Rokona, 50 mg 15 pcs.

Intake: After oral administration, fluvoxamine is completely absorbed from the gastrointestinal tract. Maximum concentrations of fluvoxamine in plasma are observed 3-8 hours after intake. Absolute bioavailability is 53% after primary metabolism in the liver. Concomitant administration of fluvoxamine with food has no effect on pharmacokinetics.

Distribution: The binding of fluvoxamine to plasma proteins is 80% (in vitro). The volume of distribution is 25 l/kg.

Metabolism: Metabolism of fluvoxamine occurs mainly in the liver. Although cytochrome P 450 isoenzyme 2D6 is major in the metabolism of fluvoxamine, plasma concentrations of the drug in individuals with decreased function of this isoenzyme are not much higher than in those with normal metabolism.

The average plasma elimination half-life, which is 13-15 hours for a single dose, is slightly longer with multiple doses (17-22 hours), and equilibrium plasma concentrations are generally reached within 10-14 days.

Fluvoxamine undergoes biotransformation in the liver (mainly by oxidative demethylation) to at least nine metabolites, which are excreted via the kidneys. The two major metabolites have negligible pharmacological activity. Other metabolites are probably pharmacologically inactive.

Fluvoxamine significantly inhibits cytochrome P450 1A2 and P450 2C19 and moderately inhibits cytochromes P450 2C9, P450 2D6 and P450 WA4.

The pharmacokinetics of a single dose of fluvoxamine is linear. The equilibrium concentration of fluvoxamine is higher than that of single dose, and this disproportionality is more pronounced at higher daily doses.

Particular patient groups: The pharmacokinetics of fluvoxamine are similar in healthy subjects, the elderly, and patients with renal impairment. The metabolism of fluvoxamine is reduced in patients with liver disease.

The equilibrium plasma concentration of fluvoxamine is twice as high in children (ages 6-11 years) than in adolescents (ages 12-17 years). Plasma concentrations of the drug in adolescents are similar to those in adults.

Receptor binding studies have shown that fluvoxamine is a potent serotonin reuptake inhibitor both in vitro and in vivo with minimal affinity for serotonin receptors.

His ability to bind to α- and β-adrenoreceptors, histamine, m-choline or dopamine receptors is negligible. Fluvoxamine has a high affinity for σ1 receptors, acting as their agonist.

Indications

Active ingredient

Composition

Active ingredient: fluvoxamine maleate (in terms of anhydrous substance) 50 mg or 100 mg.

Auxiliary substances: mannitol, corn starch, pregelatinized starch, sodium stearyl fumarate, colloidal silicon dioxide.

The composition of the shell: hypromellose, titanium dioxide, macrogol (polyethylene glycol 6000), talc.

How to take, the dosage

Tablets of fluvoxamine should be taken orally, without chewing, with water. The tablet may be divided into two equal parts.

Depression

Adults: The recommended starting dose for adults is 50 mg or 100 mg (once, in the evening). After 3-4 weeks of therapy, the dose should be reviewed and adjusted according to clinical experience with the drug. A gradual increase in dose to effective levels is recommended.

The effective daily dose, usually 100 mg, is adjusted individually depending on the patient’s response to treatment. The daily dose can be as high as 300 mg. Daily doses over 150 mg are recommended to be divided into 2 or 3 doses. The selection of the minimum effective maintenance dose should be made with caution on an individual basis.

In accordance with official WHO recommendations, antidepressant treatment should be continued for at least 6 months of remission after a depressive episode.

To prevent recurrences of depression, it is recommended that 100 mg of the drug be taken once daily, daily.

Children: Because of a lack of clinical experience, fluvoxamine is not recommended for the treatment of depression in children under 18 years of age.

Obsessive-compulsive disorder (OCD)

Adults: The recommended starting dose for adults is 50 mg of the drug daily for 3-4 days. The effective daily dose is usually 100 mg to 300 mg.

