Valdoxan (Agomelatine) - Empathy - mental health center

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.

Valdoxan

Pharmacodynamics

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

Agomelatine enhances the release of dopamine and norepinephrine, especially in the prefrontal cortex and does not affect the concentration of extracellular serotonin. In experimental studies in animals with circadian rhythm desynchronization, agomelatine was 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.

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

In a 3-week controlled study 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.

Pharmacokinetics

Suction

After oral administration, agomelatine is rapidly (≥80%) absorbed from the gastrointestinal tract. Cmax in plasma is achieved 1-2 hours after 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.

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.

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

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

Removal

Pharmacokinetics in special clinical situations

There are no data on racial differences in pharmacokinetic parameters.

Pharmacodynamics and pharmacokinetics

Agomelatine is a substance with an antidepressant effect aimed at validated models of depression and some other abnormalities in the activity of the nervous system. At the same time, drugs created on its basis do not have a strong negative effect on the activity of other body systems.

Taking agomelatine helps normalize sleep structure, lower body temperature and improve the release of melatonin . The drug can be used to treat nervous system disorders of varying degrees of complexity, therefore both short-term and long-term therapy is allowed.

As a result of internal administration, absorption occurs quite quickly and almost completely. The maximum concentration in plasma is achieved 1-2 hours after administration of the drug. When distributed within the body, the substance is almost completely bound to plasma proteins, regardless of the concentration of the drug, the age of the patient, or the presence of renal impairment. A fairly rapid elimination of the drug from the body was noted, mainly in the form of metabolites through the kidneys. A small part of the unchanged substance is also excreted in the urine.

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.

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

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 ratio of expected benefit to possible risk in patients with risk factors for developing liver dysfunction, such as:

- obesity/overweight/non-alcoholic fatty hepatosis, diabetes,

— alcoholism and/or alcohol abuse;

- taking medications that can cause liver dysfunction.

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 upper limit of normal (see section "Contraindications"). Caution should be exercised when prescribing Valdoxan® to patients with initially elevated transaminase activity (above the upper limit of normal, but not more than 3 times the upper limit of normal).

· 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, a repeat test should be performed 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 the upper limit of normal.

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 (aged 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 and Administration” and “Pharmacological Properties”).

Elderly patients with dementia

Valdoxan® 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 disorders, manic or hypomanic episodes. If symptoms of mania appear, you should stop taking the drug (see section "Side effects").

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 25 years of age 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 the concentration of agomelatine (see sections “Contraindications” and “Interaction with other drugs and other types of 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 machinery

No studies have been conducted to study the effect of 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.

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 (tablets)

She wrote that the treatment prescribed by the gastroenterologist did not help, and the diagnosis of pancreatitis was clearly erroneous.
Mountains of expensive tablets for restoring intestinal microflora, digestive enzymes, tablets for gastritis. All this could be listed for a very long time. I took the pills like pacifiers, they were practically of no use. I was diagnosed with MS already when it became clear that standard treatment for gastritis and pancreatitis did not help me at all. To be honest, I don’t remember who exactly diagnosed me with this, the local internist or the gastroenterologist, but no treatment as such was prescribed. I myself looked on the Internet, reading forums, for medications that could help me. There were not many of them, only two: Trimedat and Iberogast.

Gradually, neurosis was added to IBS, and insomnia was added to its background. And so, when I again went to the local therapist and outlined everything that was bothering me, I was finally asked not to take another pill, but to visit a psychotherapist. Which, in general, I did with “joy.” I can’t say that I immediately ran to him, I pulled him, of course, but in the end I got there. And I came to a regular regional mental health center for an appointment with a psychiatrist. But it all started with a churning in the stomach

The diagnosis was: prolonged depression and irritable bowel syndrome. What was the cause and what was the effect remains a mystery. But treatment was necessary.

For this purpose, Valdoxan was prescribed to me. Antidepressant of the latest generation, with the active substance agomelatine.

The drug is produced in France.

According to the doctor, this drug has a mild effect, does not have a negative effect on the liver, and does not contribute to weight gain. In addition to IBS, I was very worried about poor sleep. I fell asleep, but woke up every hour. The dream was superficial and disturbing. In the morning I was completely exhausted and walked around sleepy all day. Valdoxan, according to the doctor, was supposed to improve sleep.

The prescription for the pills was written out and I was on my way to the pharmacy. It will probably be problematic to buy Valdoxan without a doctor's prescription. I was personally impressed by the cost of the drug. A pack costs about 2 thousand. It contains 28 tablets. For the first 10 days I took one tablet an hour before bed. Then the dose was increased to 2 tablets. It would cost 4,000 rubles a month just for these pills. A little expensive, however , but I can say I was lucky, if you can talk about luck in such a situation. Because I was treated at a state clinic, they issued me a prescription to receive the drug Valdoxan free of charge under a regional benefit. I only bought the first 2 packs with my own money (the recipe took a month to complete), then I received it for free.

