Valdoxan pills 25mg, 28pcs

Composition

1 tablet contains:  

Active ingredient: agomelatine 25 mg. Excipients: lactose monohydrate, magnesium stearate, corn starch, povidone, colloidal silicon dioxide, sodium carboxymethyl starch, stearic acid. Film coating: glycerol, hypromellose, iron oxide yellow dye, macrogol 6000, magnesium stearate, titanium dioxide.

Pharmacological action

Agomelatine is an agonist of the melatonergic MT1 and MT2 receptors and an antagonist of the serotonin 5-HT2 C-receptors. Agomelatine is an antidepressant active in validated models of depression (acquired 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. Agomelatine has been shown to have no effect on monoamine uptake and no affinity for alpha -, beta-adrenergic, histaminergic, cholinergic, dopaminergic, and benzodiazepine receptors.

Agomelatine increases 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 stimulating 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 major depressive episodes is shown.

Agomelatine has also been shown to be effective in patients with more severe forms of depressive disorder (Hamilton score >25). Agomelatine was also effective for initially high levels of anxiety, as well as for a combination of anxiety and depressive disorders.

The maintenance antidepressant effect of agomelatine (with a study duration of 6 months) at a dose of 25-50 mg once a 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 relapse of the disease (p = 0.0001). The relapse rate was 22% in the agomelatine group and 47% in the placebo group.

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

Agomelatine has no negative effects on mindfulness 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 contributes to a faster onset of sleep with a decrease in heart rate and improved sleep quality (starting from the first week of treatment); however, daytime lethargy is not noted.

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

Taking agomelatine does not affect the heart rate and blood pressure, does not cause sexual disorders, does not cause “withdrawal” syndrome (even with abrupt termination of treatment) and “addiction”syndrome. The efficacy of agomelatine at a dose of 25-50 mg once a day was confirmed in elderly patients with depression under 75 years of age during an 8-week clinical study. In patients aged 75 years and older, there are no confirmed data on the presence of a significant effect.

The tolerability of agomelatine in elderly patients is comparable to that in young patients. During a 3-week, controlled trial involving patients with major depressive disorder and insufficient therapeutic effect from taking paroxetine (SSRI) or venlafaxine (SSRI), withdrawal syndrome was observed when switching from treatment with these antidepressants to treatment with agomelatine.

Withdrawal syndrome appeared both after simultaneous discontinuation of treatment with previously prescribed SSRIs/SSRIs, and with their gradual cancellation, which could be mistaken for the manifestation of low effectiveness of agomelatine at the initial stage of treatment. The number of patients who experienced at least one withdrawal-related symptom one week after SSRI/SSRI withdrawal was lower in the long-term dose reduction group (gradual reduction of the SSRI/SSRI dose for 2 weeks) than in the fast-dose reduction group (gradual reduction of the SSRI/SSRI dose for 1 week) and than in the single-stage withdrawal group: 56.1%,62.6%, and 79.8% of patients, respectively.

Pharmacokinetics

Absorption and bioavailability After oral use, agomelatine is rapidly (>80%) absorbed. Peak plasma concentrations are reached 1-2 hours after oral use. Absolute bioavailability after taking a therapeutic dose is low ( Bioavailability is higher in women than in men. Bioavailability increases with oral contraceptives and decreases with smoking.

When prescribing therapeutic doses, the maximum concentration of the drug increased in proportion to the dosage. When taking higher doses, a more pronounced effect of the first passage through the liver was noted. Food intake (both regular and high-fat) did not affect either bioavailability or the degree of absorption. The interindividual variability of indicators increased with the intake of food with a high fat content.

Distribution The volume of distribution in the equilibrium phase was about 35 liters. Plasma protein binding is 95%, regardless of drug concentration, age, or the presence of renal failure. With hepatic insufficiency, a twofold increase in the free fraction of the drug was noted.

Biotransformation After oral use, agomelatine undergoes rapid oxidation, mainly due to the isoenzymes 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 bound and excreted by the kidneys.

Elimination occurs quickly. The plasma half-life is 1 to 2 hours. The 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 use of the drug, the kinetics does not change.

Renal insufficiency In patients with severe renal insufficiency, the pharmacokinetic parameters did not significantly change with a single dose of agomelatine 25 mg. Due to limited clinical experience, caution should be exercised when prescribing agomelatine to patients with moderate to severe renal insufficiency.

