Valdoksan - instructions for use, dose, side effects, contraindications

Active substanceAgomelatineAgomelatine

Similar drugsTo uncover

pills inwards

Dosage form: & nbspfilm-coated tablets

Composition:

One tablet contains active substance agomelatine 25 mg.

Excipients: lactose monohydrate 61.84 mg, magnesium stearate 1.3 mg, corn starch 26.0 mg, Povidone-K30 9.1 mg, silicon dioxide colloid 0.26 mg, sodium carboxymethyl starch 3.9 mg, stearic acid 2.6 mg.

Film Sheath: glycerol 0.1966 mg, hypromellose 3.26871 mg, iron dye oxide yellow 0.19509 mg, macrogol 6000 0.20872 mg, magnesium stearate 0.1966 mg, titanium dioxide 0.43418 mg.

The logo of the company on the tablet is applied with blue paint, which includes shellac, propylene glycol, indigo carmine, aluminum lacquer.

Description:Oblong film-coated tablets, orange-yellow with a blue company logo on one side.

Pharmacotherapeutic group:Antidepressant

ATX: & nbsp

Agomelatine

Pharmacodynamics:

Agomelatine is a melatonergic receptor agonist MT₁ and MT₂ and a serotonin antagonist 5-HT2C receptors.

Agomelatine is an antidepressant, 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. It was shown that agomelatine does not affect the capture of monoamines and has no affinity for alpha, beta-adrenergic, histaminergic, 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 desynchronization of circadian rhythms, it was shown that agomelatine restores synchronization of circadian rhythms by stimulation of melatonin receptors.

Agomelatine helps restore normal sleep patterns, reduce body temperature and release melatonin. The effectiveness of short-term use of agomelatine (therapy 6-8 weeks) in doses of 25-50 mg in patients with large depressive episodes is shown. The efficacy of agomelatine in patients with more severe forms of depressive disorder (Hamilton score> 25) is also indicated.

Agomelatine was also effective at initially high levels of anxiety, as well as in the combination of anxiety and depressive disorders.A supporting antidepressant effect of agomelatine (with a duration of 6 months) in a dose of 25-50 mg once a day is confirmed. Results of the study confirmed the anti-relapse efficacy of agomelatine, which was estimated at the time before relapse (p = 0.0001). The frequency of relapse in the group of patients taking agomelatine was 22%, in the placebo group - 47%.

The efficacy of agomelatine has been demonstrated in six of the seven clinical studies (advantage (2 studies), or comparable efficacy (4 studies)) in heterogeneous populations of adult patients with depression, compared with SSRIs / SSRIssertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). The antidepressant effect was assessed on the Hamilton scale (17-point version) either as primary or as a secondary endpoint.

Agomelatine does not adversely affect care and memory, in patients with depression agomelatine in a dose of 25 mg increases the duration of the phase of slow sleep without changing the number and duration of the phases of fast sleep.Taking agomelatine in a dose of 25 mg also contributes to a faster onset of sleep with a decrease in the heart rate and improving the quality of sleep (starting from the first week of treatment); at the same time there is no slowing down in the daytime. Against the background of receiving agomelatine, there is a tendency to decrease the frequency of sexual dysfunction (effect on excitement and orgasm).

The administration of agomelatine does not affect the heart rate and blood pressure, does not cause sexual disturbances, does not cause a withdrawal syndrome (even with a sharp cessation of treatment) and the addictive syndrome.

The efficacy of agomelatine 25-50 mg once daily is confirmed in patients with depression of the elderly under the age of 75 years during an 8-week clinical trial. Patients aged 75 years and older have no confirmed data on the presence of significant effect. The tolerability of agomelatine in elderly patients is comparable to that of young patients. During a 3-week, controlled trial involving patients with major depressive disorder and inadequate therapeutic effect of taking paroxetine (SSRIs) or venlafaxine (SSRIs), withdrawal from therapy with these antidepressants for treatment with agomelatine was observed.The withdrawal syndrome appeared as after a one-stage cessation of treatment prescribed earlier SSRIs / SSRIs, and with their gradual withdrawal, which could be mistaken for the manifestation of low efficacy of agomelatine at the initial stage of treatment.

