Valdoxan [Agomelatine]

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Available since: 2019-09-19

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Clinical Pharmacology

Agomelatine is a melatoninergic receptor agonist MT1 and MT2 and an antagonist of serotonin 5-HT2C receptors. Agomelatine is an antidepressant that is active on validated models of depression (test of acquired helplessness, despair test, chronic stress of moderate severity), as well as on models with desynchronization of circadian rhythms, as well as in experimental situations of anxiety and stress. Agomelatine has not been shown to affect monoamine uptake and has no affinity for alpha, beta adrenergic, histaminergic, cholinergic, dopaminergic, and benzodiazepine receptors.
Agomelatine enhances the release of dopamine and noradrenaline, especially in the area of the prefrontal cortex and does not affect the concentration of extracellular serotonin. In animal experiments modeled with desynchronization of circadian rhythms, it was shown that agomelatine restores synchronization of circadian rhythms by stimulating melatonin receptors.
Agomelatine helps to restore normal sleep patterns, reduce body temperature and excrete melatonin.
The effectiveness of short-term use of agomelatine (therapy 6-8 weeks) in doses of 25-50 mg in patients with major depressive episodes has been shown. It also shows the effectiveness of agomelatine in patients with more severe forms of depressive disorder (Hamilton score ≥ 25). Agomelatine was also effective at initially high levels of anxiety, as well as a combination of anxiety and depressive disorders.
The supporting antidepressant effect of agomelatine (with a study duration of 6 months) at a dose of 25-50 mg once a day has been confirmed. The results of the study confirmed the anti-relapse effectiveness of agomelatine, which was evaluated by the time before the onset of the recurrence of the disease (p = 0.0001). The incidence of relapse in the group of patients taking agomelatine was 22%, in the placebo group - 47%.
Agomelatine does not adversely affect attentiveness and memory; in patients with depression, agomelatine in a dose of 25 mg increases the duration of the slow-sleep phase without changing the number and duration of the fast-sleep phases. Acceptance of agomelatine in a dose of 25 mg also contributes to a more rapid onset of sleep and an improvement in its quality (starting from the first week of treatment) and a decrease in heart rate; at the same time inhibition in the afternoon is not noted.
Against the background of taking agomelatine, there was a tendency to reduce the frequency of sexual dysfunction (the effect on arousal and orgasm).
Acceptance of agomelatine does not affect body weight, heart rate and blood pressure, does not cause sexual dysfunction, does not cause withdrawal syndrome (even with an abrupt cessation of treatment) and addiction syndrome.

Indications

Treatment of major depressive disorder in adults.

Composition

1 tab .:
- agomelatine 25 mg
Excipients: lactose monohydrate — 61.84 mg, magnesium stearate — 1.3 mg, corn starch — 26 mg, povidone — 9.1 mg, colloidal silicon dioxide — 260 μg, sodium carboxymethyl starch — 3.9 mg, stearic acid — 2.6 mg.
The composition of the film coating: glycerol - 196.65 mcg, hypromellose - 3.26871 mg, iron dye yellow oxide - 195.09 mcg, macrogol 6000 - 208.72 mcg, magnesium stearate - 916.65 mg, titanium dioxide - 434.18 mcg.
The composition of blue paint: shellac, propylene glycol, indigo carmine aluminum varnish.

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Dosage and Administration

For oral use. pills of the drug Valdoxan® can be taken regardless of the meal.
The tablet should be swallowed whole, without chewing. When you skip taking the next dose of the drug, during the next dose
Valdoxan® is taken in the usual dose (you should not take the missed dose). To improve the patient’s control of the drug intake, a calendar is printed on a blister containing pills.
The recommended daily intake is 25 mg (1 tablet) once in the evening. In the absence of clinical dynamics after two weeks of treatment, the dose may be increased to 50 mg (2 pills of 25 mg) once in the evening.
It is recommended to monitor liver function at the start of therapy and then periodically, after 3 weeks, 6 weeks (end of the stopping period of therapy), 12 weeks and 24 weeks (end of the supporting period of therapy) after the start of therapy, and further in accordance with the clinical situation.
Drug treatment of depression should be carried out for at least 6 months to completely stop the symptoms.
Termination of treatment
If treatment is discontinued, there is no need to gradually reduce the dose.