The doses should be increased gradually until the effective daily dose is reached, which should not exceed 300 mg in adults. Doses up to 150 mg may be taken once daily, preferably in the evening. Daily doses over 150 mg are recommended to be divided into 2 or 3 doses.

If there is a good therapeutic response to the drug, treatment may be continued with an individually tailored daily dose. If improvement is not achieved after 10 weeks, treatment with fluvoxamine should be reconsidered.

There have been no systematic studies organized to date to answer the question of how long treatment with fluvoxamine can be maintained, but obsessive-compulsive disorder is chronic, and therefore it may be considered appropriate to extend fluvoxamine treatment beyond 10 weeks in patients who respond well to the drug.

The selection of the minimum effective maintenance dose should be done with caution on a case-by-case basis.

The need for treatment should be reassessed periodically. Some clinicians recommend concomitant psychotherapy in patients who respond well to pharmacotherapy. Long-term efficacy (more than 24 weeks) has not been confirmed.

Children over 8 years of age and adolescents: In children over 8 years of age and adolescents, there are limited data on use at doses greater than 100 mg twice daily for 10 weeks. The starting dose for children over 8 years of age and adolescents is 25 mg/day for a single dose, preferably before bedtime.

The dose should be increased by 25 mg to the tolerated dose every 4 to 7 days until the effective daily dose is reached. The effective dose is usually 50 to 200 mg/day; the maximum dose in children should not exceed 200 mg/day. Daily doses over 50 mg are recommended to be divided into 2 doses, and if the two doses received are unequal, the larger dose should be taken before bedtime.

The “withdrawal” syndrome after discontinuation of fluvoxamine: Abrupt withdrawal of the drug should be avoided. When treatment with fluvoxamine is discontinued, the dose should be gradually reduced over at least 1-2 weeks to reduce the risk of withdrawal (see Side Effects and Precautions).

If intolerable symptoms occur after reducing the dose or after withdrawing treatment, consideration may be given to resuming treatment at the previously recommended dose. At a later date, the physician may start reducing the dose again, but more gradually.

Treatment of patients with hepatic or renal impairment should be started at low doses under close medical supervision.

Interaction

MAO inhibitors: Fluvoxamine should not be used in combination with MAO inhibitors, including linezolid, because of the risk of serotonin syndrome (see section “Contraindications”).

The effect of fluvoxamine on the oxidative process of other drugs: Fluvoxamine may inhibit the metabolism of drugs that are metabolized by certain cytochrome P450 isoenzymes. In vitro and in vivo studies have shown a potent inhibitory effect of fluvoxamine on cytochrome P450 isoenzymes 1A2 and P450 2C19 and to a lesser extent on cytochrome P450 2C9, P450 2D6 and P450 3A4.

Drugs that are significantly metabolized by these isoenzymes are more slowly excreted and may have higher plasma concentrations if concomitantly used with fluvoxamine. Such drugs should be prescribed at the lowest dose or reduced to the lowest dose when used concomitantly with fluvoxamine.

The close monitoring of plasma concentrations, effects, or adverse effects is required, and dose adjustments of these drugs, if necessary. This is especially important for drugs that have a narrow therapeutic range.

Ramelteon: When taking fluvoxamine twice daily at 100 mg for 3 days before concomitant use of ramelteon at a dose of 16 mg, the AUC (area under the concentration-time curve) for ramelteon increased by approximately 190 times and the Cmax (maximum concentration) increased by approximately 70 times compared to these parameters when ramelteon alone was prescribed.

Drugs with a narrow therapeutic range: Patients concurrently taking fluvoxamine and narrow therapeutic range drugs that are metabolized exclusively or by a combination of cytochrome isoenzymes that inhibit fluvoxamine (such as tacrine, theophylline, methadone, mexiletine, phenytoin, carbamazepine and cyclosporine) should be monitored closely. Dose adjustments for these medications are recommended if necessary.