The number of patients who had at least one symptom associated with withdrawal syndrome one week after the withdrawal of SSRIs / SSRIs was lower in the group with a prolonged dose reduction (gradual reduction of the SSRI / SSRI dose within 2 weeks) than in the group with a rapid decline dosage (gradual decline dose SSRIs / SSRIs for 1 week), and than with one-stage withdrawal: 56.1%, 62.6% and 79.8% of patients, respectively.

Pharmacokinetics:

Absorption and bioavailability

After oral administration agomelatine fast (> 80%) is absorbed. The peak concentration in the plasma is achieved 1-2 hours after ingestion. Absolute bioavailability after taking a therapeutic dose is low (<5%); interindividual variability is considerable. Bioavailability in women is higher than in men. Bioavailability increases with oral contraceptives and decreases with smoking.At the appointment of therapeutic doses, the maximum concentration of the drug increased in proportion to the dosage. When taking higher doses, there was a more pronounced effect of the first passage through the liver. The intake of food (both normal and high in fat) did not affect either bioavailability or the degree of absorption. Against the background of food intake with a high fat content interindividual variability of the indicators increased.

Distribution

The volume of distribution in the equilibrium phase was about 35 liters.

Binding to plasma proteins is 95% regardless of drug concentration, age or presence of renal insufficiency. With hepatic insufficiency, there was a twofold increase in the free fraction of the drug.

Biotransformation

After oral administration agomelatine is subjected to rapid oxidation, mainly due to isoenzymes CYP1A2 and CYP 2C9. Isozyme CYP2C19 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 excreted by the kidneys.

Excretion

ATThe withdrawal occurs quickly.the half-life of the plasma is from 1 to 2 hours, the metabolic clearance is about 1100 ml / min. excretion occurs mainly in the kidneys (80%) in the form of metabolites, the amount of unchanged drug in the urine is insignificant, with the repeated administration of the drug, the kinetics does not change.

Renal insufficiency

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

Liver failure

With the appointment of agomelatine in a dose of 25 mg patients with poorly expressed (class A by Child-Pugh classification) and moderate (class B according to the Child-Pugh classification) chronic hepatic insufficiency background of liver cirrhosis was noted increase in its concentration in plasma in 70 and 140 times, respectively, compared with volunteers, comparable by sex, age and attitude towards smoking, but without hepatic insufficiency.

Elderly patients

With the appointment of agomelatine in a dose of 25 mg elderly patients aged from 65 years of age or older, it was noted that the average AUC and average maximum concentration were 4 times and 13 times, respectively, higher in patients in the age 75 and over, compared with patients younger than 75 years. Total number patients receiving 50 mg, was too low to make any conclusions. Correction of dose depending on age is not required.

Race

There are no data on racial differences pharmacokinetic parameters.

Indications:Treatment of major depressive disorder in adults.

Contraindications:

- Hypersensitivity to agomelatine and / or any of the excipients of the drug (see section "Composition").

- Hepatic insufficiency (eg, cirrhosis or liver disease in the active phase) (see sections "Dosing and Administration" and "Special instructions"),

- Simultaneous application of strong inhibitors of cytochrome CYP1A2 (such as fluvoxamine, ciprofloxacin) (see the section "Interaction with other drugs and other types of interaction").

- Children under 18 years of age (due to lack of sufficient clinical experience).

Do not use the drug in patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption.

Carefully:

Patients with moderate and severe renal failure in the treatment of major depressive episodes, while concomitantly administering agomelatine with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin), patients with a history of manic or hypomanic episodes, patients who had a history of suicidal events, and patients who had suicidal intentions prior to initiating therapy.

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

Pregnancy and lactation:Data on the use of agomelatine during pregnancy are absent or limited (less than 300 pregnancy outcomes). Studies in animals have not revealed direct or indirect adverse effects on the course of pregnancy, embryo and fetus development, labor activity and postnatal development.

As a precaution, it is recommended to avoid the appointment of the drug Valdoxane® during pregnancy.

It is not known whether the agomelatine in breast milk in women during lactation. In animal experiments it was shown that agomelatine and its metabolites penetrate into breast milk.

If treatment with agomelatine is necessary, breastfeeding should be discontinued.