Adverse reactions

In clinical studies, Valdoxan® received more than 3,900 depressed patients.
Side effects were most often slightly or moderately pronounced and were observed in the first two weeks of treatment. The most frequently observed nausea and dizziness. The observed side effects, as a rule, were transient and, in general, did not require cessation of treatment. In some cases, it is difficult to distinguish between the symptoms of a depressive disorder and the side effects of agomelatine therapy.
The frequency of side effects of agomelatine is given as the following grades: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, - From the central nervous system
Often: headache, dizziness, drowsiness, insomnia, migraine. Infrequently: paresthesias.
- Of the gastrointestinal tract Often: nausea, diarrhea, constipation, abdominal pain.
- From the side of the hepatobiliary system. Often: an increase in the activity of ALT and / or AST (more than 3 times as compared with the upper limit of the norm against the background of taking agomelatine in 1.3% of patients and in 0.7% against the background of placebo). Rarely: hepatitis, increased activity of γ-glutamyltransferase * (gamma-GGT) (more than 3 times compared with the upper limit of the norm), increased activity of alkaline phosphatase * (more than 3 times compared with the upper limit of the norm).
- From the skin and subcutaneous tissue Often: sweating. Infrequently: eczema, pruritus *. Rarely: erythematous rash.
- On the part of the organ of vision. Infrequently: blurred vision.
- From the musculoskeletal system Often: back pain.
- Common Disorders Often: fatigue.
- Mental disorders Often: anxiety. Infrequently: agitation and associated symptoms *, such as irritability and anxiety, aggression *, nightmares *, unusual dreams *. Seldom: 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").

* Evaluation of the incidence of adverse reactions identified by spontaneous reports, conducted on the basis of clinical research data.

Contraindications

- Hypersensitivity to agomelatine and / or any of the excipients of the drug Valdoxan.
- Hepatic insufficiency (for example, cirrhosis or liver disease in the active phase) (see the sections "Route of administration and doses" and "Special instructions").
- The simultaneous use of potent inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) (see the section "Interaction with other drugs and other types of interaction").
- Children's age up to 18 years (due to the lack of sufficient experience of clinical use).In children and adolescents, while suing other antidepressants, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggressiveness, conflict behavior, irritation) were observed more often than in the placebo group.
The drug should not be used in patients with lactose intolerance: lactase deficiency, galactosemia, and glucose-galactose malabsorption.
CAREFULLY. Elderly patients (65 years and older) with major depressive episodes in patients with moderate to severe renal insufficiency, while the appointment of agomelatine with moderate inhibitors of isoenzyme of CYP1A2 (such as propranolol, grepafloksatsin, enoxacin), patients with a manic or hypomanic episodes in the history of , patients with a history of suicide-related events, as well as patients who had suicidal intentions prior to initiating therapy; treatment of major depressive episodes in elderly patients with dementia (due to the lack of data on the efficacy and safety of the drug in this group of patients).
Caution should be exercised in the appointment of the drug to patients who consume significant amounts of alcohol or taking drugs that can cause impaired liver function.

Drug interactions

The potential effect of other drugs Agomelatine is 90% metabolized in the liver with the participation of cytochrome P450 1A2 (CYP1A2) and 10% with 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 isoenzyme CYP1A2 and a moderate inhibitor of the isoenzyme CYP2С9 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 isoenzyme CYP1A2 (such as fluvoxamine, ciprofloxacin) is contraindicated. The simultaneous appointment 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 estrogen was not accompanied by a deterioration in the safety profile of the therapy, caution should be exercised when co-administering agomelatine with other moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, grepafloxacin, enoxacin) until sufficient clinical experience has been accumulated (see “Special instructions”). .
The potential effect of agomelatine on other drugs. In vivo, agomelatine does not induce cytochrome P450 isoenzymes. Agomelatine does not inhibit CYP1A2 isoenzyme in vivo and other cytochrome P450 isoenzymes in vitro. Therefore, agomelatine does not affect the concentration of drugs whose metabolism is associated with these isoenzymes.
Drugs, largely binding to plasma proteins Agomelatine did not change the free concentration of drugs, which are largely associated with plasma proteins and, in turn, they did not affect the concentration of agomelatine.
Other medicines
The absence of pharmacokinetic and pharmacodynamic interaction of agomelatine and drugs often used in the target patient population was revealed:
benzodiazepines, drugs lithium, paroxetine, fluconazole and theophylline.
Alcohol
The use of agomelatine in conjunction with alcohol is not recommended.
Electroconvulsive Therapy (ECT)
There are no data on the use of agomelatine simultaneously with ECT. Since agomelatine did not contribute to seizures in animal studies, the undesirable effects of the combined use of agomelatine and ECT seem unlikely.

