Instructions for use FEVARIN® (FEVARIN)

Composition and release form

in a blister 15 or 20 pcs.; in a cardboard pack there are 1, 2, 3 or 4 blisters.

Pharmacokinetics

When taken orally, it is completely absorbed from the gastrointestinal tract. Cmax is reached in 3–8 hours, equilibrium concentration is achieved in 10–14 days. Absolute bioavailability is 53% after primary metabolism in the liver. Simultaneous administration of Fevarin® with food does not affect the pharmacokinetics.

Plasma protein binding is approximately 80%. Volume of distribution - 25 l/kg.

Metabolism of Fevarin® occurs mainly in the liver. Although the 2D6 isoenzyme of cytochrome P450 is the main one in the metabolism of fluvoxamine, the concentration of the drug in the blood plasma in individuals with reduced function of this isoenzyme is not much higher than in individuals with normal metabolism. The average T1/2 from the blood plasma, which is 13–15 hours for a single dose, increases slightly with repeated doses (17–22 hours), and the equilibrium concentration in the blood plasma is usually achieved after 10–14 days.

Fevarin® undergoes biotransformation in the liver (mainly by oxidative demethylation) to at least 9 metabolites, which are excreted through the kidneys. The 2 main metabolites have little pharmacological activity. Other metabolites are probably pharmacologically inactive. Fluvoxamine significantly inhibits cytochrome P450 1A2, moderately inhibits cytochromes P450 2C and P450 3A4, and slightly inhibits cytochrome P450 2D6.

The pharmacokinetics of fluvoxamine are similar in healthy people, the elderly and patients with renal failure. Metabolism is reduced in patients with liver disease.

Steady-state plasma concentrations of fluvoxamine in children aged 6–11 years are twice as high as in adolescents (12–17 years). Concentrations of the drug in the blood plasma of adolescents are similar to those in adults.

Contraindications

hypersensitivity to fluvoxamine maleate or to one of the excipients included in the drug;

simultaneous use of tizanidine and MAO inhibitors.

Treatment with fluvoxamine can be started 2 weeks after stopping an irreversible MAO inhibitor or the day after taking a reversible MAO inhibitor. The time interval between stopping fluvoxamine and starting therapy with any MAO inhibitor should be at least a week.

Carefully:

liver and kidney failure;

history of seizures, epilepsy;

elderly age;

patients with a tendency to bleed (thrombocytopenia);

pregnancy.

Not recommended for the treatment of depression in children (no clinical experience).

Side effects

The most commonly observed symptom associated with the use of Fevarin® is nausea, sometimes accompanied by vomiting. This side effect usually disappears in the first 2 weeks of treatment.

Some side effects observed in clinical trials were often related to symptoms of depression rather than to treatment with Fevarin®.

General: often (1–10%) - asthenia, headache, malaise.

From the cardiovascular system: often (1–10%) - palpitations, tachycardia; sometimes (less than 1%) - postural hypotension.

From the gastrointestinal tract: often (1–10%) - abdominal pain, anorexia, constipation, diarrhea, dry mouth, dyspepsia; rarely (less than 0.1%) - impaired liver function (increased levels of liver transaminases).

From the side of the central nervous system: often (1–10%) - nervousness, anxiety, agitation, dizziness, insomnia or drowsiness, tremor; sometimes (less than 1%) - ataxia, confusion, extrapyramidal disorders, hallucinations; rarely (less than 0.1%) - convulsions, manic syndrome.

On the skin: often (1–10%) - sweating; sometimes (less than 1%) - skin hypersensitivity reactions (rash, itching, angioedema); rarely (less than 0.1%) - photosensitivity.

From the musculoskeletal system: sometimes (less than 1%) - arthralgia, myalgia.

From the reproductive system: sometimes (less than 1%) - delayed ejaculation; rarely (less than 0.1%) - galactorrhea.

