Pharmacological properties
Pharmacodynamics. Receptor binding studies have shown that fluvoxamine is a potent serotonin reuptake inhibitor both in vitro and in vivo, and has minimal affinity for serotonin receptor subtypes. The drug has negligible ability to bind to α-adrenergic, β-adrenergic, histaminergic, muscarinic, cholinergic or dopaminergic receptors.
Pharmacokinetics. Absorption. Fluvoxamine is completely absorbed after oral administration. C max in blood plasma is reached 3-8 hours after administration. The average absolute bioavailability is 53%.
Concomitant food intake does not affect the pharmacokinetics of fluvoxamine.
Distribution: In vitro, fluvoxamine is 80% bound to plasma proteins. The volume of distribution in humans is 25 l/kg body weight.
Metabolism: Fluvoxamine is extensively metabolized in the liver. Although in vitro the major isoenzyme involved in fluvoxamine metabolism is CYP 2D6, plasma concentrations in individuals with reduced CYP 2D6 activity are not significantly higher than in extensive metabolizers.
The average T½ from blood plasma is approximately 13-15 hours after a single dose and is slightly prolonged (17-22 hours) with multiple doses, with steady-state plasma concentrations usually achieved within 10-14 days.
Fluvoxamine is extensively metabolized in the liver, mainly by oxidative demethylation, resulting in the formation of at least 9 metabolites that are excreted by the kidneys. The two main metabolites are pharmacologically inactive. Fluvoxamine is a potent inhibitor of CYP 1A2, moderately inhibits CYP 2C and CYP 3A4, and has only a minimal inhibitory effect on CYP 2D6.
Fluvoxamine exhibits linear pharmacokinetics after single-dose administration.
Steady-state plasma concentrations are higher than those estimated from single-dose data and are disproportionately higher at higher daily doses.
Special patient groups: The pharmacokinetics of fluvoxamine are similar in healthy adults, the elderly and patients with renal insufficiency. The metabolism of fluvoxamine is impaired in patients with liver disease.
Indication
Depression. Obsessive-compulsive disorders.
Application
Depression. The initial daily dose for adults is 50 mg for a week, which should be taken once a day, preferably at bedtime. The dose is gradually increased until an effective dose is achieved. The effective daily dose is usually 100 mg and may in some cases be increased to 300 mg/day (selected individually, depending on the patient's response).
A daily dose exceeding 100 mg should be divided into 2 or 3 doses.
Improvement of the condition should be expected after 2-4 weeks of therapy with an adequate dose of the drug. It is recommended to continue treatment if the patient is free of symptoms of the disease for 6 months (according to WHO recommendations). The recommended dose for preventing relapse of depression is 100 mg 1 time per day.
The tablets should be swallowed whole and washed down with water.
Obsessive-compulsive disorder (adults and children aged 8 years and over). The recommended initial daily dose during the 1st week of treatment is 50 mg. Then the dose is gradually increased until an effective dose is achieved. In adults, the usual daily dose of Deprivox is 100-200 mg, the maximum - 300 mg/day. If the patient's condition does not improve within 10 weeks, treatment with Deprivox should be reviewed. No studies have been conducted on the duration of therapy with Deprivox.
Due to the chronic nature of the treatment, it is recommended to continue treatment for at least 10 weeks after a satisfactory therapeutic response to the drug has been achieved.
The dose for each patient should be selected individually, therapy is carried out with the minimum effective dose; the duration of the course of treatment should be adjusted periodically. For patients who respond well to the course of therapy, a combination of drug and behavioral therapy is recommended.
Hepatic and renal failure, heart disease. In patients with hepatic and renal failure or severe heart failure, therapy with Deprivox should be started at low doses and under constant monitoring.
Contraindication
Deprivox should not be used simultaneously with tizanidine and MAO inhibitors. The drug is prescribed 2 weeks after completion of therapy with MAO inhibitors.
Fluvoxamine maleate should not be administered to patients with known hypersensitivity to fluvoxamine maleate or any of the excipients.
