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.
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.
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.
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.
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.
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
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, grepafloxacin, enoxacin) due to the possibility of increasing the concentration of agomelatine.
Impact on the ability to drive vehicles and operate 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.
Overdose
In practical medicine, isolated cases of agomelatine . In this case, such undesirable symptoms arise as: drowsiness , stomach pain, restlessness, anxiety, weakness, tension, dizziness , and so on.
If the overdose is insignificant, then the condition will soon normalize on its own, without deviations in the activity of the cardiovascular and nervous systems, or disturbances in laboratory parameters.
If necessary, carry out symptomatic treatment and monitor the general condition of the patient.
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.
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.
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 .
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.
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.
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.
- Online pharmacies in RussiaRussia
- Online pharmacies in KazakhstanKazakhstan
ZdravCity
- Valdoxan tablets p.p.o.
25 mg 28 pcs. LLC Servier Rus 1352 rub. order
Pharmacy Dialogue
- Valdoxan tablets 25 mg No. 28 Serdix LLC
RUB 1,457 order
- Valdoxan (tablet p/o 25 mg No. 28)Servier Rus LLC
RUB 1,415 order
- Valdoxan (tablet p/o 25 mg No. 28)Servier Rus LLC
RUB 1,402 order
- Valdoxan tablets 25 mg No. 28Servier
RUB 1,402 order
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