Other: rarely (less than 0.1%) - change in body weight; serotonergic syndrome, neuroleptic malignant syndrome-like condition, hyponatremia and antidiuretic hormone deficiency syndrome; very rarely - paresthesia, anorgasmia and taste perversion.

When you stop taking fluvoxamine, withdrawal symptoms may develop - dizziness, paresthesia, headache, nausea, anxiety (most symptoms are mild and self-limiting). When discontinuing the drug, a gradual dose reduction is recommended.

Hemorrhagic manifestations - ecchymosis, purpura, gastrointestinal bleeding.

Side effects of the drug Fevarin

Nausea and vomiting are the most common symptoms associated with treatment with Fevarin. The severity of this side effect decreases significantly during the first two weeks of treatment. Other adverse events observed during clinical trials at the frequencies listed below were often disease-related and not necessarily related to treatment. Often (frequency 1–10%) Metabolic and nutritional disorders: anorexia. From the central nervous system: agitation, anxiety, dizziness, headache, insomnia, nervousness, drowsiness, tremor. From the cardiovascular system: palpitations/tachycardia. From the gastrointestinal tract: abdominal pain, constipation, diarrhea, dry mouth, dyspepsia. From the skin and subcutaneous tissues: increased sweating. General disorders and reactions at the injection site: asthenia, feeling of malaise. Uncommon (frequency ≤ 1%) Mental disorders: confusion, hallucinations. From the central nervous system: ataxia, extrapyramidal symptoms. From the cardiovascular system: (postural) hypotension. From the skin and subcutaneous tissues: rash, itching, angioedema. From the musculoskeletal system: arthralgia, myalgia. From the reproductive system: disturbance (delay) of ejaculation. Rarely (frequency ≤ 0.1%) Mental disorders: manic states. From the side of the central nervous system: convulsions. From the hepatobiliary system: impaired liver function. From the skin and subcutaneous tissues: photosensitivity. From the reproductive system and mammary glands: galactorrhea. Other side effects that were observed during use of the drug. Cases of weight gain or loss have been recorded, as well as serotonin syndrome, phenomena similar to neuroleptic malignant syndrome, hyponatremia and syndrome of impaired antidiuretic hormone secretion (see also section “Peculiarities of use”). After discontinuation of treatment with Fevarin, a withdrawal reaction may occur, although preclinical and clinical data do not indicate that this treatment is addictive. In connection with drug withdrawal, the following symptoms were observed: dizziness, paresthesia, headache, nausea and anxiety. They usually disappear on their own. Before stopping treatment, it is advisable to consider the need to gradually reduce the dose of the drug. Hemorrhagic manifestations: ecchymosis, purpura, gastrointestinal bleeding (see also section “Peculiarities of use”). Paresthesia, anorgasmia and changes in taste sensations occurred very rarely. In each frequency group, undesirable effects are arranged according to the degree of reduction in their severity.

Interaction

Fevarin® should not be used in combination with MAO inhibitors.

Fluvoxamine is a potent inhibitor of cytochrome P450 1A2, and to a lesser extent, P450 2C and P450 3A4. Drugs that are extensively metabolized by these isoenzymes are eliminated more slowly and may have higher plasma concentrations when coadministered with fluvoxamine. This is especially important for drugs that are characterized by a narrow breadth of therapeutic action. Patients require careful monitoring, and dosage adjustments are recommended if necessary.

Fluvoxamine has minimal inhibitory effects on cytochrome P450 2D6 and appears to have no effect on non-oxidative metabolism or renal excretion.

Cytochrome P450 1A2. With simultaneous use of Fevarin®, an increase in previously stable levels of tricyclic antidepressants (clomipramine, imipramine, amitriptyline) and antipsychotics (clozapine, olanzapine), which are significantly metabolized by cytochromes P450 1A2, was observed. In this regard, a reduction in the dose of these drugs may be recommended.

Patients concomitantly taking fluvoxamine and drugs with a low therapeutic effect that are metabolized by cytochrome P450 1A2 (such as tacrine, theophylline, methadone, mexiletine) should be closely monitored. If necessary, the dosages of these drugs should be adjusted.