Tricyclic antidepressants and neuroleptics: Concomitant use of fluvoxamine has shown increased concentrations of tricyclic antidepressants (e.g., clomipramine, imipramine, amitriptyline) and neuroleptics (e.g., clozapine, olanzapine, quetiapine) that are largely metabolized by cytochrome P450 1A2 isoenzymes. Therefore, if treatment with fluvoxamine is initiated, dose reduction of these drugs should be considered.

Benzodiazepines: Concomitant use with fluvoxamine of benzodiazepines that undergo oxidative metabolism, such as triazolam, midazolam, alprazolam and diazepam, may increase their plasma concentrations. The dose of these benzodiazepines should be reduced while fluvoxamine is being taken.

In cases of increased plasma concentrations: Concomitant use of fluvoxamine and ropinirole may increase the plasma concentration of ropinirole, thereby increasing the risk of overdose. In such cases, monitoring or, if necessary, reducing the dose or cancelling ropinirole during treatment with fluvoxamine is recommended.

In interaction of fluvoxamine with propranololol, increased plasma concentrations of propranolol have been noted. Therefore, it may be recommended to reduce the dose of propranolol if used concomitantly with fluvoxamine.

When using fluvoxamine in combination with warfarin, a significant increase in plasma concentrations of warfarin and prolongation of prothrombin time were observed.

In case of increased incidence of adverse effects: Single cases of cardiotoxicity have been reported with concomitant use of fluvoxamine and thioridazine.

The plasma concentration of caffeine may increase while taking fluvoxamine. Thus, patients who consume large amounts of beverages containing caffeine should decrease their intake while taking fluvoxamine, and when adverse effects of caffeine, such as tremor, palpitations, nausea, anxiety, and insomnia are observed.

P450 cytochrome P450 isoenzyme: Terfenadine, astemizole, cisapride, sildenafil: When combined therapy with fluvoxamine, plasma concentrations of terfenadine, astemizole or cisapride may increase, increasing the risk of QT interval prolongation/paroxysmal ventricular pirouette type tachycardia. Therefore, fluvoxamine should not be administered together with these drugs.

Glucuronidation: Fluvoxamine has no effect on the plasma concentration of digoxin.

Renal excretion: Fluvoxamine has no effect on the plasma concentration of atenololol.

Pharmacodynamic interactions: When fluvoxamine is used concomitantly with serotonergic drugs (such as triptans, tramadol, selective serotonin reuptake inhibitors, and St. John’s wort preparations), the serotonergic effects of fluvoxamine may be enhanced (see “Special Instructions”).

Fluvoxamine has been used in combination with lithium preparations to treat severe patients who do not respond well to pharmacotherapy. It should be noted that lithium (and possibly also tryptophan) enhances the serotonergic effects of the drug, and therefore this type of combination pharmacotherapy should be used with caution.

The simultaneous use of indirect anticoagulants and fluvoxamine may increase the risk of hemorrhages. These patients should be monitored by a physician.

Special Instructions

As with other psychotropic medications, alcohol consumption is not recommended during treatment with fluvoxamine.

Suicidal ideation/suicidal thoughts or clinical deterioration: Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide attempts (suicidal behavior). This risk persists until significant improvement.

Since improvement may not occur within the first few weeks of treatment or longer, patients should be closely monitored until such improvement occurs.

In clinical practice, there is a widespread increased risk of suicide in the early stages of recovery.

Other psychiatric disorders for which fluvoxamine is prescribed may also be associated with an increased risk of suicidal behavior. In addition, these conditions may accompany major depression. Therefore, patients with other psychiatric disorders should be closely monitored.

Patients with a history of suicidal behavior or a significant history of exhibiting suicidal ideation are known to have a greater risk of suicidal thoughts or suicide attempts before treatment and should be closely monitored during treatment.

Careful monitoring of patients, especially those at high risk, should accompany drug therapy especially in its early stages and after dose changes.

Patients (and their caregivers) should be warned to monitor for any clinical deterioration, suicidal behavior or suicidal ideation, and unusual behavioral changes, and to seek immediate professional consultation if such symptoms occur.

