Fevarin, 100 mg 15 pcs.

Antidepressant. 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-adrenoreceptors, histamine, m-cholinoreceptors or dopamine receptors is negligible.

Fluvoxamine has a high affinity for σ1 receptors, acting as their agonist.

Pharmacokinetics

Intake

Fluvoxamine is completely absorbed from the GI tract after oral administration. Cmax in blood plasma is reached after 3-8 hours. Absolute bioavailability is 53% after primary metabolism in the liver. Concomitant administration of fluvoxamine with food has no effect on pharmacokinetics.

Distribution

The degree of binding to plasma proteins is about 80% (in vitro). Vd is 25 l/kg. Css in plasma is usually reached after 10-14 days.

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

Metabolism

Fluvoxamine is biotransformed in the liver (mainly by oxidative demethylation) to at least 9 metabolites. Two of the major metabolites have negligible pharmacological activity; the others are pharmacologically inactive.

Fluvoxamine significantly inhibits cytochrome P450 (CYP) 1A2 and 2C19 isoenzymes and moderately inhibits CYP2C9, 3A4 and 2D6 isoenzymes.

While cytochrome P450 isoenzyme 2D6 is the main one 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.

Elimation

After a single dose, the average T1/2 from the blood plasma is 13-15 h, with multiple doses the T1/2 is slightly increased and is 17-22 h.

Fluvoxamine is excreted in the urine as metabolites.

Pharmacokinetics in special clinical cases

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.

Fluvoxamine plasma Css were twice as high in children (ages 6-11 years) than in adolescents (ages 12-17 years). Plasma concentrations of the drug in adolescents were similar to those in adults.

Indications

– Depression of various genesis;

– Obsessive-compulsive disorders.

Active ingredient

Composition

1 tablet contains:

The active ingredients:

fluvoxamine maleate 100 mg,

Supplementary substances:

mannitol – 303 mg,

corn starch – 80 mg,

Pregelatinized starch – 12 mg,

sodium stearyl fumarate – 3.5 mg,

silica colloidal – 1.5 mg.

Shell composition: hypromellose – 5.6 mg, macrogol 6000 – 2 mg, talc – 0.4 mg, titanium dioxide (E171) – 2.1 mg.

How to take, the dosage

Tablets of fluvoxamine should be taken orally, without chewing, with water. The tablet can be divided into 2 equal parts.

Depression

The recommended starting dose for adults is 50 mg or 100 mg once daily, in the evening. Gradual increase of the dose to an effective dose is recommended. The effective daily dose, which is usually 100 mg, is adjusted individually depending on the patient’s response to treatment. The daily dose may be as high as 300 mg. Daily doses over 150 mg should be divided into several doses.

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

To prevent recurrence of depression, Fevarin is recommended to be prescribed in a dose of 100 mg once daily.

Due to a lack of clinical experience, Fevarin is not recommended for the treatment of depression in children under the age of 18 years.

Obsessive-compulsive disorder (OCD)

The recommended starting dose for adults is 50 mg/day for 3-4 days. The effective daily dose is usually 100 to 300 mg. 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.

The starting dose for children over 8 years of age and adolescents is 25 mg/day for 1 dose. The maintenance dose is 50-200 mg/day. The maximum daily dose is 200 mg. Doses over 100 mg/day are recommended to be divided into 2 or 3 doses.

If there is a good therapeutic response, treatment may be continued with an individually tailored daily dose. If improvement is not achieved after 10 weeks of therapy, treatment with fluvoxamine should be reconsidered. So far, no systemic studies have been organized to answer the question of how long treatment with fluvoxamine can be maintained, but obsessive-compulsive disorder is chronic in nature, it may be considered reasonable to extend treatment with Fevarin beyond 10 weeks in patients with adequate therapeutic effect. The selection of the minimum effective maintenance dose should be made individually and with caution. Periodically it is required to re-evaluate the necessity of treatment. Some clinicians recommend concomitant psychotherapy in patients with good pharmacotherapy effects.

Interaction

Fluvoxamine should not be used in combination with MAO inhibitors, including linezolid, because of the risk of serotonin syndrome.

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 Р450 isoenzymes 1A2 and 2C19 and to a lesser extent on cytochrome Р450 isoenzymes 2C9, 2D6 and 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 a minimum dose or reduced to a minimum dose when used concomitantly with fluvoxamine. Close monitoring of plasma concentrations, effects or side effects is required, as well as dose adjustments of these drugs, if necessary. This is especially significant for drugs that have a narrow therapeutic range.