When used in combination with warfarin, a significant increase in warfarin plasma concentrations and prolongation of PT were observed.

Isolated cases of cardiotoxicity have been reported with concomitant use of fluvoxamine with thioridazine.

In studies examining the interactions of Fevarin®, an increase in propranolol concentrations was noted after administration of Fevarin®. In this regard, it is possible to recommend reducing the dose of propranolol in case of additional administration of Fevarin®.

Plasma caffeine levels may increase while taking fluvoxamine. Therefore, if you consume large quantities of drinks containing caffeine and if you develop adverse effects of caffeine such as tremor, palpitations, nausea, anxiety, insomnia, you should reduce your caffeine intake while taking fluvoxamine.

When taking fluvoxamine and ropinirole simultaneously, the plasma concentration of the latter may increase, thereby increasing the risk of developing an overdose. In such cases, it is recommended to control the dosage of ropinirole or reduce it during treatment with fluvoxamine.

Cytochrome P450 2C. Patients concomitantly taking fluvoxamine and drugs characterized by a low breadth of therapeutic action and undergoing metabolism by cytochrome P450 2C (phenytoin) should be closely monitored, and dosage adjustment of these drugs is recommended.

Cytochrome P450 3A4. Terfenadine, astemizole, cisapride - see "Precautions".

Patients concomitantly taking fluvoxamine and drugs characterized by a low breadth of therapeutic action and undergoing metabolism by cytochrome P450 3A4 (such as carbamazepine, cyclosporine) should be closely monitored, and dosage adjustment of these drugs is recommended.

When administered concomitantly with fluvoxamine, benzodiazepines that undergo oxidative metabolism, such as triazolam, midazolam, alprazolam and diazepam, may increase their plasma concentrations. The dosage of these benzodiazepines should be reduced while taking fluvoxamine.

Glucuronidation. Fluvoxamine has no effect on plasma digoxin concentrations.

Renal excretion. Fluvoxamine has no effect on plasma concentrations of atenolol.

Pharmacodynamic reactions. In the case of combined use of fluvoxamine with serotonergic drugs (triptans, serotonin reuptake inhibitors), tramadol, the serotonergic effects of fluvoxamine may be enhanced (see “Precautions”).

Fluvoxamine is used with lithium preparations to treat severely ill patients who respond poorly to pharmacotherapy. Lithium and possibly tryptophan enhance the serotonergic effects of Fevarin ® and therefore treatment with this combination should be carried out with caution.

When taking oral anticoagulants and fluvoxamine simultaneously, the risk of hemorrhage may increase. Such patients should be under medical supervision.

Directions for use and doses

Orally, without chewing and with a small amount of water.

Depression. The recommended starting dose is 50 or 100 mg (once, in the evening). It is recommended to gradually increase the starting dose to the effective level. The effective daily dose, usually 100 mg, is selected individually, depending on the patient's response to treatment. The daily dose can reach 300 mg. Daily doses above 150 mg should be divided into several doses. According to official WHO recommendations, treatment with antidepressants should be continued for at least 6 months of remission after a depressive episode. To prevent relapses of depression, it is recommended to take 100 mg of Fevarin® once a day.

Obsessive-compulsive disorders. It is recommended to start with a dose of 50 mg Fevarin® per day for 3–4 days. The effective daily dose is usually from 100 to 300 mg. Doses should be increased gradually until an effective daily dose is reached, which should not exceed 300 mg in adults. Doses up to 150 mg can be taken as single doses, preferably in the evening. Daily doses above 150 mg are recommended to be divided into 2 or 3 doses.

Doses for children over 8 years of age and adolescents: initial - 25 mg/day for 1 dose, maintenance - 50-200 mg/day. The daily dose should not exceed 200 mg. Daily doses above 100 mg are recommended to be divided into 2 or 3 doses.

