Valdoxan, 14 pcs., 25 mg, film-coated tablets

pharmachologic effect

Pharmacodynamics
Antidepressant, agonist of melatonergic MT1 and MT2 receptors and antagonist of serotonin 5-HT2c receptors.

Agomelatine is active in validated models of depression (learned helplessness test, despair test, moderate chronic stress), as well as in models with desynchronization of circadian rhythms, as well as in experimental situations of anxiety and stress. It has been shown that agomelatine does not affect the uptake of monoamines and has no affinity for α-, β-adrenergic receptors, histaminergic receptors, cholinergic, dopaminergic and benzodiazepine receptors.

Agomelatine enhances the release of dopamine and norepinephrine, especially in the prefrontal cortex and does not affect the concentration of extracellular serotonin. In animal experiments with circadian rhythm desynchronization, agomelatine has been shown to restore circadian rhythm synchronization through stimulation of melatonin receptors.

Agomelatine helps restore normal sleep structure, reduce body temperature and release melatonin.

The effectiveness of short-term use of agomelatine (therapy for 6-8 weeks) in doses of 25-50 mg in patients with major depressive episodes has been shown.

Agomelatine has also been shown to be effective in patients with more severe forms of depressive disorder (Hamilton scale score ≥25).

Agomelatine was also effective for initially high levels of anxiety, as well as for combined anxiety and depressive disorders.

The supporting antidepressant effect of agomelatine was confirmed (with a study duration of 6 months) at a dose of 25-50 mg 1 time/day. The results of the study confirmed the anti-relapse effectiveness of agomelatine, which was assessed by the time until the onset of disease relapse (p=0.0001). The relapse rate in the group of patients taking agomelatine was 22%, in the placebo group - 47%.

Agomelatine was shown to be effective in 6 of 7 clinical studies (benefit (2 studies) or comparable efficacy (4 studies)) in heterogeneous populations of adult patients with depression compared with selective serotonin reuptake inhibitors (SSRIs)/selective norepinephrine reuptake inhibitors (SNRIs). ) (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). Antidepressant effect was assessed using the Hamilton scale (17-item version) as either a primary or secondary endpoint.

Agomelatine does not have a negative effect on alertness and memory; in patients with depression, agomelatine at a dose of 25 mg increases the duration of the slow-wave sleep phase without changing the number and duration of REM sleep phases. Taking agomelatine at a dose of 25 mg also promotes a faster onset of sleep with a decrease in heart rate and improved sleep quality (starting from the first week of treatment); however, there is no inhibition during the daytime.

When taking agomelatine, there was a tendency to reduce the frequency of sexual dysfunction (impact on arousal and orgasm).

Taking agomelatine has no effect on heart rate and blood pressure, does not cause sexual dysfunction, does not cause withdrawal syndrome (even with abrupt cessation of treatment) and addiction syndrome.

The effectiveness of agomelatine at a dose of 25-50 mg 1 time / day was confirmed in elderly patients (younger than 75 years) with depression during an 8-week clinical trial. There is no evidence of a significant effect in patients aged 75 years and older. The tolerability of agomelatine in elderly patients is comparable to that in young patients.

In a 3-week controlled trial of patients with major depressive disorder who were not responding to paroxetine (SSRI) or venlafaxine (SNRI), withdrawal syndrome was observed when switching from these antidepressants to agomelatine. Withdrawal syndrome appeared both after immediate cessation of treatment with previously prescribed SSRIs/SNRIs, and during their gradual withdrawal, which could be mistakenly taken as a manifestation of the low effectiveness of agomelatine at the initial stage of treatment.

The number of patients experiencing at least one withdrawal symptom 1 week after SSRI/SNRI discontinuation was lower in the long-dose taper group (gradually tapering the SSRI/SNRI dose over 2 weeks) than in the rapid taper group. dose (gradual reduction of SSRI/SNRI dose over 1 week), and than with immediate withdrawal: 56.1%, 62.6% and 79.8% of patients, respectively.

Patients suffering from chronic neurological diseases often have comorbid emotional disorders such as depression and anxiety. The results of a Russian epidemiological study [1] showed that approximately 24% of neurological patients have a definite depressive state, which significantly exceeds the prevalence of depression in the general population. Depression not only negatively affects the course of the underlying (neurological) disease, but also causes a decrease in the quality of life of patients and a decrease in their physical activity, which leads to increased healthcare costs for treatment and increases the risk of mortality. It was noted [3] that even a mild form of depression, complicating the course of a chronic neurological disease, is an independent risk factor for mortality not associated with suicide. Timely treatment of depression can improve the prognosis of the underlying disease and improve the patient’s quality of life.

