phase, induces a reduction in body temperature, and promotes melatonin secretion.

Clinical efficacy and safety

The efficacy and safety of agomelatine in the treatment of major depressive episodes were evaluated in a clinical program involving 7,900 patients.

In six short-term, double-blind, placebo-controlled studies assessing the efficacy of agomelatine in treating major depressive episodes in adult patients, agomelatine at doses of 25–50 mg at the end of treatment (over 6–8 weeks) demonstrated statistically significant efficacy compared to placebo. Improvements in scores on the HAMD-17 scale (Hamilton Depression Rating Scale) were observed for the primary endpoint compared to baseline.

The efficacy of agomelatine was also demonstrated in patients with more severe depression (baseline total HAMD score ≥ 25) across all positive placebo-controlled studies.

Treatment response rates with agomelatine were statistically significantly higher compared to placebo.

In six out of seven efficacy studies in heterogeneous populations of adult patients with depression, agomelatine demonstrated either higher efficacy (2 studies) or non-inferior efficacy (4 studies) compared to selective serotonin reuptake inhibitors / serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) (sertraline, escitalopram, fluoxetine, venlafaxine, or duloxetine). Antidepressant effect was assessed using the HAMD-17 scale or as a primary or secondary endpoint.

Long-term antidepressant efficacy of agomelatine was demonstrated in a relapse prevention study. Regarding the primary endpoint—prevention of depressive relapse, measured as time to relapse—agomelatine at a dose of 25–50 mg daily showed statistically significant superiority compared to placebo (p = 0.0001). The relapse rate during the 6-month double-blind observation period was 22% and 47% in the agomelatine and placebo groups, respectively.

The drug does not affect daytime alertness or memory in healthy volunteers. In patients with depression, treatment with agomelatine at a dose of 25 mg prolonged slow-wave sleep phase without affecting rapid eye movement (REM) sleep phase or latency. Agomelatine at a dose of 25 mg also shortened the time to sleep onset (facilitated sleep initiation) and time to reach minimal heart rate. According to patient assessments, sleep onset and sleep quality significantly improved from the first week of treatment without impairing daytime functioning.

A pooled analysis of studies using the ASEX (Arizona Sexual Experience Scale) demonstrated that agomelatine use was not associated with sexual dysfunction. In healthy volunteers, agomelatine preserved sexual function compared to paroxetine.

In clinical studies, agomelatine did not affect heart rate or blood pressure.

In a study assessing discontinuation symptoms using the DESS (Discontinuation Emergent Signs and Symptoms) questionnaire in patients with depression in remission, agomelatine did not cause a withdrawal syndrome after abrupt discontinuation of treatment.

Agomelatine does not cause dependence, as determined in studies involving healthy volunteers using specific visual-analogue scales or the 49-item ARCI (Addiction Research Center Inventory) questionnaire.

An 8-week placebo-controlled study of agomelatine at a dose of 25–50 mg daily in elderly patients with depression (≥ 65 years, N = 222, of whom 151 received agomelatine) demonstrated a statistically significant difference of 2.67 points on the total HAMD scale (primary endpoint). The treatment response rate was favorable for agomelatine. In the subgroup of patients aged ≥ 75 years (N = 69, 48 of whom received agomelatine), no significant improvement was observed. The tolerability of agomelatine in elderly patients was similar to that in younger adult patients.

A specific 3-week controlled study was conducted in patients with major depressive disorders who did not achieve significant improvement with paroxetine (SSRI) or venlafaxine (SNRI). When these patients were switched to agomelatine treatment, withdrawal symptoms occurred regardless of whether the previous therapy was discontinued abruptly or gradually. These symptoms may be misinterpreted as insufficient early effect of agomelatine.

The percentage of patients experiencing at least one withdrawal symptom within 1 week after discontinuation of SSRIs/SNRIs was lower in the group with prolonged dose reduction (gradual discontinuation of prior antidepressant over 2 weeks) compared to the group with short-term dose reduction (gradual discontinuation over 1 week) and the abrupt switch group: 56.1%, 62.6%, and 79.8%, respectively.

Pharmacokinetics

Absorption and bioavailability

Agomelatine is rapidly and well absorbed (≥ 80%) after oral administration. Absolute bioavailability is low (< 5% after oral administration at therapeutic doses), with considerable inter-individual variability. Bioavailability is higher in women compared to men. Bioavailability increases with the use of oral contraceptives and decreases in smokers. Maximum plasma concentration is reached within 1–2 hours.

When administered at therapeutic doses, agomelatine concentration increases proportionally with increasing dose. At higher doses, a first-pass saturation effect occurs.