When receiving Fevarin 100 mg twice daily for 3 days prior to concomitant administration of 16 mg ramelteon, the AUC for ramelteon was increased approximately 190-fold and the Cmax was increased approximately 70-fold as compared to these parameters when ramelteon alone was administered.

Patients concomitantly taking fluvoxamine and drugs with a narrow therapeutic range that are metabolized exclusively or by a combination of cytochrome P450 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.

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 isoenzyme. Therefore, if treatment with fluvoxamine is initiated, a dose reduction of these drugs should be considered.

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

Concomitant use of fluvoxamine and ropinirole may increase plasma concentrations of ropinirole, thus 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.

Ione 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 reduce their intake while taking fluvoxamine, and when adverse effects of caffeine, such as tremor, palpitations, nausea, anxiety, and insomnia are observed.

In combination therapy with fluvoxamine, plasma concentrations of terfenadine, astemizole, or cisapride may increase, increasing the risk of QT interval prolongation/paroxysmal ventricular pirouette tachycardia. Therefore, fluvoxamine should not be administered together with these drugs.

Fluvoxamine has no effect on the plasma concentration of digoxin.

Fluvoxamine has no effect on the plasma concentration of atenolol.

When fluvoxamine is combined 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.

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 hemorrhagia. Such patients should be monitored by a physician.

Special Instructions

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

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide attempts (suicidal behavior). This risk persists until significant improvement. Because 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, an increased risk of suicide in the early stages of recovery is common.

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 who exhibit significant 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 consultation with a specialist if such symptoms occur.

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.

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 under close supervision. Treatment with Fevarin should be discontinued if epileptic seizures occur or their frequency increases.

Rare cases of serotonergic syndrome or ZNS-like conditions have been described that may be associated with the administration of fluvoxamine, especially in combination with other serotonergic and/or neuroleptic drugs. These syndromes may 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 (including pulse, respiration, BP), changes in mental status, including confusion, irritability, extreme agitation up to delirium or coma. Therefore, in such cases Pevarin should be discontinued and appropriate symptomatic treatment should be initiated.

As with other selective serotonin reuptake inhibitors, in rare cases, hyponatremia may occur, which is reversed after withdrawal of fluvoxamine. Some cases have been caused by insufficient ADH secretion syndrome. These cases were mostly observed in elderly patients.

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

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

Cases of mydriasis have been reported with SSRIs such as fluvoxamine. Therefore, fluvoxamine should be prescribed with caution in patients with elevated intraocular pressure or in patients at increased risk of acute closed angle glaucoma.

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 drugs in elderly patients and patients concomitantly receiving drugs acting on platelet function (e.g., atypical antipsychotics and phenothiazines, Many tricyclic antidepressants, acetylsalicylic acid, NSAIDs) or drugs that increase the risk of bleeding, as well as in patients with a history of bleeding or those prone to bleeding (e.g., thrombocytopenia or coagulation disorders).

The risk of QT interval prolongation/paroxysmal ventricular pirouette tachycardia increased with combination therapy of 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 bpm).

Fluvoxamine has limited clinical experience with ECT, so this therapy should be used with caution.

When fluvoxamine is discontinued, withdrawal syndrome may develop, although available data from preclinical and clinical studies have not demonstrated dependence on treatment with fluvoxamine. The most common symptoms reported when withdrawing from the drug are: dizziness, sensory disturbances (including paresthesias, visual disturbances, and a shock sensation), sleep disturbances (including insomnia and vivid dreams) agitation, irritability, confusion, emotional lability, headache, nausea and/or vomiting, diarrhea, sweating, palpitations, tremors, and anxiety. Most of these symptoms are mild to moderate and resolve on their own, but in some patients they may be severe and/or prolonged. Such 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.

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.

The treatment of patients with hepatic or renal insufficiency should be started with prescription of the drug in a low dose, such patients require close medical supervision. In rare cases, treatment with fluvoxamine may lead to increased hepatic enzyme activity, which is most often accompanied by corresponding clinical symptoms; in these cases, Fevarin should be discontinued.

The data obtained from the treatment of elderly and younger patients suggest that there are no clinically significant differences between the commonly used daily doses in them. However, increasing doses in older patients should always be done more slowly and with more caution.

A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders found an increased risk of suicidal behavior when taking 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.