Special instructions

Elderly patients
The efficacy of the drug in elderly patients (aged 65 years and older) has not been established. There are limited data on the use of the drug Valdoxan® for major depressive episodes in patients aged 65 years and older. At purpose of drug to patients of advanced age it is necessary to be careful (see the section "Special Instructions").
Patients with renal failure
There was no significant change in pharmacokinetic parameters in patients with severe renal insufficiency. However, the experience with the use of the drug Valdoxan® for major depressive episodes in patients with moderate and severe renal failure is limited. Caution should be exercised when prescribing Valdoxan® for such patients.
Bipolar disorders / mania / hypomania
Care should be taken when using Valdoxan® in patients with bipolar disorders, manic or hypomania episodes in history. If you experience symptoms of mania, you should stop taking the drug.
Suicide / suicidal behavior
In the depressed state, the risk of suicidal thoughts, self-harm and suicide (suicide-related events) is increased. The risk persists until a distinct remission occurs. Patients must be kept under medical supervision until the condition improves (after the start of therapy it may take several weeks before the condition improves). Clinical experience suggests that the risk of suicide may increase in the early stages of remission.
Patients with a history of suicide-related events, as well as patients who had suicidal intentions prior to initiating 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 treatment, 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 informed of the need for immediate medical attention in case of deterioration, suicidal and unusual behavior, as well as suicidal thoughts.
Combined use with inhibitors of an isoenzyme CYP1A2
Care should be taken when using agomelatine with moderate CYP1A2 isoenzyme inhibitors (such as propranolol, grepafloxacin, enoxacin) due to the possibility of increasing the concentration of agomelatine (see section "Interaction with other drugs and other types of interaction").
Increased transaminase activity in serum
In studies on the background of taking the drug Valdoxan®, especially at a dose of 50 mg, there was an increase in the activity of transaminases in the blood serum (more than 3 times as compared with the upper limit of the norm) (see the “Side effect” section). As a rule, after cessation of therapy, these indicators 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 (the end of the stopping period of therapy), 12 weeks and 24 weeks (the end of the supporting period of therapy) after the start of therapy, and further in accordance with the clinical situation.
At increase of activity of transaminases in blood serum it is necessary to conduct a repeated research within 48 hours. If transaminase activity is more than 3 times higher than the upper limit of normal, the drug should be stopped.In the future, you should regularly monitor the functional state of the liver to normalize the activity of transaminases.
Caution must be exercised when prescribing Valdoxan® to patients with increased transaminase activity prior to the start of therapy (above the upper limit of normal, but not more than 3 times relative to the upper limit of normal). With the development of symptoms of abnormal liver function, functional liver tests should be carried out. Taking into account laboratory data and the clinical picture, a decision should be made to discontinue or continue therapy with Valdoxan®.
With the development of jaundice, therapy should be discontinued. Care should be taken when prescribing Valdoxan® to patients with risk factors for liver dysfunction, such as obesity / overweight / non-alcoholic fatty liver, patients who consume significant amounts of alcohol or take drugs that can cause a violation liver function.

Overdosage

Data on agomelatine overdose is limited.
Symptoms: drowsiness, pain in epigastria, anxiety, weakness, anxiety, agitation, tension, dizziness, cyanosis, malaise.
When the patient was taking agomelatine at a dose of 2450 mg, the condition returned to normal on its own, without disturbances of the cardiovascular system or changes in laboratory parameters.
Treatment
Specific antidotes for agomelatine are not known. Symptomatic treatment and monitoring in specialized departments with the subsequent supervision.