Valdoxan coated pills 25mg N14
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Active ingredients
Agomelatine
Release form
Pills
Composition
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 shell: 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.
Pharmacological effect
Antidepressant, melatoninergic MT1 and MT2 receptor agonist and serotonin 5-HT2c receptor antagonist. Agomelatine is active on validated models of depression (test of acquired helplessness, test of despair, 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 α-, β-adrenergic receptors, histaminergic receptors, 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 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 1 time / day was confirmed.The results of the study confirmed the anti-relapse efficacy of agomelatine, which was evaluated by the time before the onset of disease recurrence (p = 0.0001). The incidence of relapse in the group of patients taking agomelatine was 22%, in the placebo group - 47%. Agomelatine efficacy was demonstrated in 6 of 7 clinical studies (advantage (2 studies) or comparable efficacy (4 studies)) in heterogeneous populations of adult patients with depression compared to selective serotonin reuptake inhibitors (SSRIs) / selective noradrenaline reuptake inhibitors (SSRIs). ) (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). The antidepressant effect was assessed on the Hamilton scale (17-point version) either as a primary or as a secondary end point. Agomelatine does not adversely affect attentiveness and memory; in patients with depression, agomelatine at 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 with a decrease in heart rate and an improvement in the quality of sleep (starting from the first week of treatment); at the same time inhibition in the afternoon is not noted. Against the background of taking agomelatine, a tendency to a decrease in the frequency of sexual dysfunction (effect on arousal and orgasm) was noted. Acceptance of agomelatine does not affect 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. The effectiveness of agomelatine in 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 study. Patients aged 75 years and older do not have confirmed evidence of a significant effect. The tolerability of agomelatine in elderly patients is comparable to that in the young. During a 3-week controlled trial involving patients with major depressive disorder and insufficient therapeutic effect from taking paroxetine (SSRI) or venlafaxine (SSRI), discontinuation syndrome was observed when switching from therapy with these antidepressants to treatment with agomelatine.The withdrawal syndrome appeared both after a one-time cessation of treatment by previously prescribed SSRIs / SSRIs, and with their gradual cancellation, which could be mistaken for a manifestation of the low effectiveness of agomelatine at the initial stage of treatment. The number of patients who had at least one symptom associated with withdrawal syndrome a week after the cancellation of the SSRI / SNRI was lower in the group with a prolonged dose reduction (gradual dose reduction of SSRI / SNRI over 2 weeks) than in the group with a rapid decrease doses (gradual reduction of the dose of SSRIs / SNRIs within 1 week), and than with one-time cancellation: 56.1%, 62.6% and 79.8% of patients, respectively.
Pharmacokinetics
Absorption: After oral administration, agomelatine is rapidly (≥80%) absorbed. Cmax in plasma is achieved within 1-2 hours after ingestion. Absolute bioavailability after administration of the therapeutic dose is low (less than 5%); interindividual variability is significant. Bioavailability in women is higher than in men. Bioavailability increases with oral contraceptive pills and decreases with smoking. When prescribing the drug in therapeutic doses, Cmax increased in proportion to the dose. When taken in higher doses, a more pronounced effect of the first passage through the liver was noted. Meal (both normal and high in fat) did not affect the bioavailability or the degree of absorption. Against the background of a high-fat meal, interindividual variability of indicators increased. Distribution: Vd in the equilibrium state was about 35 liters. Plasma protein binding is 95% regardless of the drug concentration, age or the presence of renal failure. When liver failure was observed a twofold increase in the free fraction of the drug. Metabolism: After oral administration, agomelatine undergoes rapid oxidation, mainly due to CYP1A2 and CYP2C9. CYP2C19 isoenzyme is also involved in the metabolism of agomelatine, but its role is less significant. The major metabolites in the form of hydroxylated and demethylated agomelatine are inactive, quickly bound and excreted by the kidneys. Withdrawal: T1 / 2 from plasma ranges from 1 to 2 h. Withdrawal 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 the repeated appointment of the drug kinetics does not change. Pharmacokinetics in special clinical situations: In patients with severe renal failure, a single dose of agomelatine in a dose of 25 mg did not change the pharmacokinetic parameters significantly. Due to limited clinical experience, care should be taken when prescribing agomelatine in patients with moderate and severe renal insufficiency. When administering agomelatine in a dose of 25 mg to patients with mild (class A on the Child-Pugh scale) and moderate (class B on the Child-Pugh scale) chronic liver failure, cirrhosis of the liver was observed to increase its plasma concentration by 70 and 140 times. , respectively, in comparison with the volunteers, comparable by sex, age and attitude to smoking, but without liver failure. When administering agomelatine at a dose of 25 mg to elderly patients (65 years and older), it was noted that the average AUC and average Cmax were 4 times and 13 times, respectively, higher in patients aged 75 and older compared with patients younger 75 years old. The total number of patients receiving the drug in a dose of 50 mg was too low to draw any conclusions. Dose adjustment depending on age is not required.