Treatment of depression in a patient suffering from a chronic somatic illness is more complex than treatment of depression in somatically healthy individuals. There is an obvious need in this category of patients for more effective and fast-acting antidepressants with an improved tolerability profile. Side effects that often accompany antidepressant use lead to poor compliance and premature discontinuation of treatment, another factor that reduces the likelihood of recovery. An important aspect of therapy in these cases is the interaction of thymoanaleptic therapy with drugs aimed at eliminating the main manifestations of the neurological disease. In connection with the above, the newest antidepressants, in particular Valdoxan, are of particular interest.

Valdoxan (agomelatine) is an agonist of MT1 and MT2 melatonergic receptors and an antagonist of 5HT2c receptors [5]. The melatonergic effect of the drug ensures normalization of sleep, while interaction with serotonin 5HT2c receptors, which are related to the pathogenesis of depression, leads to increased release of norepinephrine and dopamine. Valdoxan has a favorable side effect profile, in particular, when using the drug, withdrawal syndrome does not develop, the drug does not cause sexual dysfunction and does not affect the patient’s body weight [2]. An overdose of the drug does not have fatal consequences.

There are still very few studies assessing the effectiveness and safety of Valdoxan in neurological practice. Therefore, there remains a need to clarify the clinical potential of Valdoxan in the treatment of depressive conditions in patients suffering from chronic neurological diseases.

The purpose of this study was to evaluate the therapeutic efficacy and tolerability of Valdoxan (agomelatine) in the treatment of mild to moderate depression associated with neurological diseases.

Material and methods

8 Russian clinical centers took part in the study, in each of which 30 to 35 patients were examined. A total of 277 patients aged from 18 to 70 years (mean: 46.0±11.3 years) were included in the study. Among them were 21.66% men and 76.53% women.

All patients included in the study met the following criteria: 1) the presence of one of three categories of neurological diseases (cerebrovascular diseases, neurocirculatory dystonia, chronic pain syndrome); 2) at least 2 main symptoms for a depressive episode of mild severity (F32.0) and 4 for a depressive episode of moderate severity (F32.1), as well as additional symptoms of depression according to ICD-10 criteria, provided their duration is at least 2 week; 3) score from 8 to 24 (inclusive) points on the Hamilton Depression Scale (HAMD-17); 4) from 3 to 4 points on the clinical global impression scale - CGI-S; written informed consent of the patient to participate in the observational study.

The criteria for excluding patients from the study were: 1) presence of suicidal risk (i.e., more than 2 points on item 3 of the HAMD-17 scale and/or according to the clinical assessment of the investigator); 2) the presence of psychotic symptoms (according to the clinical assessment of the attending physician); 3) severe or decompensated somatic or neurological diseases; 4) liver failure; 5) a history of previously established individual intolerance or ineffectiveness of Valdoxan (agomelatine) when the drug was prescribed in an adequate dose (at least 25 mg per day) and for the proper duration (at least 4 weeks); 6) resistance to therapy with other antidepressants.

Valdoxan was prescribed in the evening at a starting therapeutic dose of 25 mg (1 tablet) once a day for 6 weeks. In the absence of a satisfactory initial therapeutic effect, the dose was allowed to be increased to 50 mg per day (2 tablets), starting from the 10-14th day of therapy.

To assess the effectiveness of therapy, standard psychometric instruments were used: the 17-item Hamilton Depression Scale (HAMD-17), the Hospital Anxiety and Depression Scale (HADS), the LEEDS sleep questionnaire, the Fatigue Scale (FSS), the Clinical Global Impression Scale. to assess disease severity (CGI-S) and improvement (CGI-I), Schulte test. Tolerability of Valdoxan therapy was determined based on adverse events recorded throughout the study period, as well as laboratory monitoring of basic liver function indicators (AST, ALT, alkaline phosphatase, total bilirubin).

results

Among the patients included in the study, people of working age predominated, ¾ (76.5%) of patients were aged from 30 to 59 years; 68.59% of patients maintained professional employment. Half of the patients (55.60%) had higher education. Women in the study sample dominated over men - 3:1. Most of the patients were quite prosperous socially, in particular, ⅔ (65.34%) of them were married. Thus, under our supervision there were mainly socially adapted patients.

Based on the underlying neurological disease, patients were relatively evenly distributed across 3 nosological categories (inclusion criterion 1) (Table 1).

In most cases, the underlying neurological disease had a chronic course (average duration was 6 years). In addition to the main neurological disorder, 56.68% of patients had concomitant somatic diseases, among which the leading position was occupied by arterial hypertension, observed in 28.52% of patients. According to the CGI-S scale, the majority (64.62%) of patients had a moderate condition before treatment. Throughout the study, patients continued to receive therapy for the underlying neurological and/or concomitant somatic disease.

According to the researchers, depression accompanying the underlying neurological disease was mild in 117 (42.24%) patients and had a moderate severity in 160 (57.76%) patients. The average total depression score on the HAMD-17 scale was 15.3±3.8 points. The total score on the self-rated hospital depression scale HADS-D was 9.7±3.3 points, which corresponds to subclinical depression. At the same time, the average anxiety score on the HADS-A hospital anxiety scale was 11.0±3.5, which corresponds to clinically significant anxiety, which was present in 56.02% of patients.