Food intake (normal or high-fat meal) does not affect bioavailability or the extent of absorption.

Variability increases when agomelatine is taken with a high-fat meal.

Distribution

The volume of distribution at steady state is approximately 35 L. Plasma protein binding is 95%, independent of concentration, and does not change with age or in patients with renal impairment. However, the concentration of free fraction doubles in patients with hepatic impairment.

Biotransformation

After administration, agomelatine is rapidly metabolized, primarily by hepatic enzymes CYP1A2. Isoenzymes CYP2C9 and CYP2C19 also participate in metabolism, but their contribution is negligible. The main metabolites—hydroxylated and demethylated agomelatine—are inactive and rapidly conjugated and excreted in urine.

Elimination

Elimination from the body is rapid, with an average plasma half-life of 1–2 hours. Clearance is high (approximately 1.1 mL/min) and predominantly metabolic. Excretion is primarily via urine (80%) as metabolites, while the amount of unchanged active substance excreted in urine is negligible. Pharmacokinetics do not change after repeated administration.

Patients with renal impairment

No relevant changes in pharmacokinetic parameters of agomelatine were observed in patients with severe renal impairment (n = 8, single 25 mg dose). However, Agneste® should be administered with caution in patients with moderate or severe renal impairment due to limited clinical data on agomelatine use in this patient group (see section "Dosage and administration").

Patients with hepatic impairment

A specific study in patients with liver cirrhosis and chronic mild to moderate hepatic impairment (Child-Pugh class A and B) demonstrated a 70- and 140-fold increase, respectively, in agomelatine concentration after a 25 mg dose compared to healthy volunteers with comparable characteristics (age, body weight, smoking status) without hepatic impairment (see sections "Dosage and administration", "Contraindications", and "Special warnings and precautions for use").

Elderly patients

A pharmacokinetic study in elderly patients (≥ 65 years) showed that after administration of a 25 mg dose, mean AUC and Cmax values were approximately 4 and 13 times higher, respectively, in patients aged ≥ 75 years compared to those under 75 years. Pharmacokinetics of agomelatine at a 50 mg dose in this population could not be assessed due to insufficient data. Dose adjustment is not required in elderly patients.

Ethnic groups

Data on pharmacokinetic characteristics of agomelatine according to racial background are lacking.

Clinical Characteristics

Indications

Treatment of major depressive episodes in adults.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Hepatic impairment (liver cirrhosis or active phase of liver disease) or elevated transaminase levels more than 3 times the upper limit of normal range (see sections "Method of administration and dosage" and "Special precautions").
• Concomitant use with strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Potential interactions of agomelatine

Agomelatine is metabolized primarily by cytochrome P450 1A2 (CYP1A2) (90%) and CYP2C9/19 (10%). Medicinal products interacting with these isoenzymes may decrease or increase agomelatine bioavailability.

Fluvoxamine, a strong CYP1A2 inhibitor and moderate CYP2C9 inhibitor, markedly inhibits agomelatine metabolism, resulting in a 60-fold (range 12–412) increase in agomelatine concentration. Therefore, concomitant administration of Agomelatine**®** with strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) is contraindicated.

Combination of agomelatine with estrogens (moderate CYP1A2 inhibitors) leads to several-fold increase in agomelatine concentration. Although no safety concerns have been observed in approximately 800 patients receiving concomitant treatment with agomelatine and estrogens, co-administration of agomelatine with other moderate CYP1A2 inhibitors (propranolol, enoxacin) should be done with caution until more experience with this combination is available (see section "Special precautions").

Rifampicin, an inducer of all three cytochromes involved in agomelatine metabolism, may reduce agomelatine bioavailability.

Smoking stimulates CYP1A2 induction and reduces agomelatine bioavailability, particularly in heavy smokers (≥ 15 cigarettes/day) (see section "Pharmacokinetics").

Ability of agomelatine to affect other medicinal products

In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine does not inhibit CYP1A2 in vivo, nor other CYP450 enzymes in vitro. As a result, it does not affect the concentrations of medicinal products metabolized by CYP450 enzymes.

Other medicinal products

In phase I clinical studies in the target patient population, no pharmacokinetic or pharmacodynamic interactions were observed with medicinal products commonly co-administered with agomelatine: benzodiazepines, lithium, paroxetine, fluconazole, and theophylline.

Alcohol

Alcohol consumption is not recommended during treatment with Agomelatine**®**.

Electroconvulsive therapy (ECT)

Experience with concomitant use of agomelatine and ECT is lacking. Animal studies did not reveal any properties of agomelatine to lower seizure threshold. Therefore, it is unlikely that ECT in combination with Agomelatine**®** would lead to any clinically significant complications.