Hepatic insufficiency When agomelatine was administered at a dose of 25 mg to patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) chronic liver failure on the background of cirrhosis, an increase in its plasma concentration was noted by 70 and 140 times, respectively, compared with volunteers comparable in gender, age and smoking attitude, but without liver failure.

Elderly patients When agomelatine was administered at a dose of 25 mg to elderly patients aged 65 years and older, it was noted that the average AUC and average maximum concentration were 4 times and 13 times higher, respectively, in patients aged 75 years and older, compared with patients younger than 75 years. The total number of patients receiving 50 mg was too low to draw any conclusions. No age-dependent dose adjustment is required.

Race There are no data on racial differences in pharmacokinetic parameters.

Indications

Treatment of major depressive disorder.

Use during pregnancy and lactation

Little experience with the use of agomelatine in pregnant women has not shown any side effects on the course of pregnancy, the health of the fetus or newborn. Currently, there is no other epidemiological information on this issue. During pregnancy, the drug should be used with caution and in cases where the expected benefit of therapy for the mother exceeds the potential risk to the fetus. It is not known whether agomelatine is excreted in human breast milk. If it is necessary to use Valdoxan during lactation, breastfeeding should be discontinued.

In experimental animal studies, no direct or indirect harmful effects of the drug on pregnancy, embryo or fetal development, labor or postnatal development were found. Agomelatine and its metabolites have been shown to be excreted in breast milk in rats.

Little experience with the use of agomelatine in pregnant women has not shown any side effects on the course of pregnancy, the health of the fetus or newborn. Currently, there is no other epidemiological information on this issue. During pregnancy, the drug should be used with caution and in cases where the expected benefit of therapy for the mother exceeds the potential risk to the fetus.

It is not known whether agomelatine is excreted in human breast milk. If it is necessary to use Valdoxan during lactation, breastfeeding should be discontinued.

In experimental animal studies, no direct or indirect harmful effects of the drug on pregnancy, embryo or fetal development, labor or postnatal development were found. Agomelatine and its metabolites have been shown to be excreted in breast milk in rats.

Contraindications

• Hypersensitivity to agomelatine and / or any of the excipients of the drug.
• Liver failure (for example, cirrhosis or liver disease in the active phase) or an increase in the level of transaminases by more than 3 times relative to the upper limit of normal.
• Concomitant use of potent inhibitors of the CYP1A2 isoenzyme (such as fluvoceamine, ciprofloxacin).
• Children under 18 years of age (due to lack of sufficient clinical experience). Suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggressiveness, conflict behavior, irritation) were observed more often in children and adolescents taking other antidepressants compared to the placebo group.

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

Patients with moderate to severe renal insufficiency in the treatment of major depressive episodes, with concomitant use of 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 suicidal events, 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 impaired liver function.

Side effects

In clinical trials, more than 8,000 patients with depression received Valdoxan®.

Side effects were most often mild or moderate and were observed in the first two weeks of treatment. The most common symptoms were headache, nausea, and dizziness. The reported side effects were usually transient and generally did not require discontinuation of treatment. The following are data on side effects observed in placebo-controlled and comparative clinical trials.

The frequency of side effects of agomelatine is given by the following gradation: very often (>1/10), often (>1/100, <1/10), infrequently (>1/1000, <1/100), rare (>1/10000, <1/1000); very rare (<1/10000), unspecified frequency.

From the central nervous system: 

• Very common: headache
• Often: dizziness, drowsiness, insomnia.
• Infrequently: migraines, paresthesias, restless legs syndrome*.
• Rarely:akathisia*.

From the gastrointestinal tract:

• Common: nausea, diarrhea, constipation, abdominal pain, vomiting*.

Liver and biliary tract disorders:

• Often: increased AJIT and/or ACT activity (more than 3 times higher than the upper limit of normal in 1.2% of patients receiving agomelatine at a dose of 25 mg per day and in 2.6% of patients receiving agomelatine at a dose of 50 mg per day, compared to 0.5% with placebo in clinical studies).
• Infrequently: increased activity of gamma-glutamyltransferase* (GGT) (more than 3 times higher than the upper limit of normal)
• Rare: hepatitis, increased alkaline phosphatase activity* (more than 3 times higher than the upper limit of normal), liver failure*(1), jaundice*.

Skin and subcutaneous tissue disorders:

• Infrequently: sweating, eczema, pruritus*, urticaria*.
• Rare: erythematous rash, facial edema and angioedema*.