The leading clinical symptoms of depression in the examined patients were sleep disturbances, fatigue or decreased activity, as well as low mood, which were observed in almost 90% of patients. At the same time, food and sexual motivation were rarely violated, which was apparently due to selection conditions (exclusion of patients with severe depression). The distribution of common and rare symptoms of depression is shown in Table. 2.

One of the leading complaints (in addition to mood disorders) was fatigue, which was subjectively assessed on average in the group as a severe symptom - 4.5 ± 1.15 points on the FSS scale. Patients' subjective assessment of the severity of fatigue correlated with objective indicators of stability of attention and performance according to the Schulte test. Thus, the average work efficiency for the group was 51.6±20.3 s, which corresponds to 2 points on a 5-point scale. The indicator of the degree of workability on average for the group was 1.01±0.13 units. If the workability coefficient corresponds to a level of 1.0 or higher, it indicates that the subject spends more time preparing for the main job than is normally required. The coefficient of mental stability (endurance) of patients to perform tasks also exceeded the normative indicators (less than 1.0) and amounted to 1.0+0.11 units.

Almost half (55.59%) of the patients had been treated with psychotropic drugs within the last year before inclusion in the study; 30.32% of patients used herbal drugs and 14.44% used tranquilizers, 7.94% had experience taking antidepressants. This indirectly indicates the low commitment of neurologists to prescribing specific therapy to patients with depression.

At the time of inclusion in the study, 16.61% were receiving inpatient treatment and 82.31% were receiving outpatient treatment. 11 (3.97%) patients dropped out of the study prematurely. Among the reasons for the premature withdrawal of these patients from the study were “patient refusal to further participate” and “ineffectiveness of therapy” - in 36.36% of patients, “adverse events” - in 63.64%. In the group as a whole, adverse events leading to discontinuation of treatment were observed in 7 (2.53%) patients. Their list is presented in table. 3.

Among patients who completed the study, only 10.53% of patients required an increase in the dose of Valdoxan to 50 mg. The majority (89.47%) of patients, according to doctors, responded well to the initial dose of the drug (25 mg) and in these cases there was no need to increase the dose during treatment.

The effectiveness of Valdoxan therapy

. Already after the 1st week of therapy, a significant decrease in the total score on the HAMD-17 scale was observed. The total score for it after 1 week of therapy decreased from 15.4±3.8 to 12.7±4.3 (p<0.00001). After completion of the course of therapy (after 6 weeks of treatment), the score was 4.7±3.2 points. According to the generally accepted interpretation of HAM-D results, a patient is not depressed if the total score does not exceed 7 points. Thus, by the end of treatment, in the overwhelming majority (81.20%) of patients, depressive symptoms were relieved. It is important to note that in half (55.26%) of the patients, relief of depressive symptoms occurred after 4 weeks of treatment. The dynamics of depression regression according to the HAMD-17 scale are presented in Fig. 1.

After 6 weeks of therapy, responders (patients whose score on the HAMD-17 scale decreased by at least 2 times) accounted for 82.33% of all treated patients. The appearance of responders was noted after the 1st week of therapy, and then their proportion steadily increased.

Similar results of the effect of therapy were noted on the HADS-D scale. The total score on this scale decreased statistically significantly after the 1st week of therapy (8.8±3.4 versus 9.7±3.3 points before treatment, p<0.00001); after 6 weeks it was 4.3±3.1 points (p<0.00001), and complete reduction of depressive symptoms was achieved in 83.46% of patients.

Valdoxan also had a good effect on the anxiety component of depression. The onset of the anti-anxiety effect appeared already in the 1st week of treatment. The total score on the hospital anxiety scale - HADS-A decreased statistically significantly after the 1st week of therapy (9.6±3.4 versus 11.0±3.5 points before treatment, p<0.00001); after 6 weeks of therapy, it was 4.8±3.1 points (p<0.00001), and a complete reduction of anxiety symptoms was achieved in 80.83% of patients. More than ⅔ (73.68%) of patients had neither anxiety nor depressive symptoms after completing the course of therapy.

Evaluation of the effectiveness of Valdoxan using the CGI-I scale showed that a pronounced improvement in the condition of patients and a very pronounced improvement (5 and 6 points) was achieved in (34.96%) patients after 2 weeks of treatment, in 58.65% of patients - after 4 weeks of treatment. After completion of the course of treatment, a pronounced improvement in the patients’ condition and a very pronounced improvement (5 and 6 points) was noted in 78.95% of patients; small (4 points) - in 15.41% of patients. There were no changes in condition (3 points) in 1.13% of patients, and only 1 (0.38%) patient experienced some deterioration in condition (2 points).