In the pediatric population: Fluvoxamine should not be used to treat children and adolescents under 18 years of age with the exception of patients with obsessive-compulsive disorder.

Due to a lack of clinical experience, fluvoxamine cannot be recommended for the treatment of depression in children.

In clinical studies in children and adolescents, suicidal-conditioned behavior (suicide attempts and thoughts) and hostility (mainly aggression, oppositional behavior and anger) were observed more frequently in patients who received the antidepressant compared to those who received placebo.

If, based on clinical need, a decision to treat is made, the patient should be closely monitored for suicidal symptoms.

In addition, long-term safety data for children and adolescents regarding growth, development, and establishment of cognitive behavior are not available.

Adults (18 to 24 years): A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders found an increased risk of suicidal behavior with antidepressants compared to placebo in patients younger than 25 years. When prescribing fluvoxamine, the risk of suicide should be weighed against the benefit of its use.

Elderly patients: Data from the treatment of elderly and younger patients suggest that there are no clinically significant differences between their commonly used daily doses. However, dosage escalation in older patients should always be done more slowly and with more caution.

Akathisia/psychomotor agitation: The development of akathisia associated with fluvoxamine administration is characterized by subjectively unpleasant and distressing anxiety. The need to move was often accompanied by an inability to sit or stand still. The development of this condition is most likely during the first few weeks of treatment. Increasing the dose of the drug in patients with these symptoms may worsen their condition.

Disorders of hepatic and/or renal function: Treatment of patients with hepatic or renal insufficiency should be started with low doses, patients should be under close medical supervision.

In rare cases, treatment with fluvoxamine may result in increased hepatic enzyme activity, most often accompanied by associated clinical symptoms, in which case the drug should be discontinued.

Nervous system disorders: Caution should be exercised when prescribing the drug to patients with a history of seizures. Administration of fluvoxamine in patients with unstable epilepsy should be avoided, and patients with stable epilepsy should be closely monitored.

The drug should be discontinued if epileptic seizures occur or their frequency increases.

Rare cases of serotonergic syndrome or a condition similar to malignant neuroleptic syndrome have been described, which may be associated with the administration of fluvoxamine, especially in combination with other serotonergic and/or neuroleptic drugs.

Because these syndromes can lead to potentially life-threatening conditions manifested by hyperthermia, muscle stiffness, myoclonus, autonomic nervous system lability with possible rapid changes in vital parameters (pulse, respiration, BP, etc.etc.), changes in mental status, including confusion, irritability, extreme agitation up to delirium or coma – in such cases, treatment with fluvoxamine should be stopped and appropriate symptomatic treatment initiated.

Metabolic and nutritional disorders: As with other selective serotonin reuptake inhibitors, in rare cases, hyponatremia may occur, which reverses after withdrawal of fluvoxamine. Some cases have been caused by insufficient antidiuretic hormone secretion syndrome. These cases were mostly observed in elderly patients.

Blood glucose control may be impaired (i.e., hyperglycemia, hypoglycemia, impaired glucose tolerance), especially in the early stages of treatment. If fluvoxamine is prescribed to patients with a history of diabetes mellitus, an adjustment of the dose of antidiabetic drugs may be required.

The most commonly observed symptom associated with the use of fluvoxamine is nausea, sometimes accompanied by vomiting. This side effect usually disappears within the first two weeks of treatment.

VIight disturbances: Cases of mydriasis have been reported with SSRIs such as fluvoxamine.

Therefore, fluvoxamine should be administered with caution in patients with elevated intraocular pressure or in patients at increased risk of acute closed-angle glaucoma.

Hematological disorders:

There have been reports of intradermal hemorrhages such as ecchymoses and purpura, as well as other hemorrhagic manifestations (such as gastrointestinal bleeding or gynecological bleeding) observed when using selective serotonin reuptake inhibitors.