From the side of the hearing organ:

• Infrequently: tinnitus*.

From the side of the visual organ:

• Infrequently: blurred vision.

Musculoskeletal disorders:

• Common: back pain.

Kidney and urinary tract disorders:

• Rare: urinary retention*.

Common disorders:

• Often: fatigue.

Mental disorders

• Are Common: anxiety, unusual dreams*.
• Infrequently: suicidal thoughts or suicidal behavior, agitation and related symptoms* (such as irritability and anxiety), aggressiveness*, nightmares*, mania / hypomania* (these symptoms may also be a manifestation of the underlying disease), confusion*.
• Rare: Hallucinations*.

Data from (additional) examinations

• Often: weight gain*.
• Infrequently: weight loss*.

* Assessment of the frequency of adverse reactions identified by spontaneous reports was carried out on the basis of data from clinical studies. (1) Only a few cases of fatality or liver transplantation have been reported in patients with pre-existing risk factors for liver damage.

Interaction

Potential effects of other drugs

Agomelatine is 90% metabolized in the liver by cytochrome P4501a2 (CYP1A2) and 10% by CYP2C9 / 19. Therefore, any drugs whose metabolism depends on these isoenzymes can 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 by an average of 60 (12 – 412) times. Therefore, concomitant use of agomelatine and strong inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) is contraindicated. Simultaneous use 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 is accumulated (see the section “Special Instructions”).

Rifampicin, as an inducer of all three isoenzymes involved in agomelatine metabolism, may reduce the bioavailability of agomelatine. Smoking has been shown to reduce the bioavailability of agomelatine by inducing the CYP1A2 isoenzyme, especially in patients who abuse smoking (>15 cigarettes/day).

Potential effect of agomelatine on other drugs

In vivo agomelatine does not induce cytochrome P 450 isoenzymes. Agomelatine does not inhibit the CYP1A2 isoenzyme in vivo and other cytochrome P 450 isoenzymes in vitro.

Therefore, agomelatine does not affect the concentration of drugs whose metabolism is associated with these isoenzymes. Drugs that bind significantly to plasma proteins Agomelatine did not change the free concentration of drugs that bind significantly to plasma proteins and, in turn, they did not affect the concentration of agomelatine. Other medicinal products

There was no pharmacokinetic or pharmacodynamic interaction between agomelatine and drugs commonly used in the target patient population: benzodiazepines, lithium preparations, paroxetine, fluconazole, and theophylline. Alcohol

It is not recommended to use agomelatine together with alcohol. Electroconvulsive therapy (ECT)

There are no data on the use of agomelatine simultaneously with ECT. Since agomelatine did not cause seizures in animal experiments, undesirable consequences of the combined use of agomelatine and ECT seem unlikely.

How to take, course of use and dosage

Inside. Tablets of the drug Valdoxan® can be taken regardless of food intake. The tablet should be swallowed whole, without chewing. If you miss the next dose of the drug, during the next dose, Valdoxan® is taken at 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 two weeks of treatment, the dose can 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 increased transaminase levels. Any dose increase to 50 mg should be based on a patient-specific benefit and risk assessment and strict monitoring of liver samples. Before starting therapy, functional liver tests should be performed in all patients. Therapy cannot be initiated in patients with transaminase levels more than 3 times the upper limit of normal. During treatment, liver function should be monitored periodically, approximately 3 weeks, approximately 6 weeks (end of the relief period of therapy), approximately 12 weeks and 24 weeks (end of the maintenance period of therapy) after the start of therapy, and thereafter according to the clinical situation. If the transaminase activity is more than 3 times higher than the upper limit of normal, the drug should be discontinued. 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 carried out for at least 6 months until the symptoms of depression completely disappear.

Switching from SSRI / SSRI therapy to agomelatine therapy

Possible withdrawal syndrome after discontinuation of SSRIs/SSRIs.

To reduce the risk of withdrawal symptoms after discontinuation of treatment with previously prescribed SSRIs/SSRIs, it is necessary to follow the instructions for the medical use of these drugs.

Agomelatine may be initiated on day 1 of a gradual reduction in the dose of SSRI/SSRI antidepressants.

Discontinuation of treatment

If treatment is discontinued, there is no need to gradually reduce the dose.