Under the influence of the therapy, a reduction in the functioning of patients was also observed. In particular, after a course of therapy with Valdoxan, the average degree of fatigue on the FSS scale was 2.67±1.55 versus 4.48±1.15 points before the start of therapy (p<0.00001). Thus, after completion of the course of treatment, clinically significant fatigue regressed in patients. Moreover, a significant trend of positive dynamics was observed after the 1st week of therapy. An objective assessment of work capacity using the Schulte test showed that work efficiency significantly improved under the influence of Valdoxan therapy. After the course of therapy with Valdoxan, the average work efficiency for the group was 45.0±11.7 s versus 52.0±20.6 s before the start of therapy (p<0.00001), which corresponds to an improvement in work efficiency up to 3 points out of 5 -point scale (before treatment, work efficiency was 2 points). In addition, under the influence of the treatment, the coefficient of mental stability (endurance) of patients to perform tasks reached standard indicators; it amounted to 0.989±0.098 units (normally the indicator should be less than one). The described positive dynamics were observed regardless of the nature of the underlying neurological disease.

Multidimensional assessment of subjective sleep parameters using the LEEDS scale showed that sleep improvement was observed after the 1st week of treatment and reached a maximum by the end of the course of therapy. At the same time, positive changes were noted in all analyzed sleep parameters.

Valdoxan had the most pronounced positive effect on the function of falling asleep. Also noteworthy is the subjective decrease in night awakenings and an increase in the feeling of vigor during the day.

Unlike most hypnotic drugs, Valdoxan did not have a negative effect on balance function and coordination of movements after awakening.

The overall assessment of the effectiveness of Valdoxan therapy, carried out by doctors and patients, had a general direction with the prevailing assessment of “excellent effect” (Fig. 2).

More than 95% of patients completely completed the study, indicating high adherence to treatment with Valdoxan. Also, adherence is evidenced by the desire of 84.59% of patients to continue taking Valdoxan. Doctors recommended continuing treatment with Valdoxan to 87.22% of patients.

Safety of Valdoxan therapy

. Doctors and patients highly rated the tolerability of Valdoxan therapy. Doctors noted excellent (no adverse reactions) tolerability of the drug in 78.95% of patients. In none of the patients did doctors assess the tolerability of Valdoxan therapy as poor and did not note serious adverse events. Among the patients, more than half (69.55%) also rated the tolerability of Valdoxan as excellent. Information about adverse events was included in the charts of 56 patients (20.22% of the 277 patients included in the study). All adverse events occurred with a frequency of less than 5%. The most common side effects (range: 5%) recorded during the study are presented in Table. 4.

Objectively, Valdoxan did not have any effect on blood pressure and heart rate. There were also no statistically significant changes in body weight during therapy. During the period of taking Valdoxan, the following biochemical parameters significantly increased: total bilirubin, AST, ALT, but their fluctuations remained within normal limits.

Discussion

The results of short-term (6 weeks) therapy with Valdoxan in patients with mild and moderate depression in the studied neurological diseases indicate its high therapeutic activity: the number of responders among patients who completed the study was 82.33%. Additional evidence was obtained of the rapid development of the thymoanaleptic and anxiolytic effects of Valdoxan, the first significant signs of which were recorded already in the 1st week of therapy. Such a quickly realized effect may be associated with the special mechanism of action of Valdoxan, which fundamentally distinguishes it from all other modern antidepressants.

The study once again demonstrated the clinical features of comorbid mental pathology in neurological diseases.

First of all, this concerns anxiety symptoms and the prevalence of such nonspecific symptoms as sleep disturbances and increased fatigue, which, according to the literature, are difficult to treat and, if they persist for a long time, can be the basis for the formation of a relapse of depression. At the same time, the previously established [6] effect of Valdoxan on anxiety was confirmed. The results of this study showed that the level of anxiety in patients progressively decreased throughout the course of therapy, and by the final visit, a complete reduction of anxiety symptoms was achieved in 80.83% of patients.

Disturbance of sleep structure can be considered as a target symptom when choosing Valdoxan. Valdoxan is the first drug whose antidepressant effect is realized through the normalization of circadian rhythms. The high effectiveness of Valdoxan is largely due to its dual effect on the biological mechanisms of depression. The action of Valdoxan as an agonist to melatonin receptors allows it to influence chronobiological disorders (in particular, normalize the sleep-wake cycle), while antagonism to 5-HT2C receptors allows it to activate neurotransmitter systems. Clinical studies show that, despite the antidepressant effect comparable to other drugs, Valdoxan causes a faster and more pronounced improvement in the indicators of “awakening” and “sleep quality”. The results also showed a subjective decrease in nighttime awakenings (the greatest improvement) and an increase in feelings of alertness during the day.