If there is a good response to the drug, treatment can be continued at an individually selected daily dose. If improvement is not achieved after 10 weeks of treatment, fluvoxamine should be discontinued. Until now, no systematic studies have been organized that could answer the question of how long treatment with fluvoxamine can be carried out, however, obsessive-compulsive disorders are chronic in nature, and therefore it can be considered advisable to extend treatment with Fevarin® beyond 10 weeks in patients with good responders to this drug. The selection of the minimum effective maintenance dose should be done with caution on an individual basis. Some clinicians recommend concomitant psychotherapy in patients who have responded well to pharmacotherapy.

Treatment of patients suffering from liver or kidney failure should begin with the lowest doses under strict medical supervision.

Due to the lack of clinical experience, Fevarin® is not recommended for the treatment of depression in children.

Use of the drug Fevarin

The tablets are taken orally, without chewing and with water. Depression (adults) The recommended initial dose of the drug is 50 or 100 mg 1 time per day. It should be taken once a day, before bed. The dose should be increased gradually until a clinical effect is achieved. The effective dose of fluvoxamine is usually 100 mg/day. The maximum daily dose is 300 mg/day. If the drug is prescribed at a dose exceeding 150 mg/day, it is divided into several doses throughout the day. In accordance with WHO recommendations, after the patient’s symptoms of depression disappear, treatment should be continued for at least another 6 months. The recommended dose of the drug to prevent relapse of depression is 100 mg of fluvoxamine once a day. Obsessive-compulsive disorders (adults and children aged 8 years and older) The recommended starting dose is 50 mg/day for 3–4 days, after which it should be gradually increased until the maximum effective dose is reached, which is usually 100–300 mg/day. days The maximum daily dose of Fevarin in adults is 300 mg, and in children over 8 years of age and adolescents - 200 mg. Fluvoxamine in a dose of up to 150 mg is prescribed once a day, preferably at night. If the drug is prescribed in a dose exceeding 150 mg, it should be divided into 2-3 doses during the day. Once the therapeutic effect is achieved, treatment can be continued at an individually selected dose. If after 10 weeks of treatment there is no improvement, the advisability of further use of Fevarin should be reconsidered. Although systematic studies have not been conducted on how long treatment with the drug can last for obsessive-compulsive disorders, taking into account their chronic nature, it is recommended to continue treatment after 10 weeks of continuous use of the drug, provided that a positive therapeutic effect is achieved. Dose selection must be very careful to keep the patient on the lowest effective dose. The advisability of continuing treatment should be reviewed periodically. Some clinicians recommend the combined prescription of behavioral psychotherapy for patients who achieved a positive effect during treatment with Fevarin. Patients with hepatic or renal insufficiency should begin treatment with a low dose and be under close medical supervision. The tablets should be swallowed whole with water.

Overdose

Symptoms: the most typical are gastrointestinal disorders (nausea, vomiting and diarrhea), drowsiness and dizziness. In addition, there are reports of cardiovascular disorders (tachycardia, bradycardia, hypotension), liver dysfunction, seizures and even coma. To date, there have been over 300 reports of cases of intentional overdose of Fevarin®. The highest recorded dose of Fevarin® received by one patient was 12 g; this patient was cured as a result of symptomatic therapy. More serious complications were observed in cases of deliberate overdose of Fevarin® against the background of concomitant pharmacotherapy.

Treatment: gastric lavage, which should be carried out as soon as possible after taking the drug, as well as symptomatic therapy. In addition, repeated intake of activated carbon is recommended. Increased diuresis or dialysis seems unjustified. There is no specific antidote.

Fevarin overdose, symptoms and treatment

The most common symptoms are nausea, vomiting, diarrhea, drowsiness and dizziness; possible tachycardia, bradycardia, arterial hypotension; liver dysfunction; convulsions and coma. Fevarin has a fairly wide range of safety in case of overdose. Reports of deaths due to overdose of Fevarin alone are isolated. The highest recorded dose of the drug during an overdose was 12 g. The patient who took it completely recovered. More serious complications have been reported in cases of deliberate overdose of fluvoxamine in combination with other drugs. Treatment is symptomatic. There is no special antidote. In case of overdose, you should rinse your stomach as soon as possible, take activated charcoal, and carry out maintenance therapy. If necessary, osmotic laxatives are prescribed. The effectiveness of forced diuresis or dialysis is questionable.