Dosing and Administration:

Inside. Tablets of the drug Valdoksan® can be taken regardless of food intake. The tablet should be swallowed whole, without chewing. If you miss a dose of the next dose, the next dose of Valdoxane is taken in the usual dose (do not take the missed dose). To improve the patient's control of taking the drug, a calendar is printed on the blister containing the tablets. The recommended daily dose is 25 mg (1 tablet) once before bedtime. In the absence of clinical dynamics after a two-week treatment, the dose may be increased to 50 mg (2 tablets of 25 mg) once before bedtime. The decision to increase the dose should be made taking into account the increasing risk of increasing the level of transaminases.Any increase in the dose to 50 mg should be made on the basis of an assessment of the benefit and risk for a particular patient and with strict control of hepatic samples. Before starting therapy, functional liver tests should be performed in all patients. Therapy can not be started in patients with a transaminase level more than 3 times the upper limit of the norm (see the sections "Contraindications" and "Special instructions"). During the treatment, liver function should be monitored periodically, in about 3 weeks, about After 6 weeks (the end of the period of dying therapy), about across 12 weeks and 24 weeks (the end of the maintenance period of therapy) after initiation of therapy, and further in accordance with the clinical situation (see section "Special instructions"). If the activity of transaminases is more than 3 times higher than the upper limit of the norm, the drug should be discontinued (see Sections "Contraindications" and "Special instructions").

With increasing doses, 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 conducted for at least 6 months until the symptoms disappear completely.

Transition from SSRI / SSRI therapy to agomelatine therapy

Possible withdrawal syndrome after discontinuation of SSRI / SSRIs. To reduce the risk of withdrawal syndrome after discontinuation of treatment with previously prescribed SSRIs / SSRIs, follow the instructions for the medical use of these drugs.

The intake of agomelatine can be started from the 1 st day of a gradual reduction in the dose of SSRI / SSRI antidepressants (see the section "Pharmacodynamics").

Discontinuation of treatment

In the event of discontinuation of treatment, there is no need for a gradual dose reduction.

Elderly patients

The efficacy and safety of agomelatine (in a dose of 25-50 mg per day) is confirmed in patients with depression of the elderly under 75 years. Patients aged 75 years and older have no confirmed data on the presence of significant effect. In this regard, Valdoxane® should not be prescribed to patients of this age group (see sections "Special instructions" and "Pharmacological properties"). Dose adjustments are not required depending on age (see Fig.section "Pharmacological properties").

Patients with renal insufficiency

In patients with severe renal insufficiency no significant change in pharmacokinetic parameters was noted. The experience of using Valdoxane in patients with large depressive episodes in patients with moderate to severe renal failure is limited. When appointing Valdoxane® to such patients, care should be taken (see section "Special instructions").

Patients with hepatic insufficiency

Valdoxane® is contraindicated in patients with hepatic impairment (see "Contraindications", "Special instructions" and "Pharmacokinetics").

Side effects:

In clinical trials, Waldoxan® received more 7900 patients with depression. Side effects were most often mild or moderate and were observed in the first two weeks of treatment. The most common signs of nausea and dizziness. The noted side effects, as a rule, were transient and, basically, did not require cessation of treatment. The frequency of side effects of agomelatine is given in the form of the following gradation: very often (>1/10), often (>1/100, <1/10), infrequently (>1/1000, <1/100), rarely (>1/10000, <1/1000); very rarely (<1/10000), frequency, unspecified.

From the central nervous system

Often: headache, dizziness, drowsiness, insomnia, migraine.

Infrequently: paresthesia, restless legs syndrome.

From the gastrointestinal tract

Often: nausea, diarrhea, constipation, abdominal pain, vomiting *.

From the hepatobiliary system

Often: increased activity ALT and / or ACT (more than 3 times higher than the upper limit of the norm in 1.4% of patients with agomelatine at a dose of 25 mg per day and 2.5% of patients receiving agomelatine at a dose of 50 mg per day, compared with 0, 6% per background of placebo in clinical studies).

Rarely: hepatitis, increased activity of γ -glutamyl transferase * (gamma-GGT) (more than in 3 times in comparison with the top border norms), increased activity of alkaline phosphatase * (more than 3 times compared with upper limit of the norm), hepatic insufficiency * (1), jaundice *.

From the skin and subcutaneous tissue

Often: sweating.

Infrequently: eczema, itchy skin *, urticaria *.

Rarely: erythematous rash, swelling of the face and swelling Quincke *.

From the side of the hearing organ

Infrequent: noise in the ears.

From the side of the organ of vision

Infrequently: blurred vision.

From the musculoskeletal system

Often: back pain.

General disorders

Often: fatigue.

Mental disorders

Often: anxiety.