In addition, an additional mechanism of action of Valdoxan is the indirect release of norepinephrine and dopamine in the frontal cortex, which suggests the drug is effective against cognitive impairment. The present study showed that, along with relieving the feeling of fatigue, patients’ work efficiency increases (including due to the cognitive component). It is important that under the influence of the treatment, the coefficient of mental stability (endurance) of patients to perform tasks reached standard indicators (data from the Schulte test).

Side effects of Valdoxan are few and mostly transient. The drug does not affect the function of the cardiovascular system and body weight.

Data on the evaluation of adverse events are fully consistent with the results of previous studies [4] and indicate a favorable tolerability and safety profile of Valdoxan in patients with depression associated with neurological diseases.

Such optimistic results of the effectiveness of Valdoxan obtained in the present study should motivate clinicians to expand the use of antidepressant therapy for the treatment of depression in neurological patients. Unfortunately, at present, the symptoms of depression are often ignored by clinicians, which inevitably leads to the formation of untreated chronic forms. The study showed that among the previously used psychotropic therapy in the patients included in the study, the leading position was occupied by herbal preparations (used in 30.32% of patients) and tranquilizers (used in 14.44% of patients). And only 7.94% of patients had experience taking antidepressants. These data indicate the need for further educational programs for neurologists in the treatment of patients with comorbid depression.

Pharmacokinetics

Suction

After oral administration, agomelatine is rapidly (≥80%) absorbed. Cmax in plasma is achieved 1-2 hours after oral administration. Absolute bioavailability after taking a therapeutic dose is low (<5%); interindividual variability is significant. Bioavailability is higher in women than in men. Bioavailability increases with oral contraceptives and decreases with smoking.

When the drug was prescribed in therapeutic doses, Cmax increased in proportion to the dose. When taken in higher doses, a more pronounced “first pass” effect through the liver was observed. Meal intake (both regular and high-fat) did not affect either bioavailability or extent of absorption. Interindividual variability increased when eating a high-fat diet.

Distribution

Vd in the equilibrium state was about 35 l. Plasma protein binding is 95%, regardless of drug concentration, age or the presence of renal failure.

In case of liver failure, a twofold increase in the free fraction of the drug was observed.

Metabolism

After oral administration, agomelatine undergoes rapid oxidation, mainly due to CYP1A2 and CYP2C9. The CYP2C19 isoenzyme is also involved in the metabolism of agomelatine, but its role is less significant.

The main metabolites in the form of hydroxylated and demethylated agomelatine are inactive, quickly bind and are excreted by the kidneys.

Removal

T1/2 from plasma is from 1 to 2 hours. Elimination occurs quickly. Metabolic clearance is about 1100 ml/min. Excretion occurs mainly by the kidneys (80%) in the form of metabolites. The amount of unchanged drug in the urine is insignificant. With repeated administration of the drug, the kinetics do not change.

Pharmacokinetics in special clinical situations

In patients with severe renal failure, a single dose of agomelatine at a dose of 25 mg did not significantly change the pharmacokinetic parameters. Due to limited clinical experience, caution should be exercised when prescribing agomelatine to patients with moderate to severe renal impairment.

When agomelatine was prescribed at a dose of 25 mg to patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) chronic liver failure against the background of liver cirrhosis, an increase in its plasma concentration by 70 and 140 times was noted , respectively, compared with volunteers matched for sex, age and smoking behavior, but without liver failure.

When agomelatine 25 mg was administered to elderly patients (65 years and older), it was noted that the mean AUC and mean Cmax were 4 times and 13 times higher, respectively, in patients aged 75 years and older compared with patients younger 75 years old. The total number of patients treated with the 50 mg dose was too low to draw any conclusions. No dose adjustment is required depending on age.

There are no data on racial differences in pharmacokinetic parameters.

Contraindications

- liver failure (for example, cirrhosis or active liver disease) or an increase in transaminase levels by more than 3 times relative to ULN (see sections “Dosage regimen” and “Special instructions”);

- simultaneous use of powerful inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) (see section “Drug interactions”);

- children under 18 years of age (due to lack of sufficient experience in clinical use). In children and adolescents taking other antidepressants, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggressiveness, conflict behavior, irritation) were observed more often compared to the placebo group;

- lactose intolerance (lactase deficiency, galactosemia and glucose-galactose malabsorption);

- hypersensitivity to agomelatine and/or any of the excipients of the drug (see section “Composition and release form”).

The drug should be prescribed with caution when treating major depressive episodes in patients with moderate to severe renal failure; when administering agomelatine with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin); patients with a history of manic or hypomanic episodes, patients with a history of events associated with suicide, as well as patients who had suicidal intentions before starting therapy.

Caution should be exercised when prescribing the drug to patients who abuse alcohol or take drugs that can cause liver dysfunction.

Dosage

The drug is prescribed orally. Valdoxan can be taken with or without food. The tablets should be swallowed whole without chewing.