Special precautions for use

Monitoring of liver function

During the post-marketing period, cases of liver function abnormalities have been reported in patients treated with agomelatine, including liver failure (isolated cases with fatal outcomes or requiring liver transplantation in patients with risk factors for liver dysfunction), increases in liver enzyme levels more than 10 times the upper limit of normal, hepatitis, and jaundice (see section "Side effects"). Most abnormalities occurred within the first months of treatment. Liver injury is predominantly hepatocellular in nature, and serum transaminase levels return to normal upon discontinuation of agomelatine.

Agne®** should be prescribed with caution, and all patients should be closely monitored throughout the treatment period, particularly if they have risk factors for liver dysfunction or are receiving concomitant medications that may cause liver abnormalities.**

Before starting treatment

Agne**®** should be prescribed only after careful benefit-risk assessment in patients with risk factors for liver dysfunction such as obesity / overweight / non-alcoholic fatty liver disease, diabetes mellitus, alcohol-related disorders and/or alcohol abuse, or in patients receiving concomitant medications that may cause liver abnormalities.

Before initiating treatment, liver function tests should be performed in all patients. Treatment should not be initiated in patients with baseline alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels exceeding three times the upper limit of normal (see section "Contraindications"). Agne**®** should be used with caution in patients with elevated transaminase levels prior to treatment (provided the increase is no more than three times the upper limit of normal).

Frequency of liver function testing

• Before starting treatment;
• after initiation of treatment:
  • approximately 3 weeks after starting;
  • approximately 6 weeks after starting (end of the acute phase);
  • approximately 12 and 24 weeks after starting (end of the maintenance phase);
  • and thereafter if clinically indicated.
• When dose is increased, liver tests should be repeated at the same frequency as at the beginning of treatment.

Any patient in whom elevated plasma transaminase levels are detected should have liver function retested within 48 hours.

During treatment

Treatment with Agne**®** must be discontinued immediately if:

• the patient develops symptoms suggestive of potential liver dysfunction (such as dark urine, pale stools, yellowing of the skin or eyes, upper right abdominal pain, or new onset of persistent unexplained fatigue);
• serum transaminase levels exceed three times the upper limit of normal.

After discontinuation of Agne**®**, liver function tests should be repeated until serum transaminase levels return to normal.

Patients aged 75 years and older

The efficacy of agomelatine has not been demonstrated in patients aged ≥75 years; therefore, agomelatine should not be used in this age group (see sections "Dosage and administration" and "Pharmacodynamics").

Elderly patients with dementia

Agne**®** should not be used for the treatment of major depressive episodes in elderly patients with dementia, as the safety and efficacy of agomelatine have not been established in this patient group.

Bipolar disorder / mania / hypomania

Agne**®** should be used with caution in patients with a history of bipolar disorder, mania, or hypomania. The medication should be discontinued if manic symptoms occur (see section "Side effects").

Suicide / suicidal thoughts

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal behaviour). This risk persists until significant remission occurs. Since improvement may not occur during the first few weeks or longer of treatment, close monitoring of the patient is essential until improvement is observed. Clinical experience generally indicates that the risk of suicide may increase during the early stages of improvement.

Patients with a history of suicidal behaviour, as well as those exhibiting high levels of suicidal ideation before treatment initiation, are at increased risk of suicidal thoughts or attempts and should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients under 25 years of age.

Close monitoring is required during treatment, especially in the early stages and after dose adjustments, particularly for patients at high risk. Patients (and caregivers) should be advised to monitor for any worsening of clinical condition, emergence of suicidal thoughts or behaviour, or unusual changes in behaviour, and to seek immediate medical attention if such symptoms occur.

Use in combination with CYP1A2 inhibitors (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction")

Agne**®** should be prescribed with caution in combination with moderate CYP1A2 inhibitors (e.g., propranolol, enoxacin), as this may lead to increased agomelatine concentrations.

Use during pregnancy or breastfeeding

Pregnancy

Use of Agne**®** during pregnancy should be avoided. Data on the use of agomelatine in pregnant women are lacking or limited (fewer than 300 cases). Animal studies have not shown direct or indirect harmful effects of agomelatine on pregnancy, embryofetal development, parturition, or postnatal development.

Breastfeeding

It is unknown whether agomelatine/metabolites are excreted in human breast milk. Available pharmacodynamic/toxicological data from animal studies have shown that agomelatine/metabolites are excreted in milk. A risk to newborns/infants cannot be excluded. The decision whether to discontinue breastfeeding or to discontinue/abstain from Agne**®** therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Fertility

Animal reproductive studies showed no effect of agomelatine on fertility.