Indications
Treatment of major depressive disorder in adults.
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 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 taking 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. Do not use the drug 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.
Precautionary measures
Caution should be taken when treating major depressive episodes in patients with moderate and severe renal insufficiency; while 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 suicide, as well as patients who had suicidal intent before the start of therapy. Caution should be exercised in the appointment of the drug to patients who abuse alcohol or taking drugs that can cause impaired liver function.
Use during pregnancy and lactation
Data on the use of agomelatine during pregnancy are not available or are limited (less than 300 pregnancy outcomes). Animal studies have not revealed any direct or indirect effects on pregnancy, embryo and fetus development, generic activity and postnatal development. As a precautionary measure, it is recommended to avoid prescribing Valdoxan during pregnancy. It is not known whether agomelatine passes into breast milk in women during lactation. In experimental animal studies, agomelatine and its metabolites have been shown to pass into breast milk. If treatment with agomelatine is necessary, breastfeeding should be discontinued.
Dosage and administration
InsideTablets drug Valdoxan can be taken regardless of the meal. The tablet should be swallowed whole, without chewing. When skipping the next dose of the drug, during the next dose Valdoxan is taken in the usual dose (do 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 can 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, after 6 weeks (the 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 therapy for depression should be carried out for at least 6 months to completely stop the symptoms. Termination of treatment In the event of termination of treatment there is no need to gradually reduce the dose.
Side effects
In clinical studies, Valdoxan received more than 3,900 depressed patients. Most often, they were slightly or moderately expressed and were observed in the first two weeks of treatment. The most frequently observed nausea and dizziness. Marked side effects, as a rule, were transient and, in general, did not require cessation of treatment. In some cases, it is difficult to distinguish the symptoms of a depressive disorder and side effects of agomelatine therapy. The frequency of side effects of agomelatine is given as the following gradation very often (≥1 / 10), often (≥1 / 100, less than 1/10), infrequently (≥1 / 1000 - From the side of the central nervous system. Often headache, dizziness, drowsiness, insomnia, migraine. Infrequently paresthesias. - From the gastrointestinal tract. Often nausea, diarrhea, constipation, pain in the stomach. and / or AST (more than 3 times compared to the upper limit of normal with agomelatine in 1.3% of patients and 0.7% in foneplacebo. Rarely, hepatitis, increased activity of γ-glutamyltransferase * (gamma-GGT) (more than 3 times compared to upper limit of the norm), increased alkaline phosphatase activity * (more than 3 times as compared with the upper limit of the norm) .- On the part of the skin and subcutaneous tissue Frequently sweating. Infrequently eczema, pruritus *. Rarely: erythematous rash.- .Infrequently blurred vision. - Of the musculoskeletal system. Often back pain. - Common disorders. Often fatigue. Mental disorders, anxiety. Infrequently: agitation and associated symptoms *, such as irritability and anxiety, aggressiveness *, 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 data from clinical studies.
Overdose
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 state 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 are carried out in specialized departments with subsequent observation.
