Drimex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DREAMEX (DREAMEX)

Composition:

Active substance: agomelatine;

1 tablet contains agomelatine citrate and citric acid – 44.739 mg (equivalent to 25 mg of agomelatine);

Excipients: microcrystalline cellulose silicified, mannite (E 421), povidone 30, silicon dioxide colloidal anhydrous, crospovidone (type A), sodium stearyl fumarate, magnesium stearate, stearic acid 50;

Coating: 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, 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 an antagonist at 5-HT2C receptors. 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 noradrenaline, 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 (behavioral despair test, 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 efficacy studies in adult patients with major depressive episodes, agomelatine at doses of 25–50 mg at the end of treatment (over 6–8 weeks) demonstrated statistically significant efficacy compared to placebo. Changes in the primary endpoint, assessed using the HAMD-17 (Hamilton Depression Rating Scale), were significantly different from baseline.

The efficacy of agomelatine was also demonstrated in patients with more severe depression (baseline total HAM-D 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 conducted in heterogeneous populations of adult patients with depression, agomelatine demonstrated either higher (2 studies) or non-inferior (4 studies) efficacy 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, either as a primary or secondary endpoint.

Long-term antidepressant efficacy of agomelatine was demonstrated in a relapse prevention study. In terms of the primary endpoint—prevention of depressive relapse, measured by 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 6 months of double-blind observation was 22% in the agomelatine group and 47% in the placebo group.

The drug does not affect daytime alertness or memory in healthy volunteers. In patients with depression, treatment with agomelatine 25 mg prolonged slow-wave sleep phase without affecting rapid eye movement (REM) sleep phase or latency. Agomelatine 25 mg also reduced 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.

In a specific comparative study on sexual dysfunction involving patients in remission from depression, there was a numerical trend (statistically non-significant) toward less treatment-emergent sexual dysfunction in the agomelatine group compared to venlafaxine, based on the SEXFX (Sex Effects Scale) scores for arousal and orgasm. A pooled analysis 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 following abrupt discontinuation of treatment.

Agomelatine is not associated with 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 in elderly patients (≥ 65 years, N = 222, of whom 151 received agomelatine) with depression demonstrated a statistically significant difference of 2.67 points on the total HAM-D scale (primary endpoint). The treatment response rate was favorable for agomelatine. In patients aged ≥ 75 years (N = 69, of whom 48 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 disorder who did not achieve significant improvement with paroxetine (SSRI) or venlafaxine (SNRI). When these patients were switched to agomelatine, regardless of whether the prior treatment was discontinued abruptly or gradually, withdrawal symptoms occurred. These symptoms may be mistakenly interpreted as insufficient early efficacy of agomelatine.

The percentage of patients experiencing at least one withdrawal symptom within one week after discontinuation of SSRIs/SNRIs was lower in the group undergoing gradual dose reduction over two weeks (56.1%) compared to the group with a shorter tapering period over one week (62.6%) and the group with abrupt discontinuation (79.8%).

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 than in men. It is increased by the use of oral contraceptives and decreased in smokers. Maximum plasma concentration is reached within 1–2 hours.

At therapeutic doses, agomelatine plasma concentration increases proportionally with dose. At higher doses, a first-pass saturation effect occurs.

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

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 the free fraction is doubled in patients with hepatic impairment.

Biotransformation

After administration, agomelatine is rapidly metabolized, primarily by hepatic enzymes CYP1A2; CYP2C9 and CYP2C19 isoenzymes also contribute to metabolism, but their involvement is minor. The main metabolites—hydroxylated and demethylated agomelatine—are inactive and rapidly conjugated and excreted in urine.

Elimination

Elimination 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 mainly 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, DRIMEKS should be used with caution in patients with moderate or severe renal impairment due to limited clinical data in this patient group (see section "Dosage and Administration").

Patients with Hepatic Impairment

A specific study in patients with liver cirrhosis and mild to moderate chronic hepatic impairment (Child-Pugh class A and B) demonstrated a 70-fold 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) and normal liver function (see sections "Dosage and Administration", "Contraindications", and "Special Warnings and Precautions for Use").

Elderly Patients

Pharmacokinetic studies in elderly patients (≥ 65 years) showed that, after 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 after 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 related to race 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 (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 forms of interaction").

Interaction with other medicinal products and other forms of interaction

Possible interactions of agomelatine

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

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

Combination of agomelatine with estrogens (moderate inhibitors of CYP1A2) leads to several-fold increase in agomelatine concentration. Although no specific safety signal was observed in 800 patients receiving agomelatine concomitantly with estrogens, co-administration of agomelatine with other moderate CYP1A2 inhibitors (propranolol, enoxacin) should be done with caution until more experience with this combination is obtained (see section "Special precautions").

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

Smoking stimulates induction of CYP1A2 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 the isoenzymes of the CYP450 system. 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

Phase I clinical studies in the target patient population have not provided data on pharmacokinetic and pharmacodynamic interactions with medicinal products that may be co-administered with agomelatine: benzodiazepines, lithium, paroxetine, fluconazole, and theophylline.

Alcohol

Alcohol consumption is not recommended during treatment with DREMEKX.

Electroconvulsive therapy (ECT)

There is no experience with the use of agomelatine concomitantly with ECT. Animal studies have not revealed any properties of agomelatine to increase seizure susceptibility. Therefore, it is unlikely that ECT in combination with treatment with DREMEKX 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 "Adverse reactions"). Most abnormalities occurred within the first months of treatment. Liver injury is predominantly hepatocellular in nature, and serum transaminase levels usually return to normal upon discontinuation of agomelatine.