Side effects
Nausea, sometimes accompanied by vomiting, is the most common symptom of fluvoxamine treatment. The severity of this side effect usually decreases within the first 2 weeks of treatment. Other side effects are often associated with the disease and do not require appropriate treatment.
The frequency of side effects is determined as follows:
very often (≥1/10); often (≥1/100, 1/10); infrequently (≥1/1000, 1/100); rarely (≥1/10,000, 1/1000); very rarely (≥1/10,000); unknown (cannot be determined based on the data of the studies conducted).
Cardiovascular system disorders: common: palpitations (increased sensation of heartbeat)/tachycardia; uncommon: (orthostatic) hypotension; rare: hemorrhages, ecchymoses, purpura.
Nervous system disorders: often - headache, dizziness, drowsiness, tremor, agitation, anxiety, insomnia, nervousness; infrequently - ataxia, extrapyramidal symptoms; rarely - convulsions, akathisia (see Features of use), serotonin syndrome or neuroleptic malignant syndrome (see Features of use); very rarely - paresthesia, change in taste perception.
Gastrointestinal disorders: often - abdominal pain, constipation, diarrhea, dry mouth, dyspepsia; unknown - nausea, sometimes accompanied by vomiting; gastrointestinal bleeding.
Skin disorders: often - increased sweating; infrequently - hypersensitivity skin reactions (rash, itching, angioedema); rarely - photosensitivity.
Musculoskeletal and connective tissue disorders: infrequently - arthralgia, myalgia.
Endocrine system disorders: rarely - syndrome of inappropriate secretion of antidiuretic hormone (see Special warnings and precautions for use).
Metabolism and digestion disorders: unknown - weight change; often - anorexia (loss of appetite); rarely - hyponatremia (see Features of use).
General disorders: often - asthenia, malaise.
Hepatobiliary disorders: rarely - liver dysfunction.
Reproductive system disorders: infrequently - impaired (delayed) ejaculation; rarely - galactorrhea.
Psychiatric disorders: often - agitation, anxiety, insomnia, nervousness; infrequently - agitation, hallucinations; rarely - mania; very rarely - anorgasmia, paresthesia, change in taste sensations; unknown - suicidal thoughts and mood.
Cases of suicidal thoughts and mood have been observed during treatment and upon discontinuation of fluvoxamine therapy (see Precautions).
Withdrawal reactions may occur after discontinuation of therapy, although available preclinical and clinical data do not indicate that this treatment is addictive. The following symptoms have been observed in connection with discontinuation of the drug: dizziness, paresthesia, headache, nausea and anxiety. These were usually mild and resolved spontaneously. Before discontinuation of treatment, it is advisable to consider the need for a gradual reduction in the dose of the drug.
In placebo-controlled studies of the drug for 10 weeks in children and adolescents with obsessive-compulsive disorder, the following side effects were commonly observed: insomnia, asthenia, agitation, hyperkinesia, drowsiness and dyspepsia. Serious side effects in this study included agitation and hypomania. Seizures were observed in children and adolescents during treatment.
Special instructions
When switching from MAO inhibitor therapy to Deprivox (fluvoxamine), the course of treatment should begin no less than 2 weeks after completion of therapy with reversible or irreversible MAO inhibitors.
Treatment with MAO inhibitors should be started at least 1 week after completion of Deprivox therapy. In patients with hepatic or renal insufficiency, severe heart failure, increased levels of liver enzymes with pronounced symptoms are rarely noted. In such cases, the drug should be discontinued.
Special caution should be exercised in patients with epilepsy. If seizures occur, Deprivox therapy should be discontinued.
As with any treatment for depression, there is a risk of suicidal ideation at the beginning of therapy between the start of treatment and clinical improvement. As with other antidepressants, the therapeutic effect may not be clinically apparent for the first ≥2 weeks.
As with other antidepressants, Deprivox should be discontinued if a manic phase develops.
