Fevarin® [Fluvoxamine maleate]

Pharmacological properties

receptor binding studies have shown that fluvoxamine is a potent inhibitor of serotonin reuptake both in vitro and in vivo and has minimal affinity for serotonin receptor subtypes. the drug has little ability to bind to α- and β-adrenergic, histaminergic, muscarinic, cholinergic or dopaminergic receptors.

Pharmacokinetics Fluvoxamine is completely absorbed after oral administration. The maximum plasma concentration is reached 3-8 hours after taking the drug. The average absolute bioavailability is 53% (due to the effect of the primary passage through the liver). Concomitant food intake does not affect the pharmacokinetics of fluvoxamine. In vitro, 80% of fluvoxamine binds to plasma proteins. The distribution volume in humans is 25 l / kg. Fluvoxamine is extensively metabolized in the liver. Although in vitro, the main isoenzyme involved in the metabolism of fluvoxamine is CYP 2D6, its plasma concentration in individuals with reduced CYP 2D6 activity is not much higher than in individuals with an intense metabolism.

The average half-life from blood plasma is 13-15 hours after a single dose and slightly increases (17-22 hours) with repeated use, while the equilibrium concentration of the drug in blood plasma is reached within 10-14 days.

Fluvoxamine is intensively transformed in the liver, mainly through oxidative demethylation, resulting in at least 9 metabolites that are excreted by the kidneys. The 2 main metabolites have insignificant pharmacological activity. The remaining metabolites are pharmacologically inactive. Fluvoxamine is a potent inhibitor of CYP 1A2 and moderately inhibits CYP 3A4 and has only a limited inhibitory effect on CYP 2D6.

Fluvoxamine is characterized by a linear pharmacokinetics when taking a single dose. The equilibrium concentration in the blood plasma is higher than that with a single dose and disproportionately higher when taken in higher daily doses.

The pharmacokinetics of fluvoxamine are identical in healthy adult volunteers, the elderly, and in patients with renal failure. Fluvoxamine metabolism is impaired in patients with liver disease. The equilibrium plasma concentrations of fluvoxamine are twice as high in children aged 6 to 11 years old than in children 12-17 years old. The concentration of the drug in blood plasma in children aged 12 to 17 years is the same as in adults.

Indications

Depression, obsessive-compulsive disorders.

Application

The tablets are taken orally without chewing and drinking with water.

Depression (adults)

The recommended initial dose of the drug is 50 or 100 mg once a day. It should be taken 1 time a day before bedtime. The dose should be increased gradually until a clinical effect is achieved. The effective dose of fluvoxamine is usually 100 mg / day. The maximum daily dose is 300 mg / day. In the case of the appointment of the drug in a dose exceeding 150 mg / day, it is distributed into several doses during the day. In accordance with the recommendations of the WHO, after the patient has no symptoms of depression, treatment should be continued for at least another 6 months. The recommended dose of the drug to prevent recurrence of depression is 100 mg of fluvoxamine once a day.

Obsessive-compulsive conditions (adults and children aged 8 years and older)

The recommended initial dose is 50 mg / day for 3-4 days, after which it should be gradually increased until the maximum effective dose, which is usually 100-300 mg / day, is reached. The maximum daily dose of Fevarin in adults is 300 mg, and in children over 8 years of age and adolescents - 200 mg.Fluvoxamine in a dose of up to 150 mg is prescribed 1 time per day, preferably at night. In case of prescribing the drug in a dose exceeding 150 mg, it should be distributed into 2-3 doses during the day. Upon reaching the therapeutic effect, treatment can be continued in an individually selected dose. If, after 10 weeks of treatment, improvement does not occur, the feasibility of further use of Fevarin must be reviewed. Although systematic studies of how long the drug can last for obsessive-compulsive disorders have not been carried out, taking into account their chronic nature, it is recommended to continue treatment after 10 weeks of continuous drug administration, provided that a positive therapeutic effect is achieved. Dose selection must be very careful in order to use the drug at the lowest effective dose. The appropriateness of continuing treatment should be periodically reviewed. Some clinicians recommend a combined prescription of behavioral psychotherapy for patients who have achieved a positive effect during the treatment with Fevarin.

Patients with hepatic or renal failure should begin treatment with a low dose and should be closely monitored by a physician. The tablets should be swallowed whole, washed down with water.

Contraindications

Hypersensitivity to the drug. Fevarin cannot be prescribed simultaneously with tizanidine and MAO inhibitors. Fevarin treatment can be started no earlier than 2 weeks after stopping the use of irreversible MAO inhibitors and the day after the withdrawal of reversible MAO inhibitors (for example, moclobemide). treatment with any of the drugs of the MAO inhibitor group can be started no earlier than 1 week after the abolition of fevarin.

Side effects

Nausea and vomiting are the most common symptoms associated with fevarin treatment. the severity of this side effect is significantly reduced during the first 2 weeks of treatment.

Other adverse events that were observed during clinical trials with the frequency indicated below were often associated with the disease and were not necessarily related to treatment.

Often (1-10%)

Metabolic and nutritional disorders: anorexia.

From the side of the central nervous system: agitation, anxiety, dizziness, headache, insomnia, nervousness, drowsiness, tremor.

From the cardiovascular system: palpitations / tachycardia.

From the digestive tract: abdominal pain, constipation, diarrhea, dry mouth, dyspepsia.

On the part of the skin and subcutaneous tissue: increased sweating.

General disorders and reactions at the injection site: asthenia, a feeling of malaise.

Infrequently (1%)

Mental disorders: confusion, hallucinations.

From the side of the central nervous system: ataxia, extrapyramidal symptoms.