If you miss taking the next dose of the drug, during the next dose Valdoxan is taken at the usual dose (you should not take the missed dose of the drug).

To improve control over taking the drug, a calendar is printed on the blister containing the tablets.

The recommended dose is 25 mg (1 tablet) 1 time/day before bedtime. In the absence of clinical dynamics after two weeks of treatment, the dose can be increased to 50 mg (2 tablets of 25 mg each) 1 time/day before bedtime.

The decision to increase the dose should be made taking into account the increasing risk of increased transaminase activity. The dose should be increased to 50 mg after assessing the benefits and risks for the individual patient and under strict monitoring of liver function tests.

Before starting therapy, liver function tests should be performed in all patients. Therapy cannot be started in patients with transaminase levels more than 3 times the upper limit of normal (see sections “Contraindications” and “Special Instructions”). During treatment, liver function should be monitored periodically at approximately 3 weeks, approximately 6 weeks (end of the treatment period), approximately 12 weeks and 24 weeks (end of the maintenance period) after the start of therapy, and thereafter according to the clinical situation. (see section "Special instructions"). If transaminase activity is more than 3 times the upper limit of normal, the drug should be discontinued (see sections “Contraindications” and “Special Instructions”).

When increasing the dose, liver function should be monitored at the same frequency as at the beginning of the drug.

Duration of treatment

Drug therapy for depression should be continued for at least 6 months until symptoms of depression completely disappear.

Switching from SSRI/SNRI therapy to agomelatine therapy

Withdrawal syndrome is possible after stopping SSRIs/SNRIs.

To reduce the risk of withdrawal syndrome after stopping treatment with previously prescribed SSRIs/SNRIs, you must follow the instructions for medical use of these drugs.

Taking agomelatine can be started on the 1st day of gradually reducing the dose of SSRI/SNRI antidepressants (see section “Pharmacodynamics”).

Stopping treatment

If treatment is stopped, there is no need to gradually reduce the dose.

Elderly patients

The effectiveness and safety of agomelatine (at a dose of 25-50 mg/day) has been confirmed in elderly patients (younger than 75 years) with depression. There is no evidence of a significant effect in patients aged 75 years and older. In this regard, Valdoxan should not be prescribed to patients of this age group (see sections “Special instructions” and “Pharmacological action”). No dose adjustment is required depending on age (see section “Pharmacological action”).

Patients with kidney failure

In patients with severe renal failure, no significant changes in pharmacokinetic parameters were observed. Experience with the use of Valdoxan for major depressive episodes in patients with moderate to severe renal failure is limited. When prescribing Valdoxan to such patients, caution should be exercised (see section "Special Instructions").

Patients with liver failure

Valdoxan is contraindicated in patients with liver failure (see sections “Contraindications”, “Special instructions” and “Pharmacokinetics”).

Valdoxan price, where to buy

This drug can be bought in Moscow, in almost any pharmacy. At the same time, the price of Valdoxan varies from 1670 to 2060 rubles.

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Side effects

In clinical studies, Valdoxan was administered to more than 7,900 patients with depression. Side effects were most often mild or moderate and were observed in the first 2 weeks of treatment. The most common symptoms were nausea and dizziness. The observed side effects were usually transient and generally did not require discontinuation of treatment.

The frequency of side effects of agomelatine is given in the following gradation: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/100). 10,000, <1/1000); very rare (<1/10,000), unspecified frequency.

From the side of the central nervous system: often - headache, dizziness, drowsiness, insomnia, migraine; infrequently - paresthesia, restless legs syndrome*.

Mental disorders: often - anxiety; uncommon - agitation and associated symptoms*, such as irritability and restlessness, aggressiveness*, nightmares*, unusual dreams*; rarely - mania/hypomania* (these symptoms may also be a manifestation of the underlying disease (see section “Special Instructions”)), hallucinations*; unspecified frequency - suicidal thoughts or suicidal behavior (see section "Special instructions").

From the gastrointestinal tract: often - nausea, diarrhea, constipation, abdominal pain, vomiting*.

From the hepatobiliary system: often - increased activity of ALT and/or AST (more than 3 times compared to ULN in 1.4% of patients while taking agomelatine at a dose of 25 mg per day and in 2.5% of patients when taking agomelatine at a dose of 50 mg per day, compared to 0.6% with placebo in clinical studies); rarely - hepatitis, increased gamma-GGT* activity (more than 3 times compared to ULN), increased ALP activity* (more than 3 times compared to ULN), liver failure*(1), jaundice*.

From the skin and subcutaneous tissue: often - sweating; uncommon - eczema, skin itching*, urticaria*; rarely - erythematous rash, facial swelling and angioedema*.

On the part of the hearing organ: infrequently - tinnitus.

From the side of the organ of vision: infrequently - blurred vision.

From the musculoskeletal system: often - back pain.