Synopsis

Contraindications

– concomitant use with tizanidine and MAOI inhibitors (treatment with fluvoxamine may be started 2 weeks after discontinuation of an irreversible MAOI inhibitor, the day after discontinuation of a reversible MAOI inhibitor (e.g., moclobemide, linezolid). The time interval between discontinuation of fluvoxamine and initiation of therapy with any MAO inhibitor should be at least 1 week;

– concomitant use with ramelteon;

– hypersensitivity to the active substance or to any of the drug components.

The drug should be used with caution in patients with hepatic and renal insufficiency, history of seizures, epilepsy, patients with a tendency to bleeding (thrombocytopenia), in pregnancy, during lactation and in patients of advanced age.

Side effects

Some side effects observed in clinical trials were often related to the disease and not to the treatment with Fevarin. All reactions are distributed by organ system and frequency of development: frequently (>1% and0.1% and0.01% and

With the blood clotting system: frequency unknown – bleeding (e.g., gastrointestinal bleeding, gynecological bleeding, ecchymosis, purpura).

Endocrine system disorders: frequency is unknown – hyperprolactinemia, syndrome of inadequate ADH production.

Metabolism and nutrition: often – anorexia; frequency unknown – hyponatremia, weight loss, weight gain.

Psychiatric: infrequent – hallucinations, state of confusion; rare – mania; frequency unknown – suicidal thinking, suicidal behavior.

Nervous system disorders: frequently – anxiety, increased excitability, restlessness, insomnia, somnolence, tremor, headache, dizziness; infrequently – extrapyramidal disorders, ataxia; rarely – seizures; frequently unknown – serotonin syndrome, MNS, akathisia/psychomotor agitation, paresthesia, dysgeusia.

VIight: frequency unknown – glaucoma, mydriasis.

Cardiovascular system: frequent – palpitations, tachycardia; infrequent – orthostatic hypotension.

Digestive system disorders: frequently – abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, nausea, vomiting; rarely – liver dysfunction (increased liver enzymes activity).

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

Muscular system disorders: infrequent – arthralgia, myalgia; frequency unknown – bone fractures.

The sexual system: infrequent – disruption (delay) of ejaculation; rarely – galactorrhea; frequency unknown – anorgasmia, menstrual disorders (such as amenorrhea, hypomenorrhea, metrorrhagia, menorrhagia).

General disorders: common – asthenia, malaise; common unknown – drug withdrawal syndrome, including withdrawal syndrome in infants whose mothers have taken fluvoxamine late in pregnancy.

* – 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 abruptly) often leads to the development of withdrawal syndrome. For this reason, if treatment with fluvoxamine is no longer needed, it is recommended that the dose be gradually reduced until the drug is completely withdrawn.

Overdose

Symptoms: nausea, vomiting, diarrhea, drowsiness, dizziness are most common. There have been reports of cardiac disorders (tachycardia, bradycardia, arterial hypotension), liver dysfunction, seizures, coma.

Fluvoxamine has a wide therapeutic dose range. To date, deaths associated with fluvoxamine overdose have been extremely rare. The highest recorded dose taken in one patient was 12 g (the patient was cured). More serious complications were observed in cases of intentional overdose of fluvoxamine with concomitant pharmacotherapy.

Treatment: gastric lavage, which should be performed as soon as possible after taking the drug; symptomatic therapy is carried out. In addition, repeated intake of activated charcoal is recommended, if necessary prescription of osmotic laxatives. There is no specific antidote. Forced diuresis or dialysis are ineffective.

Pregnancy use

Epidemiologic data suggest that the use of selective serotonin reuptake inhibitors (SSRIs) in pregnancy, particularly in the last months of pregnancy, may increase the risk of persistent pulmonary hypertension (PHH) in newborns. Available data show that PAH occurs in about 5 cases per 1,000 births (as opposed to 1-2 cases per 1,000 births if the mother did not use SSRIs in the last months of pregnancy).

The use of fluvoxamine in pregnancy is not recommended unless the woman’s clinical condition indicates a need for it.

In isolated cases of neonatal withdrawal syndrome have been described following the use of fluvoxamine late in pregnancy.

. Some neonates have experienced difficulty feeding and/or breathing, seizure disorders, unstable body temperature, hypoglycemia, tremor, impaired muscle tone, increased neuroreflex agitation syndrome, cyanosis, irritability, lethargy, drowsiness, nausea, difficulty falling asleep and continuous crying after SIOPS exposure in the third trimester of pregnancy, which may require longer hospitalizations.

Fluvoxamine passes into breast milk in small amounts. Because of this, the drug should not be used during lactation.

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

Experimental 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 was observed in pre- and postnatal studies. The significance of these data for humans is unknown.

Similarities