Ability to influence reaction speed when driving or operating machinery

Agomelatine has negligible influence on the ability to drive a car or operate machinery. However, since dizziness and somnolence are common side effects of the drug, patients should exercise caution when driving or operating machinery.

Dosage and Administration

Route of Administration

For oral use.

Agneсти® film-coated tablets can be taken independently of food intake.

Dosage

The recommended dose is 25 mg once daily, taken at bedtime.

If after 2 weeks of treatment there is insufficient clinical improvement, the dose may be increased to 50 mg once daily (i.e., two 25 mg tablets taken together at bedtime).

When considering dose escalation, the increased risk of elevated transaminase levels should be taken into account. Dose increase to 50 mg should be individualized for each patient based on benefit/risk assessment, with mandatory liver function tests.

Liver function tests should be performed in all patients prior to initiating treatment. Treatment should not be initiated if transaminase levels exceed three times the upper limit of normal (see sections "Contraindications" and "Special Warnings and Precautions for Use").

During treatment, transaminase levels should be monitored periodically: approximately at 3 weeks, 6 weeks (end of acute phase), 12 weeks, 24 weeks (end of maintenance phase), and thereafter as clinically indicated (see section "Special Warnings and Precautions for Use"). Treatment should be discontinued if transaminase levels increase to more than three times the upper limit of normal (see sections "Contraindications" and "Special Warnings and Precautions for Use").

When increasing the dose, liver function tests should be repeated with the same frequency as at the beginning of treatment.

Duration of Treatment

Patients with depression should continue treatment for at least 6 months to ensure symptom remission.

Switching from antidepressants of the selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) class to agomelatine

Withdrawal symptoms may occur in patients after discontinuation of SSRIs/SNRIs. To avoid such symptoms, recommendations for discontinuation contained in the patient's current antidepressant product information should be followed. Agomelatine treatment may be initiated immediately, concurrently with tapering the dose of the antidepressant (see section "Pharmacodynamics").

Discontinuation of Treatment

If a decision is made to discontinue treatment, there is no need for gradual dose reduction.

Special Patient Populations

Elderly Patients

The safety and efficacy of agomelatine (25–50 mg/day) have been established in elderly patients with depression (< 75 years of age). Reliable data are lacking in patients aged ≥ 75 years. Therefore, agomelatine should not be used in this age group (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics"). No dose adjustment based on age is required (see section "Pharmacokinetics").

Patients with Renal Impairment

No relevant changes in pharmacokinetic parameters of agomelatine have been observed in patients with severe renal impairment. However, clinical data on the use of agomelatine in patients with depression and moderate to severe renal impairment are limited. Therefore, Agneсти® should be prescribed with caution in such patients.

Patients with Hepatic Impairment

Agneсти® is contraindicated in patients with hepatic impairment (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics").

Children

Agneсти® is not recommended for the treatment of depression in children, as the safety and efficacy of agomelatine have not been established in this patient population. Data are lacking. In clinical trials with other antidepressants in children, suicidal behavior (suicidal attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) occurred more frequently compared to placebo-treated patients.

Overdose

Symptoms

Data on agomelatine overdose are limited. Following overdose, epigastric pain, somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis, or malaise have been reported. One case of ingestion of 2450 mg of agomelatine has been documented, with spontaneous recovery occurring without cardiovascular or biological abnormalities.

Treatment

There are no specific antidotes for agomelatine. Management of overdose should consist of symptomatic treatment and routine patient monitoring. Medical observation should be conducted in a specialized facility.

Side Effects

Side effects usually occurred during the first 2 weeks of treatment and were mild to moderate in severity. The most common side effects were headache, nausea, and dizziness. These side effects were generally transient in nature and usually did not lead to discontinuation of therapy.

The table below lists side effects identified during placebo-controlled clinical studies and trials using active comparators.

The adverse reactions listed below are presented with the following frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data). The frequency was not adjusted for the placebo group.

* Frequency of adverse reactions identified through spontaneous reporting calculated from clinical trial data.

(1) Isolated cases of fatalities or cases requiring liver transplantation have been reported in patients with risk factors for hepatic dysfunction.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging to protect from moisture. No temperature restrictions apply. Keep out of reach and sight of children.

Packaging. 14 tablets in a blister pack. 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak" (secondary packaging, labelling, batch release from bulk product manufactured by MEDIS International a.s., plant (production site) in Bolatice, Czech Republic, and manufacturer Zentiva k.s., Czech Republic).

Manufacturer's address and location of its business operations

74, Kyrylivska Street, Kyiv, 04080, Ukraine