General disorders: often - fatigue.

Data from additional examinations: rarely - weight gain, weight loss.

* — the frequency of adverse reactions identified by spontaneous reports was assessed based on data from clinical studies.

(1) Only a few cases of death or liver transplantation have been reported in patients with preexisting risk factors for liver disease.

Side effects

As a rule, the manifestation of side effects is observed at the very beginning of treatment. Patients are especially often concerned about: nausea, dizziness, drowsiness, headache, insomnia, fatigue, anxiety, sweating, and so on. All these symptoms are not severe and usually do not require additional treatment. Gradually their manifestation decreases and completely disappears.

Overdose

Data on agomelatine overdose are limited.

Symptoms: drowsiness, epigastric pain, restlessness, weakness, anxiety, agitation, tension, dizziness, cyanosis, malaise. When the patient took agomelatine at a dose of 2450 mg, the condition returned to normal independently, without disturbances in the cardiovascular system or changes in laboratory parameters.

Treatment: Specific antidotes for agomelatine are not known. Symptomatic treatment and monitoring are carried out in specialized departments with subsequent observation.

Drug interactions

Potential influence of other medicinal products

Agomelatine is metabolized 90% in the liver with the participation of cytochrome P450 1A2 (CYP1A2) and 10% by CYP2C9/19. Therefore, any drugs whose metabolism depends on these isoenzymes may increase or decrease the bioavailability of agomelatine.

Fluvoxamine is a strong inhibitor of the CYP1A2 isoenzyme and a moderate inhibitor of the CYP2C9 isoenzyme and significantly slows down the metabolism of agomelatine, while the concentration of agomelatine increases approximately 60 (12-412) times. Therefore, the simultaneous use of agomelatine and strong inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) is contraindicated.

The simultaneous administration of agomelatine and estrogens, which are moderate inhibitors of the CYP1A2 isoenzyme, leads to an increase in the concentration of agomelatine several times. Although the combined use of agomelatine and estrogens was not accompanied by a deterioration in the safety profile of the therapy, caution should be exercised when co-prescribing agomelatine with other moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) until sufficient clinical experience has been gained (see section "Special Instructions").

Rifampicin, as an inducer of both cytochromes involved in the metabolism of agomelatine, can reduce the bioavailability of agomelatine. It has been shown that smoking, by inducing the CYP1A2 isoenzyme, reduces the bioavailability of agomelatine, especially in patients who smoke excessively (≥15 cigarettes/day) (see section “Pharmacokinetics”).

Potential effects of agomelatine on other medicinal products

In vivo, agomelatine does not induce cytochrome P450 isoenzymes. Agomelatine does not inhibit the CYP1A2 isoenzyme in vivo or other cytochrome P450 isoenzymes in vitro. Therefore, agomelatine does not affect the concentration of drugs whose metabolism is associated with these isoenzymes.

Drugs that are significantly bound to plasma proteins

Agomelatine does not change the free concentration of drugs that are significantly bound to plasma proteins and, in turn, they do not affect the concentration of agomelatine.

Other medicines

There was no pharmacokinetic and pharmacodynamic interaction between agomelatine and drugs commonly used in the target patient population: benzodiazepines, lithium, paroxetine, fluconazole and theophylline.

Alcohol

The use of agomelatine in combination with alcohol is not recommended.

Electroconvulsive therapy (ECT)

There are no data on the use of agomelatine concomitantly with electroconvulsive therapy (ECT). Since agomelatine did not cause seizures in animal studies, adverse effects from the combined use of agomelatine and ECT seem unlikely.

Reviews about Valdoxan

This remedy is quite often used in clinical practice. At the same time, its mild but effective effect was noted. Some patients report that the treatment was quite successful, without unwanted symptoms or intolerance reactions.

However, there are also reviews of Valdoxan when patients were bothered by: a feeling of nausea , attacks of aggression , and a lack of appetite . Such symptoms persisted not only at the initial stage, so it was necessary to change the drug.

In any case, the choice of an antidepressant must be approached with special responsibility and only take drugs prescribed by a specialist in a certain dosage.

special instructions

Liver function monitoring

Cases of liver damage have been reported, including liver failure (leading in exceptional cases to death or requiring liver transplantation in patients with pre-existing risk factors for liver damage), elevation of liver enzymes more than 10 times the upper limit of normal, hepatitis and jaundice in patients taking Valdoxan during the post-registration period (see section "Side effects"). Most of these disorders occurred in the first months of treatment. The nature of liver damage appears to be primarily hepatocellular. As a rule, after cessation of therapy, transaminase levels returned to normal values.

Caution should be exercised before starting treatment and close monitoring during treatment in all patients, especially those with risk factors for liver disease or those receiving concomitant therapy with drugs that can cause liver damage.