It is recommended to adjust the dose for elderly patients, who are usually much more sensitive to the side effects of the drug.
Isolated cases of bleeding (usually ecchymoses and purpura) have been reported. Deprivox should be used with caution in patients taking medicinal products that adversely affect platelet function (antipsychotics, phenothiazine neuroleptics, tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, acetylsalicylic acid) or with a pre-existing high risk of bleeding.
To avoid the development of withdrawal syndrome during the end of the course of therapy, the dose should be reduced gradually.
Clinical experience with the simultaneous use of Deprivox and electroconvulsive therapy is insufficient.
Deprivox may increase blood glucose levels, especially in the initial stages of treatment. Therefore, patients may require dose adjustment of antidiabetic agents.
When combined with Deprivox, plasma concentrations of terfenadine, astemizole or cisapride may increase, which increases the risk of QT prolongation and torsade de pointes arrhythmias. Therefore, the drug should not be prescribed together with these drugs.
In rare cases, treatment with fluvoxamine is accompanied by the appearance of serotonin syndrome or neuroleptic malignant syndrome, especially when fluvoxamine is combined with other serotonergic and / or neuroleptic drugs (including triptans, tramadol, selective serotonin reuptake inhibitors and St. John's wort preparations). Since these syndromes can lead to the appearance of life-threatening conditions, treatment with fluvoxamine should be discontinued if symptoms (groups of symptoms) such as hyperthermia, muscle rigidity, myoclonus, instability of the autonomic nervous system with possible rapid changes in blood pressure, heart rate and respiratory rate, changes in mental status, including agitation, irritability, excessive excitement with progression to delirium and coma) appear and symptomatic treatment is carried out.
As with other serotonin reuptake inhibitors, hyponatremia is rare and resolves after discontinuation of fluvoxamine. In some cases, hyponatremia has been associated with the syndrome of inappropriate antidiuretic hormone secretion. Most cases have been reported in elderly patients.
Deprivox may cause a slight decrease in heart rate (by 2-6 beats/min).
Pregnancy and breast-feeding. Clinical data on the use of the drug during pregnancy are not available. Preclinical studies have not revealed any negative effect of the drug in therapeutic doses on the course of pregnancy, fetal development, childbirth or postnatal development. However, some caution should be observed when prescribing Deprivox during pregnancy.
Fluvoxamine is excreted in breast milk (the milk/blood plasma ratio is about 0.3). Therefore, Deprivox should not be used during breastfeeding, and breastfeeding should be discontinued while taking the drug.
Children and adolescents (under 18 years of age). Currently, there is insufficient data on the use of Deprivox in the treatment of depression in adolescents and children under 18 years of age. For obsessive-compulsive disorder, the drug is used in children over 8 years of age according to the dosages specified in the USAGE section.
Effect on the ability to drive vehicles and use precise mechanisms. The effect of the drug at a dose of 150 mg/day on psychomotor function and reaction was studied in experimental conditions on healthy volunteers: no negative effects were noted. However, in some cases the ability to drive vehicles and work with precise mechanisms was reduced. High doses of the drug or its use in combination with alcohol or drugs that affect the central nervous system (benzodiazepines) significantly changed the ability to respond adequately.
It should be taken into account at the beginning of treatment that a side effect of the drug is drowsiness.
Interactions
The drug is not prescribed in combination with MAO inhibitors.
Fluvoxamine is a potent inhibitor of CYP 1A2 and to a lesser extent CYP 2C and CYP 3A4. Drugs that are primarily metabolized by these isoenzymes are eliminated more slowly and may have high plasma concentrations when co-administered with Deprivox. This is especially true for drugs with a narrow therapeutic index. Patients should be closely monitored and, if necessary, dosage adjustments should be made.
Fluvoxamine has a marginal effect on CYP 2D6. It is not thought to affect non-oxidative metabolism or renal excretion.
