Properties
What is it?
International Nonproprietary Name (INN): Fluvoxamine Composition: Active substance: Fluvoxamine tablet – 50, 100 mg. Excipients: Mannitol – 152.0 mg, Corn starch – 40.0 mg (80.0 mg), Gelatinized starch – 6.0 mg (12.0 mg), Sodium stearyl fumarate – 1.8 mg (3.5 mg), Colloidal silicon dioxide – 0.8 mg (1.5 mg). Coating: Hypromellose – 4.1 mg (5.6 mg), Macrogol 6000 – 1.5 mg (2.0 mg), Talc – 0.3 mg (0.4 mg), Titanium dioxide (E 171) – 1.5 mg (2.1 mg). Description: Tablet "50 mg": White, round, biconvex, film-coated tablet, with a score line on one side, marked "291" on both sides of the score line; the other side of the tablet is embossed with "Sh" above the "S" mark. Tablet "100 mg": White, round, biconvex, film-coated tablet, with a score line on one side, marked "313" on both sides of the score line; the other side of the tablet is embossed with "Sh" above the "S" mark. Pharmacotherapeutic group: Antidepressant. Pharmacological action: Pharmacodynamics The mechanism of action of Fevarin is based on selective inhibition of serotonin reuptake by brain neurons and is characterized by minimal effect on the noradrenergic system. Fevarin® has a weak affinity for α-adrenergic, β-adrenergic, histaminergic M-cholinergic, dopaminergic, or serotonergic receptors. Pharmacokinetics Absorption: After oral administration, Fevarin® is completely absorbed from the gastrointestinal tract. The maximum plasma concentration of the drug is observed 3-8 hours after administration. Absolute bioavailability is 53% after first-pass metabolism in the liver. Concomitant intake of Fevarin with food does not affect pharmacokinetics. Distribution: The binding of Fevarin to plasma proteins is approximately 80% (in vitro), and the volume of distribution is 25 L/kg. Metabolism: The metabolism of Fevarin occurs mainly in the liver. Although cytochrome P450 2D6 plays a major role in the metabolism of fluvoxamine, the plasma concentration of the drug in individuals with impaired function of this isoenzyme does not significantly exceed the same indicator in individuals with normal metabolism. The mean elimination half-life from plasma after a single dose is 13-15 hours; after multiple doses, it increases to 17-22 hours, and steady-state plasma concentration is usually reached within 10-14 days. Fevarin® undergoes biotransformation in the liver (mainly via oxidative demethylation) into at least nine metabolites, which are excreted by the kidneys. Two main metabolites have negligible pharmacological activity. Other metabolites are likely not pharmacologically active. Fluvoxamine significantly inhibits cytochrome P450 1A2, moderately inhibits cytochromes P450 2C and P450 3A4; inhibition of cytochrome P450 2D6 is negligible. Special patient groups: The pharmacokinetics of fluvoxamine are similar in healthy individuals, the elderly, and patients with renal insufficiency. The metabolism of fluvoxamine is impaired in liver disease. The steady-state plasma concentration of fluvoxamine in children aged 6-11 years is twice that in adolescents (12-17 years). The plasma concentration of the drug in adolescents is similar to that in adults. Indications: Depressions of various origins; obsessive-compulsive disorder. Contraindications: 1. Concomitant use with tizanidine and monoamine oxidase inhibitors. Treatment with fluvoxamine can be initiated: – two weeks after discontinuation of an irreversible monoamine oxidase inhibitor; – on the second day after discontinuation of a reversible monoamine oxidase inhibitor. The interval between discontinuation of fluvoxamine and initiation of therapy with any monoamine oxidase inhibitor should be at least one week. Hypersensitivity to the active substance or any other component of the preparation. Precautions: Hepatic and renal insufficiency, history of seizures, epilepsy, advanced age, tendency to bleeding (thrombocytopenia), pregnancy. Use during pregnancy and lactation: Limited observations have not revealed any negative effects of fluvoxamine on pregnancy. The potential risk is unknown. The preparation is prescribed with caution during pregnancy. Isolated cases of neonatal withdrawal syndrome have been described when fluvoxamine was used in late pregnancy. Fluvoxamine passes into breast milk in small amounts, so its use during lactation is not recommended. Use in childhood: Due to lack of clinical experience, the use of Fevarin in children for the treatment of depression is not recommended. Dosage and administration: Depression: The recommended starting dose is 50 or 100 mg (once daily, in the evening). It is recommended to gradually increase the dose to an effective dose. The effective daily dose is selected individually based on the patient's response to treatment; it is usually 100 mg. The daily dose can reach 300 mg. Daily doses higher than 150 mg should be divided into several administrations. According to the official recommendations of the World Health Organization, antidepressant treatment should be continued during remission for at least 6 months after a depressive episode. To prevent recurrence of depression, it is recommended to take 100 mg of fluvoxamine daily; once a day. Obsessive-compulsive disorder: It is recommended to start Fevarin at a dose of 50 mg for 3-4 days. The effective daily dose is usually 100-300 mg. It is recommended to gradually increase the dose to an effective dose, which should not exceed 300 mg in adults. A dose of 150 mg can be taken once a day, preferably in the evening. It is recommended to divide daily doses higher than 150 mg into two or three administrations. Dosage in children and adolescents over 8 years of age: The starting dose of Fevarin is 50 mg, and the maintenance dose is 50-200 mg per day. The daily dose should not exceed 200 mg. It is recommended to divide daily doses higher than 100 mg into two or three administrations. If there is a good response to the preparation, treatment can be continued with an individually selected daily dose. If no improvement is observed after 10 weeks of treatment, fluvoxamine should be discontinued. Systematic studies to answer the question of how long fluvoxamine treatment can be continued have not been conducted, but obsessive-compulsive disorder is chronic in nature, so it may be advisable to continue Fevarin treatment for more than 10 weeks if the patient has a good response to the preparation. The minimum effective maintenance dose should be carefully selected on an individual basis. Some clinicians recommend concomitant psychotherapy for patients who have responded well to the preparation. Treatment of patients with hepatic or renal insufficiency is initiated with the minimum dose under strict medical supervision. Fevarin tablets should not be chewed; they should be swallowed whole with a small amount of water. Side effects: The most common side effect associated with the use of Fevarin is nausea, sometimes with vomiting. This side effect usually subsides within the first two weeks of treatment. Some side effects identified during clinical trials were related not to Fevarin treatment but to the symptoms of depression. Frequent (frequency 1-10%): General: Asthenia, headache, malaise. Cardiovascular system: Palpitations, tachycardia. Gastrointestinal tract: Abdominal pain, anorexia, constipation, diarrhea, dry mouth, dyspepsia. Nervous system: Nervousness, anxiety, agitation, dizziness, insomnia or somnolence, tremor. Skin: Sweating. Relatively rare (frequency <1%): Cardiovascular system: Postural hypotension. Musculoskeletal system: Arthralgia, myalgia. Nervous system: Ataxia, confusion, extrapyramidal disorders, hallucinations. Reproductive system: Delayed ejaculation. Skin: Hypersensitivity reactions – itching, rash, angioneurotic edema. Rare (frequency <0.1%): Gastrointestinal tract: Liver function impairment (increased levels of liver transaminases). Nervous system: Convulsions, manic syndrome. Reproductive system: Galactorrhea. Skin: Photosensitivity. Other side effects: Changes in body weight. Rarely: Serotonin syndrome, neuroleptic malignant syndrome-like condition, hyponatremia and syndrome of inappropriate secretion of antidiuretic hormone (see "Special Instructions"). Withdrawal symptoms may develop after discontinuation of fluvoxamine, although dependence on fluvoxamine treatment has not been identified in preliminary studies and clinical trials. Symptoms that develop upon discontinuation of the preparation: dizziness, headache, vomiting; anxiety. Most of these symptoms are mild and resolve without intervention. Gradual dose reduction is recommended when discontinuing the preparation. Hemorrhagic manifestations, such as ecchymosis, purpura, gastrointestinal bleeding (see "Special Instructions"). Very rarely: Paresthesia, anorgasmia, and taste disturbance. Overdose: Symptoms: The most common symptoms include gastrointestinal discomfort (nausea, vomiting, and diarrhea), somnolence, and dizziness. In addition, there is information about cardiac dysfunction (tachycardia, bradycardia, arterial hypotension), liver dysfunction, seizures, and even coma. Fluvoxamine has a wide therapeutic dose range. Currently, the number of deaths attributed to fluvoxamine overdose is very small. The highest recorded overdose (in one patient) was 12 grams. This patient recovered completely. More serious complications are observed when large doses of fluvoxamine and other medications are taken intentionally. Treatment: There is no specific antidote. In case of overdose, gastric lavage, which should be performed as soon as possible, and symptomatic treatment are recommended. In addition, repeated administration of activated charcoal is recommended, and if necessary, a laxative with osmotic action. Forced diuresis or dialysis is not justified. Interactions with other drugs: Fevarin should not be taken with monoamine oxidase inhibitors (see "Contraindications"). Fevarin is a potent inhibitor of cytochrome P450 1A2, and a weaker inhibitor of cytochromes P450 2C and P450 3A4. Drugs whose metabolism is significantly mediated by these isoenzymes are eliminated more slowly, and their plasma concentrations may increase if these drugs are prescribed concomitantly with fluvoxamine. This is particularly important for drugs with a narrow therapeutic index. Patients require careful monitoring, and dose adjustment of these drugs is recommended if necessary. Fluvoxamine has a minimal inhibitory effect on cytochrome P450 2D6 and appears to have no effect on non-oxidative metabolism and renal excretion. Cytochrome P450 1A2: Concomitant administration with Fevarin has been associated with an increase in stable levels of tricyclic antidepressants (clomipramine, imipramine, amitriptyline) and neuroleptics (clozapine, olanzapine) whose metabolism is significantly mediated by this isoenzyme. Therefore, a dose reduction of these drugs is recommended. When taking drugs with a narrow therapeutic index whose metabolism is mediated by cytochrome P450 1A2 (tacrine, theophylline, methadone, mexiletine) with Fevarin, careful monitoring is required. Dose adjustment of these drugs is recommended if necessary. In the combination of Fevarin and warfarin, a significant increase in warfarin plasma concentration and prolongation of prothrombin time has been observed. There are reports of isolated cases of cardiotoxicity with concomitant administration of Fevarin and thioridazine. In a study of Fevarin interactions, an increase in propranolol concentration was observed after Fevarin administration. Therefore, a dose reduction of propranolol is recommended when used with Fevarin. The plasma concentration of caffeine may increase when taking Fevarin. Therefore, during Fevarin treatment, it is necessary to reduce the consumption of caffeine-containing beverages if undesirable effects of caffeine such as tremor, palpitations, nausea, restlessness, insomnia are observed. Concomitant administration of fluvoxamine and ropinirole may increase plasma concentrations of ropinirole and thus the risk of overdose. In such cases, monitoring or, if necessary, dose reduction of ropinirole during fluvoxamine treatment is recommended. Cytochrome P450 2C: When taking drugs with a narrow therapeutic index whose metabolism is mediated by cytochrome P450 2C (phenytoin) with Fevarin, careful monitoring is necessary. Dose adjustment of these drugs is recommended if necessary. Cytochrome P450 3A4: Terfenadine, astemizole, cisapride (see "Special Instructions"). When taking drugs with a narrow therapeutic index whose metabolism is mediated by cytochrome P450 3A4 (such as carbamazepine, cyclosporine) with Fevarin, careful monitoring is required. Dose adjustment of these drugs is recommended if necessary. When prescribing benzodiazepines that undergo oxidative metabolism (triazolam, midazolam, alprazolam, and diazepam) with Fevarin, their plasma concentrations may increase. The dose of these benzodiazepines should be reduced during Fevarin treatment. Fluvoxamine does not affect the plasma concentration of digoxin through glucuronidation. Renal excretion. Fluvoxamine does not affect the plasma concentration of atenolol. Pharmacodynamic reaction: When fluvoxamine is taken with serotonergic agents (such as triptans, tramadol, serotonin reuptake inhibitors), the serotonergic effect of fluvoxamine may be enhanced (see "Special Instructions"). Fluvoxamine has been used in combination with lithium preparations to treat severely ill patients for whom pharmacotherapy has not yielded the desired