Before starting therapy

Treatment with Valdoxan should be prescribed only after a careful assessment of the expected benefit to possible risk in patients with risk factors for liver dysfunction, such as obesity/overweight/non-alcoholic fatty liver disease, diabetes, alcohol abuse and taking drugs that can cause liver dysfunction liver.

Before starting therapy, liver function tests should be performed in all patients, and therapy cannot be started if the level of liver enzymes ALT and/or AST is more than 3 times the ULN (see section "Contraindications").

Caution should be exercised when prescribing Valdoxan to patients with initially elevated transaminase activity (above ULN, but not more than 3 times relative to ULN).

Frequency of liver function tests:

- before starting therapy;

and further:

- in approximately 3 weeks,

- after approximately 6 weeks (end of the stopping period of therapy),

- after approximately 12 and 24 weeks (end of the maintenance period of therapy),

- in the future - in accordance with the clinical situation.

When increasing the dose, liver function should be monitored at the same frequency as at the beginning of therapy.

If the activity of transaminases in the blood serum increases, the test should be repeated within 48 hours.

During treatment

Treatment with Valdoxan should be stopped immediately if:

- the appearance of symptoms and signs of possible liver dysfunction (such as dark urine, discolored stools, yellow skin/eyes, pain in the right upper abdomen, new persistent and unexplained fatigue);

- increase in transaminase levels by more than 3 times compared to ULN.

After discontinuation of therapy with Valdoxan, liver function tests should be performed regularly until transaminase levels normalize.

Elderly patients

The effectiveness of the drug in elderly patients (75 years and older) has not been established. In this regard, Valdoxan should not be prescribed to patients in this age group (see sections “Dosage regimen” and “Pharmacological action”).

Elderly patients with dementia

Valdoscan should not be prescribed for the treatment of major depressive episodes in elderly patients with dementia (due to the lack of data on the effectiveness and safety of the drug in this group of patients).

Patients with kidney failure

In patients with severe renal failure, no significant changes in pharmacokinetic parameters were observed. However, experience with the use of Valdoxan for major depressive episodes in patients with moderate to severe renal failure is limited. When prescribing Valdoxan to such patients, caution should be exercised.

Bipolar disorders/mania/hypomania

Caution should be exercised when using Valdoxan in patients with a history of bipolar disorder, manic or hypomanic episodes. If symptoms of mania appear, you should stop taking the drug.

Suicide/suicidal behavior

People who are depressed have an increased risk of suicidal ideation, self-harm, and suicide (suicide-related events). The risk remains until a clear remission occurs. Patients should be under medical supervision until the condition improves (after starting therapy, it may take several weeks for the condition to improve). Clinical experience suggests that the risk of suicide may increase in the early stages of remission.

Patients with a history of events associated with suicide, as well as patients who had suicidal intentions before starting therapy, are at risk and should be under close medical supervision during therapy.

The results of a meta-analysis of clinical trials of antidepressants in patients with mental disorders indicate an increased risk of suicidal behavior in patients under the age of 25 years while taking antidepressants compared with placebo.

During the treatment period, patients, especially those at risk, should be under close medical supervision, especially at the beginning of therapy and when changing the dose of the drug. Patients (and their caregivers) should be advised to seek immediate medical attention if their condition worsens, if they experience suicidal or unusual behavior, or if they experience suicidal thoughts.

Combined use with CYP1A2 isoenzyme inhibitors

Caution should be exercised when using agomelatine simultaneously with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) due to the possibility of increasing agomelatine concentrations (see sections “Contraindications” and “Drug Interactions”).

Patients with lactose intolerance

The drug should not be used in patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption (see section “Contraindications”).

Impact on the ability to drive vehicles and operate machinery

No studies have been conducted to study the effect of the drug Valdoxan on the ability to drive a car or use other mechanisms. It should be remembered that dizziness and drowsiness are common side effects of agomelatine.

Pregnancy and lactation

There are no or limited data on the use of agomelatine during pregnancy (less than 300 pregnancy outcomes).

Animal studies have not revealed direct or indirect harmful effects on pregnancy, embryonic and fetal development, labor and postnatal development. As a precaution, it is recommended to avoid prescribing Valdoxan during pregnancy.

It is not known whether agomelatine passes into breast milk in women during lactation. Experimental studies in animals have shown that agomelatine and its metabolites pass into breast milk. If treatment with agomelatine is necessary, breastfeeding should be discontinued.

Analogues of Valdoxan

Level 4 ATC code matches:
Pipofezin

Bethol

Incazan

Melitor

Azafen

Miaser

Velafax

Mirtazonal

Venlaxor

Remeron

Venlafaxine

Lerivon

Mirtazapine

Cymbalta

Velaxin

Coaxil

Pyrazidol

Deprim

Gelarium Hypericum

Negrustin

The main analogue is Agomelatine . There are also other analogues of Valdoxan, for example – Adaptol and Paxil .