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

Depression of various origins, obsessive-compulsive disorders.

Pharmacological effect

Absorption: After oral administration, fluvoxamine is completely absorbed from the gastrointestinal tract. Maximum concentrations of fluvoxamine in blood plasma are observed 3-8 hours after administration. Absolute bioavailability is 53% after primary metabolism in the liver. Concomitant use of fluvoxamine with food does not affect pharmacokinetics.

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

Metabolism: Metabolism of fluvoxamine occurs primarily in the liver. Although the 2D6 isoenzyme of cytochrome P 450 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 half-life 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 within 10-14 days.

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

Fluvoxamine significantly inhibits cytochrome P450 1A2 and P450 2C19, moderately inhibits cytochromes P450 2C9, P450 2D6 and P450 3A4.

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

Special Populations: 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 steady-state plasma concentration of fluvoxamine is twice as high in children (aged 6–11 years) than in adolescents (aged 12–17 years). Plasma concentrations of the drug in adolescents are similar to those in adults.

Pharmacodynamics

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.

Its ability to bind to α- and β-adrenergic receptors, histamine, m-cholinergic or dopamine receptors is insignificant. Fluvoxamine has a high affinity for σ1 receptors, acting as their agonist.

Special instructions

As with other psychotropic drugs, it is not recommended to consume alcohol during treatment with fluvoxamine.

Suicide/suicidal ideation or clinical worsening: Depression is associated with an increased risk of suicidal ideation, self-harm, and suicide attempts (suicidal behavior). This risk persists until the condition significantly improves.

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

Increased risk of suicide in the early stages of recovery is widespread in clinical practice.

Other mental 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 mental disorders should be closely monitored.

Patients with a history of suicidal behavior or a significant degree of suicidal ideation are known to be at greater risk of suicidal ideation 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 thoughts, or unusual changes in behavior, and to immediately seek professional advice if such symptoms occur.

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

In clinical studies conducted among children and adolescents, suicidal behavior (suicidal attempts and thoughts) and hostility (mainly aggression, oppositional behavior and anger) were observed more often in patients receiving an antidepressant compared to those receiving placebo.

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

Additionally, long-term safety data for children and adolescents regarding growth, development, and cognitive development are lacking.

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

Elderly patients: Data obtained from the treatment of elderly patients and younger patients indicate that there are no clinically significant differences between the daily doses usually used in them. However, dose increases in elderly patients should always be done more slowly and with greater caution.

Akathisia/psychomotor agitation: The development of akathisia associated with fluvoxamine is characterized by subjectively unpleasant and distressing restlessness. 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 such symptoms may worsen their condition.

Impaired liver and/or kidney function: Treatment of patients suffering from hepatic or renal failure should begin with low doses and patients should be under strict medical supervision.

In rare cases, treatment with fluvoxamine may lead to an increase in the activity of liver enzymes, most often accompanied by corresponding clinical symptoms and in such cases the drug should be discontinued.

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

Treatment with the drug should be discontinued if epileptic seizures occur or their frequency increases.

There have been rare cases of serotonin syndrome or a neuroleptic malignant syndrome-like condition that may be associated with fluvoxamine, especially in combination with other serotonergic and/or neuroleptic medicinal products.

Because these syndromes can lead to potentially life-threatening conditions manifested by hyperthermia, muscle rigidity, myoclonus, lability of the autonomic nervous system with possible rapid changes in vital parameters (pulse, respiration, blood pressure, etc.), changes in mental status including confusion, irritability, extreme agitation, reaching delirium or coma – in such cases, treatment with fluvoxamine should be discontinued and appropriate symptomatic treatment was started.

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

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

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

Visual impairment: Cases of mydriasis have been reported with the use of SSRIs such as fluvoxamine.

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

Hematological disorders:

There are reports of intradermal hemorrhages such as ecchymosis and purpura, as well as other hemorrhagic manifestations (for example, gastrointestinal bleeding or gynecological bleeding), observed with the use of selective serotonin reuptake inhibitors.

Caution should be exercised when prescribing these drugs to elderly patients and to patients concomitantly receiving drugs that affect platelet function (for example, atypical antipsychotics and phenothiazines, many tricyclic antidepressants, acetylsalicylic acid, non-steroidal anti-inflammatory drugs) or drugs that increase the risk of bleeding, as well as patients with a history of bleeding or a tendency to bleeding (for example, with thrombocytopenia or disorder coagulation).

Cardiac disorders: Increased risk of prolongation of the QT interval/torsade de pointes (TdP) during combination therapy of fluvoxamine with terfenadine or astemizole or cisapride, due to an increase in the concentration of the latter in the blood plasma. Therefore, fluvoxamine should not be coadministered with these drugs.