Interaction with other drugs
Potential effects of other drugs: Agomelatine is 90% metabolized in the liver by 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 isoenzyme CYP1A2 and a moderate inhibitor of the isoenzyme CYP2C9 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 mild 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 with the simultaneous administration of agomelatine with other moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) until sufficient clinical experience has been gained (see the Special Instructions section).Rifampicin, as an inducer of both cytochromes involved in the metabolism of agomelatine, can reduce the bioavailability of agomelatine. Smoking, inducing CYP1A2 isoenzyme, has been shown to decrease the bioavailability of agomelatine, especially in patients who abuse smoking (≥15 cigarettes / day) (see Pharmacokinetics). Potential effects of agomelatine on other drugs: In vivo, agomelatine does not induce cytochrome P450 isoenzymes. Agomelatine does not inhibit the 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 that largely bind to plasma proteins: Agomelatine does not alter the free concentration of drugs that are largely associated with plasma proteins and, in turn, they do not affect the concentration of agomelatine. Other drugs: The absence of pharmacokinetic and pharmacodynamic interactions of agomelatine and drugs commonly used in the target patient population: benzodiazepines, lithium preparations, paroxetine, fluconazole and theophylline. Alcohol: Agomelatine in conjunction with alcohol is not recommended. Electroconvulsive therapy (ECT): There are no data on the use of agomelatine simultaneously with electroconvulsive therapy (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
Monitoring of liver function indicators It has been reported that liver damage has occurred, including liver failure (resulting in fatal cases in exceptional cases or requiring liver transplantation in patients with previously existing risk factors for liver damage), an increase in liver enzymes more than 10 times the upper normal limit, Hepatitis and jaundice in patients treated with Valdoxan during the post-registration period (see the Adverse Effects section). Most of these disorders occurred in the first months of treatment. The nature of the damage to the liver is mainly hepatocellular.As a rule, after cessation of therapy, transaminase levels returned to normal values. Caution should be exercised before starting treatment and should be closely monitored during treatment for all patients, especially those with risk factors for liver disease or receiving concomitant therapy with drugs that may cause liver damage. Prior to therapy, treatment with Valdoxan should be prescribed only after a careful assessment of the ratio of expected benefit to potential risk in patients with risk factors for liver dysfunction, such as obesity / overweight / non-alcoholic fatty hepatosis, diabetes, alcohol abuse and taking drugs that can cause abnormal liver function. Before starting therapy, functional liver tests should be carried out in all patients, and therapy cannot be started if the level of liver enzymes ALT and / or ACT is more than 3 times higher than VGN (see Contraindications section). Caution should be exercised in the appointment of the drug Valdoxan to patients with initially increased transaminase activity (higher VGN, but not more than 3 times relative to VGN). Frequency of functional liver tests: before the start of therapy and further: after about 3 weeks, after about 6 weeks (ending the stopping period of therapy), after about 12 and 24 weeks (ending of the supporting period of therapy), then in accordance with the clinical situation. With increasing doses, liver function should be monitored with the same frequency as at the beginning of therapy. If transaminases increase in serum, a retest should be conducted within 48 hours. During treatment, treatment with Valdoxan should be stopped immediately in case of: the onset of symptoms and signs of possible impaired liver function (such as dark urine, discolored stools, yellowness of the skin / eyes , pain in the right upper abdomen, recently appeared constant and unexplained fatigue), increases in transaminase levels by more than 3 times, compared with VGN. After discontinuation of therapy with Valdoxan, regular hepatic function tests should be carried out until transaminase levels are normalized.Elderly patients: The efficacy of the drug in elderly patients (75 years and older) has not been established. In this regard, Valdoxan should not be prescribed to patients of 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 efficacy and safety of the drug in this group of patients). Patients with renal insufficiency: In patients with severe renal insufficiency, no significant change in pharmacokinetic parameters was observed. However, experience with the use of the drug Valdoxan in major depressive episodes in patients with moderate and severe renal insufficiency is limited. Caution should be exercised when prescribing Valdoxan to such patients. Bipolar disorders / mania / hypomania: Use caution when using the drug 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 (suicidal 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 treatment, are at risk and should be under close medical supervision during treatment. 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 CYP1A2 isoenzyme inhibitors: Care should be taken with simultaneous use of agomelatine with moderate inhibitors of CYP1A2 isoenzyme (such as propranolol, enoxacin) due to the possibility of increasing the concentration of agomelatine (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 control mechanisms: Studies on the effect of the drug Valdoxan on the ability to drive and other mechanisms have not been conducted. It should be remembered that dizziness and drowsiness are frequent side effects of agomelatine.