results. It should be noted that lithium (and possibly tryptophan) enhances the serotonergic effect of fluvoxamine, so such combination pharmacotherapy requires caution. Concomitant administration of oral anticoagulants and fluvoxamine may increase the risk of bleeding. Such patients require medical supervision. Special Instructions: Like other psychotropic drugs, alcohol consumption is not recommended during treatment with fluvoxamine. In depression, there is usually a high risk of suicide attempts, which may persist until adequate remission is achieved. Such patients require medical supervision. Treatment of patients with hepatic or renal insufficiency should be initiated with the minimum effective dose, selected individually, under strict medical supervision. Rarely, treatment with fluvoxamine may be accompanied by increased levels of liver transaminases, usually with corresponding clinical symptoms. In such cases, discontinuation of fluvoxamine is necessary. Impaired control of blood glucose levels may occur, especially in the early stages of treatment. Dose adjustment of antidiabetic drugs may be necessary. The preparation is prescribed with caution in patients with a history of seizures. Fluvoxamine should not be prescribed to patients with unstable epilepsy, while patients with stable epilepsy require strict observation. If an epileptic seizure occurs or its frequency increases, treatment with fluvoxamine should be discontinued. Rare cases of serotonin syndrome or neuroleptic malignant syndrome-like condition have been described, which may be associated with the intake of fluvoxamine in combination with other serotonergic antidepressants and neuroleptic drugs. Since these syndromes can lead to potentially life-threatening conditions, manifested by hyperthermia, muscle rigidity, myoclonus, autonomic nervous system lability, rapid changes in vital parameters such as changes in mental status, including increased irritability, agitation, confusion, delirious disorder, and coma, it is necessary to discontinue treatment with fluvoxamine. Symptomatic treatment should be provided as needed. Like other selective serotonin reuptake inhibitors, hyponatremia may rarely develop against the background of fluvoxamine intake, which resolves after discontinuation of the preparation. Some such cases were caused by syndrome of inappropriate secretion of antidiuretic hormone. All of these were observed in elderly patients. There are reports of the occurrence of subcutaneous hemorrhages, such as ecchymosis, as well as hemorrhagic manifestations (e.g., gastrointestinal bleeding), observed with the use of selective serotonin reuptake inhibitors. The use of these drugs requires caution, especially in elderly patients and patients who are concurrently prescribed drugs affecting platelet function (e.g., atypical antipsychotics and phenothiazines, tricyclic antidepressants, aspirin, non-steroidal anti-inflammatory drugs) or drugs that increase the risk of bleeding. In addition, in patients with a history of bleeding and a tendency to bleeding (e.g., patients with thrombocytopenia). With combination therapy with fluvoxamine, plasma concentrations of terfenadine, astemizole, or cisapride may increase, increasing the risk of QT interval prolongation. Therefore, fluvoxamine should not be prescribed with these drugs. Comparison of treatment outcomes in elderly and younger patients showed no clinically significant difference in the daily doses used. Nevertheless, dose escalation in elderly patients should be slower and more cautious. Ferfarin may cause a slight decrease in heart rate (2-6 beats per minute). Effect of the preparation on the ability to drive and operate machinery: In healthy volunteers, fluvoxamine at a dose of 150 mg had a negligible effect on the ability to drive and operate machinery. However, there is data on somnolence during fluvoxamine treatment. Therefore, caution is required until the individual response to the preparation is fully determined. Dosage form: Film-coated tablet 50 mg, 100 mg; 15 or 20 tablets in a blister. 1, 2, 3 or 4 blisters are placed in a cardboard box with instructions for use. Shelf life: 3 years. Do not use the preparation after the expiry date. Storage conditions: List B. In the original packaging, in a dry, protected from light place, at a temperature of 15-30°C. Keep out of reach of children! Dispensing from pharmacy: By prescription. Manufacturer: Solvay Pharmaceuticals B.V. C. van Houtenlaan 36, The Netherlands.