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

Electroconvulsive therapy (ECT): Clinical experience with fluvoxamine in conjunction with ECT is limited and should be used with caution.

Withdrawal reactions: When you stop taking fluvoxamine, a withdrawal syndrome may develop, although available data from preclinical and clinical studies have not revealed dependence on fluvoxamine treatment.

The most common symptoms noted in case of drug withdrawal: dizziness, sensory disturbances (including paresthesia, visual disturbances and electric shock sensations), sleep disturbances (including insomnia and vivid dreams), agitation, irritability, confusion, emotional lability, headache, nausea and/or vomiting, diarrhea, sweating, palpitations, tremor and anxiety (see section “Side effects”).

Most of these symptoms are mild or moderate and self-limiting, but in some patients they can be severe and/or prolonged.

These symptoms usually occur within the first few days after stopping treatment. For this reason, it is recommended to gradually reduce the dose of fluvoxamine before complete discontinuation in accordance with 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. If the patient develops a manic phase, fluvoxamine should be discontinued.

Effect on the ability to drive vehicles and machines: Fluvoxamine, administered to healthy volunteers in doses of up to 150 mg, had no or insignificant effect on the ability to drive a car and operate machines.

At the same time, there are reports of drowsiness noted during treatment with fluvoxamine. Therefore, caution is recommended until the individual response to the drug is definitively determined.

Active ingredient

Fluvoxamine

Composition

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

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

Shell composition: hypromellose, titanium dioxide, macrogol (polyethylene glycol 6000), talc.

Pregnancy

Pregnancy:

Epidemiological data suggest that the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, particularly in the last months of pregnancy, may increase the risk of persistent pulmonary hypertension (PPH) in the newborn. Available data indicate that PLH occurs in approximately 5 cases per 1000 births (as opposed to 1-2 cases per 1000 births if the mother did not use SSRIs in late pregnancy).
The use of fluvoxamine during pregnancy is not recommended, unless the woman’s clinical condition indicates the need for its use.
Isolated cases of withdrawal syndrome in newborns have been described following the use of fluvoxamine at the end of pregnancy.
Some neonates exposed to SSRIs in the third trimester of pregnancy have experienced feeding and/or breathing difficulties, seizure disorders, unstable body temperature, hypoglycemia, tremors, abnormal muscle tone, hyperexcitability syndrome, cyanosis, irritability, lethargy, somnolence, nausea, difficulty falling asleep and continuous crying, which may require longer hospitalization.

Lactation: Fluvoxamine passes into breast milk in small quantities. In this regard, the drug should not be used during breastfeeding.

Fertility: Reproductive toxicity studies 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 the maximum recommended human dose.

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

Fluvoxamine should not be prescribed to patients who are planning pregnancy, unless the patient’s clinical condition requires the use of fluvoxamine.

Contraindications

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

With caution: Hepatic and renal failure, history of seizures, epilepsy, old 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 treatment with fluvoxamine.

All reactions are distributed according to organ systems and frequency of development: often from >1/100 to 1/1000 to 1/10000 to

Blood and lymphatic system disorders: frequency not established – bleeding (eg gastrointestinal bleeding, gynecological bleeding, ecchymosis, purpura).

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

Metabolic and nutritional disorders: often – anorexia; frequency not established – hyponatremia, weight loss, weight gain.

Mental disorders: infrequently – hallucinations, state of confusion, aggressiveness; rarely – mania; frequency not established – suicidal thinking, suicidal behavior (see section “Special instructions”).

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

Visual disorders: frequency not established – glaucoma, mydriasis.

Cardiac disorders: often – palpitations/tachycardia.

Vascular disorders: uncommon – orthostatic hypotension.

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

Liver disorders: rarely – dysfunction (increased activity of liver enzymes).

Disorders of the skin and subcutaneous tissues: often – increased sweating; uncommon – skin hypersensitivity reactions (including rash, itching, angioedema); rarely – photosensitivity reactions.

Musculoskeletal and connective tissue disorders: uncommon – arthralgia, myalgia; frequency not established – bone fractures**.

Renal and urinary tract disorders: frequency not established – urinary disorders (including urinary retention, urinary incontinence, pollakiuria, nocturia and enuresis).

Disorders of the genital organs and mammary gland: infrequently – disturbance (delay) of ejaculation; rarely – galactorrhea; frequency not established – anorgasmia, menstrual irregularities (such as amenorrhea, hypomenorrhea, metrorrhagia, menorrhagia).

General disorders: often – asthenia, malaise; frequency not established – drug withdrawal syndrome, including withdrawal syndrome in newborns whose mothers took fluvoxamine in late pregnancy.

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

** – Epidemiological studies performed primarily on patients aged 50 years and older have shown an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants. The mechanism by which this risk increases is unknown.