. Caution should be exercised when prescribing these medications in elderly patients and, patients concomitantly receiving medications acting on platelet function (e.g., atypical antipsychotics and phenothiazines, many tricyclic antidepressants, Acetylsalicylic acid, non-steroidal anti-inflammatory drugs) or drugs that increase the risk of bleeding, and patients with a history of bleeding or those prone to bleeding (e.g., thrombocytopenia or coagulation disorders).

Heart disorders: Increased risk of QT interval prolongation/paroxysmal ventricular pirouette tachycardia when combining fluvoxamine with terfenadine or astemizole or cisapride, due to increased plasma concentrations of the latter. Therefore, fluvoxamine should not be administered together with these drugs.

Fluvoxamine may cause a slight decrease in HR (2-6 beats per minute).

Electroconvulsive therapy (ECT): There is limited experience with the clinical use of fluvoxamine with ECT, so this therapy should be used with caution.

Withdrawal reactions: Withdrawal from fluvoxamine may occur, although available data from preclinical and clinical studies have not demonstrated dependence on fluvoxamine treatment.

The most common symptoms noted if the drug is withdrawn are: dizziness, sensory disturbances (including paresthesias, visual disturbances and a current sensation), sleep disturbances (including insomnia and vivid dreams) agitation, irritability, confusion, emotional lability, headache, nausea and/or vomiting, diarrhea, sweating, palpitations, tremors and anxiety (see See side effects section).

The majority of these symptoms are mild to moderate and resolve on their own, but in some patients they may be severe and/or prolonged.

These symptoms usually occur within the first few days of stopping treatment. For this reason, it is recommended that the dose of fluvoxamine be gradually reduced before complete withdrawal according to the patient’s condition (see section “Dosage and administration”).

Mania/hypomania: Fluvoxamine should be used with caution in patients with a history of mania/hypomania. Fluvoxamine should be discontinued if the patient develops a manic phase.

Impact on driving, operating machinery: Fluvoxamine administered to healthy volunteers in doses up to 150 mg had no or negligible effect on driving and operating machinery.

At the same time, there have been reports of somnolence noted during treatment with fluvoxamine. Therefore, caution is advised until a final determination of the individual response to the drug is made.

Contraindications

Hypersensitivity to the active substance or to any of the ingredients of the drug.

With caution: Hepatic and renal failure, history of seizures, epilepsy, advanced age, patients with a tendency to bleeding (thrombocytopenia), pregnancy, lactation.

Side effects

Some side effects observed in clinical trials were often related to the disease and not to the treatment with fluvoxamine.

All reactions are categorized by organ system and frequency of development: frequently >1/100 to 1/1000 to 1/10000 to

Blood and lymphatic system disorders: frequency not determined – bleeding (e.g., gastrointestinal bleeding, gynecological bleeding, ecchymosis, purpura).

Endocrine system disorders: frequency is not established – hyperprolactinemia, syndrome of inadequate production of antidiuretic hormone.

Metabolic and nutrition disorders: frequent – anorexia; frequency is not established – hyponatremia, weight loss, weight gain.

Psychiatric disorders: infrequent – hallucinations, confusion, aggression; rare – mania; frequency is not established – suicidal ideation, suicidal behavior (see section “Special Precautions”).

Nervous system disorders: frequently – anxiety, increased excitability, restlessness, insomnia, somnolence, tremor, headache, dizziness; infrequently – extrapyramidal disorders, ataxia; rarely – convulsions; frequency not established – serotonin syndrome, malignant neuroleptic syndrome, akathisia/psychomotor agitation, paresthesia, dysgeusia.

Visual organ disorders: frequency not determined – glaucoma, mydriasis.

Cardiac disorders: often – palpitations/tachycardia.

Vascular disorders: infrequent – orthostatic hypotension.

Gastrointestinal disorders: frequently – abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, nausea, vomiting

Liver disorders: rarely – abnormal function (increased activity of “liver” enzymes).