Precautionary measures

During treatment with the drug, drinking alcohol is not recommended.

Patients suffering from depression generally have a high risk of attempting suicide, which may persist until sufficient remission is achieved. Such patients should be monitored.

Treatment of patients suffering from liver or kidney failure should begin with the minimum effective doses of Fevarin® under strict medical supervision. In rare cases, treatment with Fevarin® may lead to increased levels of liver transaminases, most often accompanied by corresponding clinical symptoms. In these cases, Fevarin® should be discontinued.

Blood glucose control may be impaired, especially in the early stages of treatment. Dosage adjustments of antidiabetic medications may be necessary.

Caution should be exercised when prescribing the drug to patients with a history of seizures. Prescribing Fevarin® to patients with unstable epilepsy should be avoided, and patients with stable epilepsy should be under strict medical supervision. Treatment with Fevarin should be discontinued if epileptic seizures develop or their frequency increases.

Rare cases of the development of serotonergic syndrome or a condition similar to neuroleptic malignant syndrome have been described, which may be associated with taking fluvoxamine in combination with other serotonergic antidepressants and antipsychotics. Because these syndromes can lead to potentially life-threatening conditions manifested by hyperthermia, muscle rigidity, myoclonus, autonomic lability with possible rapid changes in vital signs, mental status changes including irritability, agitation, confusion, delirium and coma, - Treatment with fluvoxamine should be discontinued. If necessary, appropriate treatment should be started.

As with the use of other selective serotonin reuptake inhibitors, in rare cases, while taking fluvoxamine, hyponatremia may occur, which reverses after discontinuation of the drug. Some cases have been caused by antidiuretic hormone deficiency syndrome. These cases were mainly observed in elderly patients.

There are reports of intradermal hemorrhages such as ecchymosis and purpura, as well as hemorrhagic manifestations (eg gastrointestinal bleeding) observed with the use of selective serotonin reuptake inhibitors. Caution should be exercised when prescribing these drugs in elderly patients and patients concomitantly receiving drugs that affect platelet function (atypical antipsychotics and phenothiazines, many tricyclic antidepressants, aspirin, NSAIDs) or drugs that increase the risk of bleeding, as well as in patients with bleeding history and prone to bleeding (for example, in patients with thrombocytopenia).

When combined with fluvoxamine, plasma concentrations of terfenadine, astemizole or cisapride may increase, increasing the risk of QT prolongation. Therefore, fluvoxamine should not be given with these drugs.

Data obtained from the treatment of elderly patients and younger patients indicate the absence of clinically significant differences between the daily doses usually used in them. However, increasing doses of the drug in elderly patients should always be done more slowly and with greater caution. Fevarin® may lead to a slight decrease in heart rate (by 2–6 beats per minute).

Due to the lack of clinical experience, Fevarin® is not recommended for the treatment of depression in children.

Fevarin®, administered to healthy volunteers in doses of up to 150 mg, had no or negligible effect on the ability to drive a car or control machines. At the same time, there are reports of drowsiness noted during treatment with the drug. In this regard, caution is recommended until the individual response to the drug is definitively determined.