Elderly patients

The efficacy and safety of agomelatine (at a dose of 25-50 mg per day) has been confirmed in elderly patients with depression younger than 75 years. In patients aged 75 years and older, there are no confirmed data on the presence of a significant effect. Therefore, Valdoxan® should not be used in patients of this age group. No age-dependent dose adjustment is required.

Patients with renal insufficiency

No significant changes in pharmacokinetic parameters were observed in patients with severe renal insufficiency. Experience with the use of Valdoxan® in major depressive episodes in patients with moderate to severe renal insufficiency is limited. Caution should be exercised when prescribing the drug Valdoxan® to such patients.

Patients with hepatic insufficiency

Valdoxan® is contraindicated in patients with hepatic insufficiency.

Overdose

Data on agomelatine overdose are limited. Symptoms: drowsiness, epigastric pain, restlessness, weakness, anxiety, agitation, tension, dizziness, cyanosis, malaise. When the patient received agomelatine at a dose of 2450 mg, the condition returned to normal independently, without any disorders 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 follow-up.

Special instructions

Monitoring of liver function indicators:

Cases of liver damage have been reported, including liver failure (which in exceptional cases resulted in death or required liver transplantation in patients with pre-existing risk factors for liver damage), increased liver enzyme levels more than 10 times higher than the upper limit of normal, hepatitis and jaundice 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 is mainly hepatocellular. As a rule, after discontinuation of therapy, transaminase levels returned to normal values. Caution should be exercised before starting treatment and careful monitoring should be carried out during treatment for all patients, especially those with risk factors for developing liver disease or receiving concomitant therapy with drugs that may cause liver damage.

• Before starting therapy

Treatment with Valdoxan should only be initiated after careful evaluation of the expected benefit-to-risk ratio in patients with risk factors for hepatic impairment, such as::

• obesity/overweight/non-alcoholic fatty liver disease, diabetes,
• alcoholism and / or alcohol abuse;
• and taking medications that may cause liver dysfunction.

Before starting therapy, functional liver tests should be performed in all patients, and therapy cannot be initiated if the level of liver enzymes AJIT and / or ACT is more than 3 times higher than the upper limit of normal. Caution should be exercised when prescribing the drug Valdoxan® to patients with initially increased transaminase activity (above the upper limit of normal, but not more than 3 times relative to the upper limit of normal).

• Frequency of functional liver tests
  • Before starting therapy
  • And then:
    • approximately 3 weeks,
    • approximately 6 weeks (end of the relief period of therapy),
    • 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 second study should be performed within 48 hours.

• During treatment

Treatment with Valdoxan® should be discontinued 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, recent persistent and unexplained fatigue).
• increases in the level of transaminases by more than 3 times, compared with the upper limit of normal.

After discontinuation of therapy with Valdoxan®, regular liver function tests should be performed until the level of transaminases normalizes. Elderly patients

The efficacy of the drug in elderly patients (aged 75 years and older) has not been established. Therefore, Valdoxan® should not be used in patients of this age group. Elderly patients with dementia

Do not prescribe Valdoxan® 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 renal insufficiency

No significant changes in pharmacokinetic parameters were observed in patients with severe renal insufficiency. However, there is limited experience with the use of Valdoxan® for major depressive episodes in patients with moderate to severe renal insufficiency. Caution should be exercised when prescribing Valdoxan to such patients. Bipolar disorder/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

Depressed people have an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). The risk persists until a clear remission occurs. Patients should be kept under medical supervision until the condition improves (after starting 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 before starting therapy, are at risk and should be closely monitored during therapy. The results of a meta-analysis of clinical trials of antidepressants in patients with psychiatric disorders indicate an increased risk of suicidal behavior in patients under the age of 25 years while taking antidepressants compared to placebo. During treatment, patients, especially those at risk, should be closely monitored, especially at the beginning of therapy and when changing the dose of the drug. Patients (and their caregivers) should be informed about the need to immediately consult a doctor if their condition worsens, suicidal or unusual behavior occurs, or if suicidal thoughts occur. Co-use with CYP1A2 isoenzyme inhibitors

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

Patients with lactose intolerance

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

Influence on the ability to drive vehicles and mechanisms

Studies on the effect of the drug Valdoxan® on the ability to drive a car and other mechanisms have not been conducted. Keep in mind that dizziness and drowsiness are common side effects of agomelatine.

Form of production

Film-coated tablets

Storage conditions

No special storage conditions are required

Shelf life

3 years

Active ingredient

Agomelatine

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Depression