CYP 1A2. When used together with Deprivox, an increase in the previously stable plasma concentrations of such tricyclic antidepressants (e.g. clomipramine, imipramine, amitriptyline) and neuroleptics (e.g. clozepine, olanzapine), which are predominantly metabolized by cytochrome CYP 1A2, has been observed. The need for a dose reduction of these drugs should be considered before starting treatment with Deprivox.
It is necessary to carefully monitor the condition of patients who simultaneously take Deprivox and drugs with a narrow therapeutic index that are metabolized by CYP 1A2 (tacrine, theophylline, methadone, mexiletine) and, if necessary, change the dosage of this drug.
When used together with Deprivox, the concentration of warfarin in the blood plasma increases significantly and the prothrombin time increases.
Isolated cases of cardiotoxic effects of the combination of fluvoxamine with thioridazine have been reported.
Since the concentration of propranolol in the blood plasma increases when taken simultaneously with Deprivox, it may be necessary to reduce its dose.
Caffeine levels in the blood plasma may increase when caffeine-containing beverages are used with Deprivox. Therefore, patients who consume significant amounts of caffeine-containing beverages should reduce their intake if they are prescribed Deprivox and experience caffeine side effects (tremor, palpitations, nausea, restlessness, insomnia).
When ropinirole is taken in combination with Deprivox, its plasma concentration may increase, which increases the risk of overdose. Therefore, patients should be monitored and, if necessary, the dose of ropinirole should be reduced during treatment with Deprivox and after its withdrawal.
CYP 3A4. Terfenadine, astemizole, cisapride (see Precautions).
Patients taking fluvoxamine and drugs with a narrow therapeutic index that are metabolized by CYP 3A4 (such as carbamazepine, cyclosporine) should be carefully monitored and, if necessary, the doses of these drugs should be adjusted.
When taken simultaneously with Deprivox, an increase in the plasma concentration of benzodiazepines that are metabolized by oxidation (e.g. triazolam, midazolam, alprazolam and diazepam) is possible. The dose of these benzodiazepines should be reduced when used simultaneously with Deprivox.
Glucuronidation. The drug does not affect the concentration of digoxin in blood plasma.
Renal excretion. The drug does not affect the concentration of atenolol in blood plasma.
Pharmacodynamic interactions: Serotonergic effects may be enhanced when Deprivox is used in combination with other serotonergic drugs (including triptans, tramadol, selective serotonin reuptake inhibitors and St. John's wort preparations) (see Precautions).
Deprivox is prescribed in combination with lithium for patients with severe forms of the disease, resistant to drug treatment. However, lithium (and possibly tryptophan) may enhance the serotonergic effects of Deprivox. Therefore, the combination of these drugs should be prescribed with caution in patients with severe, treatment-resistant depression.
Patients receiving oral anticoagulants and Deprivox may be at increased risk of bleeding. Therefore, careful monitoring of the condition of such patients is necessary.
While using Deprivox, as with other psychotropic drugs, patients should avoid drinking alcohol.
Overdose
There have been reports of overdose with Deprivox as monotherapy or in combination with other drugs. Most cases of overdose are characterized by gastrointestinal symptoms (nausea, vomiting and diarrhea), drowsiness, dizziness. In addition, there have been reports of disorders of the cardiovascular system (tachycardia, bradycardia and hypotension), consciousness, as well as convulsions, coma and impaired liver function.
In some cases, overdose has been observed when using Deprivox in combination with other drugs.
There have been reports of deaths in patients who have deliberately taken a very high dose of Deprivox in combination with other medicines or, in exceptional cases, Deprivox alone.
The maximum recorded dose of Deprivox taken by the patient was 12 g; the patient's condition was fully recovered with symptomatic treatment.
Treatment: there is no specific antidote. In case of overdose, immediately after taking the tablets, the stomach should be washed and symptomatic treatment should be started. The use of activated charcoal and laxatives is recommended (laxatives should be avoided in case of diarrhea).
Storage conditions
At a temperature not exceeding 25 °C in the original packaging.