As I already said, for the first 10 days I took Valdoxan one tablet 15-20 minutes before going to bed. For the first 3-4 days, the hypnotic effect was pronounced. I was literally knocked off my feet. I barely had time to wash off my makeup and collapse into bed. But my sleep didn’t last as long as I would have liked. Having fallen asleep at 11 pm, I could wake up at 4 am and stare at the ceiling for a couple of hours. Having learned that I was still not sleeping soundly, the dose of Valdoxan was increased to 2 tablets per day. Plus, the drug Teraligen was added to it (1 tablet before bedtime).

These are the remains of my drug. Very conveniently made. Especially for the absent-minded and forgetful.

Gradually (1-2 months), my sleep improved. The mood also became more joyful. Tearfulness has almost completely disappeared. But things weren’t going so well with Srk. Immediately after starting to take Valdoxan, all his symptoms disappeared. But the joy did not last long. Two weeks later, all the unpleasant sensations returned again. Plus a state of incomprehensible anxiety and a feeling of fear in the morning...:(

I complained to the attending physician that the main problem had not gone away, but she did not advise me to stop taking the drug. The minimum course of antidepressants is six months, and in my case, according to her, at least a year.

As a result, I took Valdoxan for 5 months and when it became clear that the effect was minimal, I was sent for a consultation with another psychotherapist. When I complained to him about anxiety and remaining stomach troubles, he immediately stopped Valdoxan for me and prescribed another drug - Rexetine. Valdoxan, he said, was too weak for me.

Now I continue treatment, now with Rexetine. I give Valdoxan 4- (3+) points. Still, he helped me in some way. There were no side effects, including excess weight. Therefore I can recommend it. Be sure to listen to your doctor and do not self-medicate. I wish everyone health and good mood, and then no antidepressants will be needed

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.

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.

Interaction

The simultaneous use of this drug and various isoenzyme inhibitors, for example, fluvoxamine, Ciprofloxacin , leads to a significant slowdown in the metabolism of agomelatine , and accordingly to an increase in its concentration. Therefore, simultaneous therapy with these drugs is contraindicated.

Also, Rifampicin , which takes part in the metabolism of agomelatine, can reduce its bioavailability. This can also occur in patients who abuse smoking. As for the potential effect of agomelatine on other types of drugs, it is insignificant or not fully studied.

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.

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.

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:

- 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

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.

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.

Valdoxan®

Liver function monitoring

Cases of liver damage (including liver failure, increases in liver enzyme levels more than 10 times the ULN, hepatitis and jaundice) have been reported in patients taking Valdoxan® in the post-marketing period. 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.

It is recommended to monitor liver function at the beginning of therapy and then periodically, after 3 weeks, after 6 weeks (end of the relief period of therapy), 12 weeks and 24 weeks (end of the maintenance period of therapy) after the start of therapy, and thereafter in accordance with the clinical situation. When increasing the dose, liver function should be monitored at the same frequency as at the beginning of the drug.

If the activity of transaminases in the blood serum increases, a repeat test should be performed within 48 hours. If the activity of transaminases is more than 3 times higher than the ULN, the drug should be discontinued. In the future, the functional state of the liver should be regularly monitored until transaminase activity normalizes.

If you experience 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), Valdoxan should be stopped immediately.

Caution should be exercised when prescribing Valdoxan® to patients with elevated transaminase activity before starting therapy (above the ULN, but not more than 3 times the ULN).

Caution should be exercised when prescribing Valdoxan® to patients with risk factors for developing liver dysfunction, such as obesity/overweight/non-alcoholic fatty liver disease, diabetes mellitus, drinking significant amounts of alcohol, or taking medications that can cause liver dysfunction.

Elderly patients

The effectiveness of the drug in elderly patients (aged 65 years and older) has not been established. There is limited data on the use of Valdoxan® for major depressive episodes in patients aged 65 years and older. When prescribing the drug to elderly patients, caution should be exercised.

Patients with kidney failure

In patients with severe renal failure, no significant changes in pharmacokinetic parameters were observed. However, experience with the use of the drug for major depressive episodes in patients with moderate or 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 disorders, manic or hypomanic episodes. If symptoms of mania appear, you should stop taking the drug.

Suicide/suicidal behavior

Combined use with CYP1A2 isoenzyme inhibitors

Caution should be exercised when using agomelatine simultaneously with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, grepafloxacin, enoxacin) due to the possibility of increasing the concentration of agomelatine.

Impact on the ability to drive vehicles and operate machinery

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.

Instructions for Valdoxan (Method and dosage)

The tablets are intended to be taken orally, regardless of food, whole - without crushing or chewing. If the next dose of the drug was missed, then no additional medication is required, and the next tablet is taken as usual.

At the same time, the instructions for use of Valdoxan indicate that you need to take 25 mg or 1 tablet daily. If there is no improvement within 2 weeks, it is possible to increase the dosage as prescribed by the doctor.

During treatment, it is necessary to monitor liver function at the initial stage, then periodically throughout therapy. The average treatment course is 6 months or until the unwanted symptoms completely disappear.