DRIMEKS should be prescribed with caution and close monitoring of all patients throughout the treatment period, especially in the presence of risk factors for liver dysfunction or when concomitant medications are used that may cause liver function abnormalities.

Before starting treatment

DRIMEKS 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 taking concomitant medications that may cause liver function 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"). DRIMEKS should be used with caution in patients who have elevated transaminase levels prior to treatment initiation (provided the elevation does not exceed three times the upper limit of normal).

During the treatment period

Treatment with the medicinal product DREMEKS should be discontinued immediately if:

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

After discontinuation of DREMEKS, 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 established 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

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

Bipolar disorder / mania / hypomania

DREMEKS should be used with caution in patients with a history of bipolar disorder, mania, or hypomania. The medicinal product should be discontinued if manic symptoms occur (see section “Adverse reactions”).

Suicide / suicidal thoughts

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal manifestations). This risk persists until significant remission occurs. Since the patient's condition may not improve during the first few weeks or longer of treatment, careful monitoring of the patient is required until improvement occurs. Clinical experience indicates that the risk of suicide may increase during the early stages of improvement.

Patients with a history of suicidal manifestations, as well as those exhibiting high levels of suicidal ideation prior to 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 behavior with antidepressants compared to placebo in patients under 25 years of age.

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

Concomitant use with CYP1A2 inhibitors (see sections “Contraindications” and “Interaction with other medicinal products and other forms of interaction”)

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

Sodium content

DREMEKS contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

It is advisable to avoid using DREMEKS during pregnancy. 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, embryonal/fetal 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 demonstrated that agomelatine/metabolites are excreted in breast milk. A risk to newborns/infants cannot be excluded. The decision whether to discontinue breastfeeding or to discontinue/abstain from DREMEKS therapy should be made by weighing the benefits of breastfeeding for the child against the benefits of treatment for the mother.

Fertility

Reproductive function studies in animals showed no effect of agomelatine on fertility.

Ability to influence reaction speed while driving or operating machinery

Agomelatine has a minor influence on the ability to drive and operate machinery. However, considering that dizziness and somnolence are common adverse reactions of the drug, patients should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Method of Administration

For oral use.

DREMEKS, film-coated tablets, can be administered regardless of food intake.

Dosage

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

If after 2 weeks of starting therapy there is insufficient clinical improvement, the dose may be increased to 50 mg once daily (i.e., 2 tablets of 25 mg taken simultaneously 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 after benefit/risk assessment, with mandatory liver function tests (see sections "Contraindications" and "Special Warnings and Precautions for Use").

All patients must undergo liver function tests prior to initiating treatment. Treatment should not be initiated if transaminase levels exceed the upper limit of normal by 3 times (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, and 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 exceed the upper limit of normal by 3 times (see sections "Contraindications" and "Special Warnings and Precautions for Use").

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

Duration of Treatment

Patients with depression should be treated for at least 6 months to ensure symptom remission.

Switching from Antidepressants of the Selective Serotonin Reuptake Inhibitors / Serotonin-Norepinephrine Reuptake Inhibitors (SSRIs/SNRIs) 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's instructions should be followed. Agomelatine therapy may be initiated immediately, concurrently with tapering the antidepressant dose (see section "Pharmacodynamics").

Discontinuation of Treatment

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

Special Patient Groups

Elderly Patients

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

Patients with Renal Impairment

No relevant changes in the pharmacokinetic parameters of agomelatine were 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, agomelatine should be administered with caution in these patients.

Patients with Hepatic Impairment

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

Children

DREMEKS is not recommended for the treatment of depression in children, as the safety and efficacy of this medicinal product have not been established in this patient group. Data are lacking. In clinical studies involving children and adolescents treated with other antidepressants, suicidal behavior (suicidal attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) occurred more frequently compared to patients receiving placebo.

Overdose

Symptoms

Data on agomelatine overdose are limited. Symptoms reported in cases of overdose include epigastric pain, somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis, or malaise. One case of ingestion of 2450 mg of agomelatine has been documented; recovery occurred spontaneously without cardiovascular or biological abnormalities.

Treatment

There are no known 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.

Adverse Reactions

Summary of safety profile

Adverse reactions generally occurred during the first 2 weeks of treatment and were mild or moderate in severity. The most commonly reported adverse reactions were headache, nausea, and dizziness. These adverse reactions were generally transient in nature and usually did not lead to discontinuation of therapy.

List of adverse reactions

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

The adverse reactions are listed below by 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 is not adjusted for the placebo group.

* Frequency of adverse reactions identified from spontaneous reporting data was calculated based on clinical trial data.

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

Suspected adverse reactions reporting

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are requested to report all suspected adverse reactions and/or lack of efficacy of the medicinal product via the automated pharmacovigilance information system at: 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 special temperature requirements. Keep out of reach and sight of children.

Packaging

14 tablets per blister, 2 blisters per cardboard pack.

Prescription status

Prescription only.

Manufacturer

Zentiva, k.s.

Manufacturer's address and location of its business operations

U Kabelovny 130, Dolni Mecolupy, Prague 10, 102 37, Czech Republic.

Marketing Authorization Holder

LLC "ZDRAVO".

Address of the Marketing Authorization Holder

54/19, Avtozavodska Street, Lit. A, Office, Kyiv, 04114, Ukraine.