Withdrawal syndrome after stopping fluvoxamine use

Stopping the use of fluvoxamine (especially abruptly) often leads to the development of withdrawal syndrome. The most common symptoms noted in case of drug withdrawal: dizziness, sensory disturbances (including paresthesia, visual disturbance and sensation of electric shock), difficulty falling asleep (including insomnia and vivid dreams), agitation, irritability. confusion, emotional lability, headache, nausea and/or vomiting, diarrhea, sweating, palpitations, tremors and anxiety (see section “Special Instructions”.)

Most of these symptoms are mild or moderate and self-limiting, but in some patients they can be severe and/or prolonged.

For this reason, if treatment with fluvoxamine is no longer required, it is recommended to gradually reduce the dose until the drug is completely discontinued (see section “Dosage and Administration” and “Special Instructions”).

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

Seizures in children and adolescents have been reported outside of clinical studies.

Interaction

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

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 powerful inhibitory effect of fluvoxamine on the cytochrome P450 1A2 and P450 2C19 isoenzymes and, to a lesser extent, on the cytochrome P450 2C9, P450 2D6 and P450 3A4 isoenzymes.

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

Close monitoring of plasma concentrations, effects or side effects is required, and dosage adjustments of these drugs are required if necessary. This is especially important for drugs that have a narrow therapeutic index.

Ramelteon: When taking fluvoxamine 100 mg twice daily for 3 days before concomitant use of ramelteon 16 mg, the AUC (area under the concentration-time curve) value for ramelteon increased approximately 190-fold and the Cmax (maximum concentration) increased approximately 70-fold compared with these parameters when administering ramelteon alone.

Drugs with Narrow Therapeutic Range: Patients concomitantly taking fluvoxamine and drugs with a narrow therapeutic range that are metabolized solely or by a combination of cytochrome isoenzymes that inhibit fluvoxamine (such as tacrine, theophylline, methadone, mexiletine, phenytoin, carbamazepine, and cyclosporine) should be closely monitored. If necessary, dose adjustment of these drugs is recommended.

Tricyclic antidepressants and antipsychotics: With simultaneous use of fluvoxamine, an increase in the concentration of tricyclic antidepressants (for example, clomipramine, imipramine, amitriptyline) and antipsychotics (for example, clozapine, olanzapine, quetiapine), which are significantly metabolized by the cytochrome P450 1A2 isoenzyme, was observed. Therefore, if treatment with fluvoxamine is initiated, a dose reduction of these drugs should be considered.

Benzodiazepines: When used concomitantly with fluvoxamine, 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 taking fluvoxamine.

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, dose reduction or discontinuation of ropinirole during treatment with fluvoxamine is recommended.

When fluvoxamine interacted with propranolol, an increase in plasma concentrations of propranolol was observed. In this regard, it can be recommended to reduce the dose of propranolol in case of simultaneous use with fluvoxamine.

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

Cases of increased incidence of side effects: Isolated cases of cardiotoxicity have been reported with the simultaneous use of fluvoxamine and thioridazine.

Plasma concentrations of caffeine may increase while taking fluvoxamine. Therefore, patients who consume large amounts of caffeine-containing beverages should reduce their consumption while taking fluvoxamine and when adverse effects of caffeine, such as tremor, palpitations, nausea, restlessness, and insomnia, are observed.

Cytochrome P450 isoenzyme 3A4: Terfenadine, astemizole, cisapride, sildenafil: when combined with fluvoxamine, plasma concentrations of terfenadine, astemizole or cisapride may increase, increasing the risk of QT prolongation/torsade de pointes (TdP). Therefore, fluvoxamine should not be prescribed together with these drugs.

Glucuronidation: Fluvoxamine has no effect on plasma concentrations of digoxin.

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

Pharmacodynamic interactions: In case of simultaneous use of fluvoxamine 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 drugs to treat severely ill patients who respond poorly 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 carried out with caution.

With the simultaneous use of indirect anticoagulants and fluvoxamine, the risk of hemorrhage may increase. Such patients should be under medical supervision.

Overdose

Symptoms: The most characteristic symptoms include gastrointestinal disorders (nausea, vomiting and diarrhea), drowsiness and dizziness. In addition, there are reports of cardiac dysfunction (tachycardia, bradycardia, hypotension), liver dysfunction, seizures and coma.

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

The highest recorded dose of fluvoxamine taken by one patient was 12 g. This patient was completely cured. More serious complications have been observed in cases of deliberate 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 carried out as soon as possible after taking the drug, as well as symptomatic treatment. In addition, repeated intake of activated carbon is recommended, and, if necessary, the appointment of osmotic laxatives.

Forced diuresis or dialysis are not effective.

Manufacturer

Rapharma JSC, Russia