Not often: agitation and related Symptoms *, such as irritability and anxiety, aggressiveness *, night nightmares *, unusual dreams *.

Rarely: mania / hypomania *. The symptoms can also be a manifestation of the main disease (see section "Special instructions ").

Hallucinations *.

Unspecified frequency: suicidal ideation or suicidal behavior (see section "Special instructions"). Data of (additional) surveys

Rarely: weight gain, weight loss.

* An estimate of the incidence of adverse reactions identified by spontaneous reports was made on the basis of clinical trial data.

(1) Only a few cases with fatal outcome or liver transplantation have been reported in patients with pre-existing risk factors for liver damage.

Overdose:

Data on an overdose of agomelatine are limited.

Symptoms: drowsiness, epigastric pain, anxiety, weakness, anxiety, agitation, stress, dizziness, cyanosis, malaise. When a patient receives agomelatine at a dose of 2,450 mgit was normalized independently, without disturbances from the cardiovascular system or changes in laboratory parameters.

Treatment:

Specific antidotes for agomelatine are not known.

Symptomatic treatment and monitoring in specialized departments with follow-up.

Interaction:

Potentially possible effects of other drugs

Agomelatine is 90% metabolized in the liver with 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 CYP1A2 isoenzyme and a moderate inhibitor of the CYP2C9 isoenzyme and significantly slows the metabolism of agomelatine, while the concentration of agomelatine increases approximately 60 (12-412) times. Therefore, simultaneous use of agomelatine and strong inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) is contraindicated. Simultaneous administration of agomelatine and estrogen that are moderate inhibitors of isoenzyme CYP1A2, leads to an increase in the concentration of the agomelatine several times.Although combined use of agomelatine and estrogens has not been associated with a worsening of the safety profile of ongoing therapy, care should be taken when concomitantly administering agomelatine with other mild inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) before the accumulation of sufficient clinical experience (see section "Special instructions"),

Rifampicin, as an inducer of both cytochromes involved in the metabolism of agomelatine, may lower the bioavailability of agomelatine. It is shown that smoking, inducing the isoenzyme CYP1A2, lowers the bioavailability of agomelatine, especially in patients who abuse smoking (> 15 cigarettes / day) (see section "Pharmacokinetics").

Potentially possible impact agomelatine for other medicines

In vivo agomelatine does not induce cytochrome P450 isoenzymes. Agomelatine does not inhibit isoenzyme CYP1A2 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 did not change the free concentration of drugs that largely bind to 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 population of patients: benzodiazepines, lithium preparations, paroxetine, fluconazole and theophylline has been revealed.

Alcohol

It is not recommended to use agomelatine together with alcohol.

Electroconvulsive therapy (ECT)

There is no data on the application agomelatine concomitantly with ECT. Since in animal experiments agomelatine did not contribute to the occurrence of seizures, the undesirable effects of the combined use of agomelatine and ECT seem unlikely.

Special instructions:

Monitoring of indicators of liver function:

There have been reports of liver damage, including liver failure (leading to death in exceptional cases or requiring liver transplantation in patients with previous risk factors for liver damage);increase in liver enzymes more than 10 times the upper limit of the norm, hepatitis and jaundice in patients taking Valdoxane® at the post-marketing period (see section "Side effect"). Most of these disorders occurred during the first months of treatment. The nature of the liver lesion is mainly hepatocellular. As a rule, after discontinuation of therapy, transaminase levels returned to normal values. Care should be taken before starting treatment and carefully monitored during treatment for all patients, especially those with risk factors for developing liver disease or receiving concomitant therapy with drugs that can cause liver damage.

- Before the start of therapy

Treatment with Valdoxane should only be given after a thorough assessment of the relationship between the expected benefit and the potential risk in patients with risk factors for liver dysfunction, such as obesity / overweight / non-alcoholic fatty liver, diabetes, alcohol abuse, and medication function of the liver.Before starting therapy, functional liver tests should be performed in all patients, and therapy can not be initiated if the level of hepatic enzymes ALT and / or ACT more than 3 times exceeds the upper limit of the norm (see the section "Contraindications"). Caution should be exercised when administering Valdoxane to patients with an initially increased activity of transaminases (above the upper limit of the norm, but no more than 3 times the upper limit of the norm).