Skin and subcutaneous tissue disorders: frequently – increased sweating; infrequent – skin hypersensitivity reactions (including rash, itching, angioedema); rarely – photosensitivity reactions.

Muscular and connective tissue disorders: infrequent – arthralgia, myalgia; frequency is not known – bone fractures**.

Kidney and urinary tract disorders: frequency is not known – urinary disorders (including urinary retention, urinary incontinence, pollakiuria, nocturia and enuresis).

Gender and mammary disorders: infrequent – disruption (delay) of ejaculation; rare – galactorrhea; frequency is not established – anorgasmia, menstrual disorders (such as amenorrhea, hypomenorrhea, metrorrhagia, menorrhagia).

General disorders: frequent – asthenia, malaise; frequency not established – drug withdrawal syndrome, including withdrawal syndrome in infants whose mothers have taken fluvoxamine late in pregnancy.

* – Nausea, sometimes accompanied by vomiting, is the most commonly observed side effect associated with treatment with fluvoxamine. The frequency of occurrence usually decreases within the first two weeks of using the drug.

** – Epidemiologic studies, performed primarily with patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants. The mechanism for the increased risk is unknown.

Withdrawal syndrome after discontinuation of fluvoxamine

Cessation of fluvoxamine (especially abrupt) often leads to the development of withdrawal syndrome. The most common symptoms noted when withdrawing from the drug are: dizziness, sensory disturbances (including paresthesias, visual disturbances, and electrical shock sensations), sleep disturbances (including insomnia and vivid dreams) agitation, irritability Confusion, emotional lability, headache, nausea and/or vomiting, diarrhea, sweating, palpitations, tremors, and anxiety (see Special Indications.)

The majority of these symptoms are mild to moderate and manage on their own, but in some patients they may be severe and/or prolonged.

For this reason, if treatment with fluvoxamine is no longer required, it is recommended that the dose be gradually reduced until the drug is completely withdrawn (see Dosage and Administration and Special Precautions).

Children: During a 10-week placebo-controlled study in children and adolescents with OCD, adverse events such as insomnia, asthenia, hypervigilance, hyperkinesia, somnolence, and dyspepsia occurred more frequently in patients receiving the drug compared to patients receiving placebo. Serious adverse events in this study included hyperexcitability and hypomania.

Convulsions in children and adolescents have been reported outside of clinical trials.

Overdose

Symptoms: the most characteristic symptoms include gastrointestinal disturbances (nausea, vomiting and diarrhea), drowsiness and dizziness. In addition, there have been reports of cardiac abnormalities (tachycardia, bradycardia, arterial hypotension), liver dysfunction, seizures, and coma.

Fluvoxamine has a wide therapeutic dose range with respect to overdose safety. Since its release to the market, reports of deaths attributed to overdose with fluvoxamine alone have been extremely rare.

The highest reported dose of fluvoxamine taken by one patient was 12 g. This patient was completely cured. More serious complications were observed in cases of intentional overdose of fluvoxamine in combination with other drugs.

Treatment: There is no specific antidote for fluvoxamine. In case of overdose, gastric lavage is recommended, which should be performed as soon as possible after taking the drug, as well as symptomatic treatment. In addition, repeated administration of activated charcoal is recommended, if necessary, the appointment of osmotic laxatives.

Forced diuresis or dialysis is not effective.

Pregnancy use

Pregnancy:

Lactation period: Fluvoxamine passes into breast milk in small amounts. Therefore, the drug should not be used during lactation.

Fertility: Studies of reproductive toxicity in animals have shown that fluvoxamine affects male and female reproductive function, increases the risk of intrauterine fetal death and reduces fetal body weight at doses approximately 4 times greater than the maximum recommended doses for humans.

In addition, an increased incidence of perinatal mortality in pups has been observed in pre- and postnatal studies. The significance of these data for humans is unknown.

Fluvoxamine should not be administered to patients who are planning to become pregnant unless the clinical condition of the patient requires fluvoxamine.

Similarities