Special instructions for the use of the drug Fevarin

In patients with depression and obsessive-compulsive disorder, there is a constant tendency to commit suicide, which may persist throughout the entire period of treatment until significant remission is achieved. Careful monitoring of this category of patients is necessary. In patients with impaired renal or liver function, treatment should begin with low doses of the drug and under close medical supervision. Occasionally, treatment with Fevarin was accompanied by an increase in the activity of liver enzymes and corresponding clinical symptoms. In such cases, treatment with the drug should be discontinued. Glycemic control may be impaired, especially in the early stages of treatment, which may require dose adjustment of hypoglycemic drugs. Despite the fact that Fevarin did not cause seizures in animal experiments, special caution is required if it is prescribed to patients with a history of seizures. The drug should not be prescribed to patients with unstable epilepsy, and patients with controlled epilepsy should be closely monitored. If the patient develops convulsions or their frequency increases, Fevarin should be discontinued. There are isolated reports of the occurrence of serotonin syndrome or phenomena similar to neuroleptic malignant syndrome, especially when Fevarin is used simultaneously with other serotonergic and/or neuroleptic drugs. Since these syndromes can cause life-threatening conditions, if symptoms such as hyperthermia, rigidity, myoclonus, frequent changes in blood pressure, pulse and respiratory rate, confusion, irritability, agitation with progression to delirium and coma appear, treatment with Fevarin should be stopped and symptomatic treatment should be performed. therapy. Rarely, while taking Fevarin (as well as other selective serotonin reuptake inhibitors), hyponatremia occurs. Plasma sodium levels return to normal after stopping the drug. Sometimes the occurrence of hyponatremia may be due to the syndrome of inappropriate secretion of antidiuretic hormone. Most cases of hyponatremia have been reported in elderly people. There have been reports of cases of ecchymosis, purpura and gastrointestinal bleeding while taking selective serotonin reuptake inhibitors. These drugs are prescribed with caution, especially in the elderly, concomitantly with drugs that affect platelet function (for example, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and other NSAIDs), as well as in patients with a history of hemorrhagic conditions or conditions which are caused by a tendency to bleeding (for example, thrombocytopenia). When used concomitantly with fluvoxamine, plasma concentrations of terfenadine, astemizole or cisapride may increase, increasing the risk of QT and torsade de pointes (TdP). Therefore, Fevarin should not be prescribed together with these medications. The results of a study of fluvoxamine in elderly patients taking the drug in the usual daily dose indicate the absence of clinically significant differences compared with younger patients. However, the dose of the drug in elderly patients should be increased more slowly and carefully. Fevarin may slightly reduce heart rate (by 2–6 beats/min). Use during pregnancy and lactation. Data from a limited number of cases of use of Fevarin in pregnant women do not indicate side effects. No other epidemiological data are available. Animal reproductive studies have shown impaired fertility (at doses 4 times the maximum recommended human dose), increased fetal mortality, decreased fetal weight, and increased incidence of fetal eye abnormalities (puckered retina) at doses of fluvoxamine that significantly exceeded the maximum recommended doses for humans. The potential risk to humans is unknown. Caution must be exercised when prescribing the drug to pregnant women. There have been isolated cases of withdrawal symptoms in newborns after using Fevarin at the end of pregnancy. After the use of selective serotonin reuptake inhibitors during the third trimester of pregnancy, some newborns experienced swallowing and/or breathing disorders, convulsions, temperature instability, hypoglycemia, tremors, impaired muscle tone, trembling and constant crying, which required prolonged hospitalization. The drug is excreted in small amounts in breast milk, so it should not be prescribed to women who are breastfeeding. Children. Fevarin should not be used to treat children except for patients with OCD. In clinical studies, among children who received antidepressants, compared with the placebo group, suicide attempts and suicidal thoughts and aggressiveness (conflict behavior, anger) were more often observed. If a decision is made to prescribe therapy based on clinical indications, the patient must be carefully monitored for the possible emergence of suicidal symptoms. In addition, there are no long-term safety data in children regarding growth, maturation, and cognitive development. The drug cannot be used to treat depression in children due to lack of sufficient experience. The ability to influence the reaction rate when driving vehicles or other mechanisms. Fevarin in a daily dose of 150 mg has no or almost no effect on the ability to drive vehicles and work with potentially dangerous machines and mechanisms. However, during treatment with Fevarin, drowsiness may occur, which must be taken into account before establishing an individual response to the drug.