- Frequency of functional liver tests

- Before the start of therapy

- And further:

- After about 3 weeks,

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

- approximately 12 and 24 weeks (the end of the maintenance period of therapy) in the future - in accordance with the clinical situation.

- With increasing doses, liver function should be monitored at the same frequency as at the beginning of therapy. When the activity of transaminases in the serum increases, a re-examination should be carried out within 48 hours.

- In the process of treatment

Treatment with Valdoxane® should be immediately stop in case of:

- the appearance of symptoms and signs of possible impairment of liver function (such as dark urine, discolored stool, yellowness of the skin / eye, pain in the right upper abdomen, recently appeared permanent and unexplained fatigue).

- increase the level of transaminases more than 3 times, but compared with the upper limit of the norm.

After the abolition of Valdoxane therapy, functional liver tests should be performed regularly until the transaminase level is normal.

Elderly patients

Efficacy of the drug in elderly patients (aged 75 years and older) is not established. In this regard, Valdoxane® should not be prescribed to patients of this age group (see sections "Dosage and Administration" and "Pharmacological properties").

Older patients with dementia

Do not prescribe Valdoxane® for the treatment of major depressive episodes in elderly patients with dementia (due to 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 noted.However, the experience with the use of the drug Valdoxane in large depressive episodes in patients with moderate to severe renal failure is limited. Care should be taken when administering Valdoxane® to such patients.

Bipolar disorder / mania / hypomania

Care should be taken when using the drug Valdoxane in patients with bipolar disorders, manic or hypomanic episodes in the anamnesis. When symptoms of mania appear, stop taking the drug.

Suicide / suicidal behavior

In a depressed state, the risk of suicidal thoughts, self-harm and suicide (events associated with suicide) is increased. The risk persists until a distinct remission occurs. Patients should be under medical supervision until the condition improves (after the start of therapy, it may take several weeks before the condition improves). Clinical experience indicates that the risk of suicide may increase in the early stages of the onset of remission.

Patients who had a history of suicidal events, as well as patients who had suicidal intent before initiating therapy,are at risk and should be under close medical supervision during therapy.

Results of a meta-analysis of clinical trials of antidepressants in patients with mental disorders suggest an increased risk of suicidal behavior in patients under the age of 25 years when 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 the druga. Patients (and caregivers) should be informed of the need for immediate access to the doctor with worsening of the condition, suicidal and unusual behavior, as well as with the appearance of suicidal thoughts.

Combined use with isoenzyme inhibitors CYPIA2

Caution should be exercised while using agomelatine with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) because of the possibility of increasing the concentration of agomelatine (see the sections "Contraindications" and "Interaction with other drugs and other forms of interaction").

Patients with lactose intolerance

Do not use the drug in patients with lactose intolerance: lactase insufficiency, galactosemia and glucose-galactose malabsorption (see section "Contraindications").

Effect on the ability to drive transp. cf. and fur:Studies to study the effect of the drug Valdoxane® on the ability to drive a car and other mechanisms have not been conducted. It should be remembered that dizziness and drowsiness are frequent side effects of agomelatine.

Form release / dosage:

Film-coated tablets, 25 mg.

Packaging:

14 tablets per blister (PVC / Al), 1, 2, 7 blisters with instructions for medical use in a pack of cardboard.

Packing for hospitals:

For 10 tablets per blister (PVC / Al). For 10 blisters with instructions for medical use in a pack of cardboard.

When packaging (packaging) at the Russian company LLC "Serdiks":

For 14 tablets per blister (PVC / Al). For 1.2 blisters with instructions for medical use in a pack of cardboard.

For 10 tablets per blister (PVC / Al). For 10 blisters with instructions for medical use in a pack of cardboard.

Packing for hospitals:

For 14 tablets per blister (PVC / Al).For 7 blisters with instructions for medical use in a pack of cardboard.

Storage conditions:Special storage conditions are not required. Keep out of the reach of children.

Shelf life:

3 years.

DO NOT USE AFTER THE TERM OF THE YEAR ENDED PACKAGING.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000540/08

Date of registration:11.02.2008/02.04.2014

Expiration Date:Unlimited

The owner of the registration certificate:Servier LaboratoriesServier Laboratories France

Manufacturer: & nbsp

Laboratories Servier France

Representation: & nbspServier Laboratories Servier Laboratories France

Information update date: & nbsp20.01.2017

Illustrated instructions

Instructions

Valdoxane® (Valdoxan®)