From the cardiovascular system: postural hypotension.

From the skin and subcutaneous tissues: rash, itching, angioedema.

From the musculoskeletal system: arthralgia, myalgia.

From the reproductive system: violation (delay) of ejaculation.

Rare (0.1%)

Mental disorders: manic states.

From the side of the central nervous system: convulsions.

From the hepatobiliary system: impaired liver function.

On the part of the skin and subcutaneous tissues: photosensitivity.

From the reproductive system and mammary glands: galactorrhea.

Other side effects that were observed during the use of the drug

There have been cases of increase or decrease in body weight, as well as serotonin syndrome, phenomena similar to malignant antipsychotic syndrome, hyponatremia and syndrome of impaired secretion of antidiuretic hormone (see also SPECIAL INSTRUCTIONS).

After the cessation of treatment with Fevarin, a withdrawal reaction may occur, although preclinical and clinical data do not indicate that this treatment is addictive.In connection with the withdrawal of the drug, the following symptoms were observed: dizziness, paresthesia, headache, nausea, and a sense of anxiety. Usually disappear on their own. Before discontinuing treatment, it is advisable to consider the need to gradually reduce the dose of the drug.

Hemorrhagic manifestations: ecchymosis, purple, gastrointestinal bleeding (see also SPECIAL INSTRUCTIONS).

Very rarely, paresthesia, anorgasmia, and a change in taste sensations occurred.

In each group, by the frequency of occurrence, undesirable effects are located according to the degree of decrease in their severity.

special instructions

Patients with depression and obsessive-compulsive disorders constantly have a tendency to suicide, which can persist throughout the treatment period until a pronounced remission is achieved. careful monitoring of this category of patients is necessary.

In patients with impaired renal or hepatic function, treatment should begin with taking the drug in low doses and under close medical supervision. Occasionally, Fevarin treatment was accompanied by an increase in the activity of liver enzymes and the corresponding clinical symptoms. In such cases, drug treatment should be discontinued.

Glycemic control may be impaired, especially in the early stages of treatment, which may require dose adjustment of hypoglycemic drugs.

Despite the fact that Fevarin did not cause seizures in animal experiments, in case of its appointment to patients with a history of convulsive syndrome, special care is necessary. The drug should not be prescribed to patients with unstable epilepsy, and the condition of patients with controlled epilepsy should be carefully monitored. In the event of a patient having seizures or an increase in the frequency of their occurrence, Fevarin must be canceled.

There are separate reports of the occurrence of serotonin syndrome or phenomena similar to malignant antipsychotic syndrome, especially with the simultaneous use of Fevarin with other serotonergic and / or antipsychotic drugs. Since these syndromes can cause life-threatening conditions, with the appearance of symptoms such as hyperthermia, rigidity, myoclonus, frequent changes in blood pressure, pulse and respiratory rate, confusion, irritability, agitation with progression to delirium and to whom, treatment with Fevarin should be discontinued and symptomatic therapy.

Rarely, with fevarin (as well as other selective serotonin reuptake inhibitors), hyponatremia occurs. Plasma sodium levels normalize after discontinuation of the drug. Sometimes the occurrence of hyponatremia may be due to the syndrome of inadequate secretion of antidiuretic hormone. Most cases of hyponatremia have been reported in the elderly.

There are reports of cases of ecchymosis, purpura, and gastrointestinal bleeding during the administration of selective serotonin reuptake inhibitors. With caution, these drugs are prescribed, especially for the elderly, simultaneously with drugs that affect platelet function (for example, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and other NSAIDs), as well as patients with a history of hemorrhagic conditions or conditions, which are caused by a tendency to bleed (e.g. thrombocytopenia).

With simultaneous use with fluvoxamine, the concentration of terfenadine, astemizole, or cisapride in blood plasma may increase with an increased risk of an increase in the Q – T interval and the occurrence of pirouette type arrhythmias. Therefore, Fevarin should not be prescribed in conjunction with these drugs.

The results of a study of fluvoxamine in elderly patients who took the drug in the usual daily dose indicates the absence of clinically significant differences compared with patients of a younger age. However, increasing the dose of the drug in elderly patients should be slower and more careful.

Fevarin can slightly reduce heart rate (by 2-6 beats / min).

Use during pregnancy and lactation. Data from a limited number of cases of Fevarin in pregnant women do not indicate side effects. Other epidemiological data are not available.

A study of reproductive function in animals showed impaired fertility (in doses that are 4 times higher than the maximum recommended doses for humans), an increase in mortality in the embryo fetal period, a decrease in fetal body weight and an increase in the frequency of fetal eye abnormalities (folded retina) at doses of fluvoxamine, which significantly exceeded the maximum recommended doses for humans. The potential risk to humans is not known. Caution must be exercised in case of prescribing the drug to pregnant women.

Isolated cases of withdrawal symptoms in newborns after the use of Fevarin at the end of pregnancy were recorded. After the use of selective serotonin reuptake inhibitors during the third trimester of pregnancy, some newborns experienced disturbances in swallowing and / or breathing, convulsions, temperature instability, hypoglycemia, tremor, muscle tone disturbance, trembling and constant crying, which requires prolonged hospitalization.

The drug is excreted in small amounts with breast milk, so it should not be prescribed during lactation.

Children. Fevarin should not be used to treat children with the exception of patients with OCD. In clinical trials, among children receiving antidepressants, suicidal attempts and suicidal thoughts and aggressiveness (conflicting behavior, anger) were more often observed compared with the placebo group. If, based on clinical indications, it was decided to prescribe therapy, it is necessary to carefully monitor the possible occurrence of suicidal symptoms in the patient.

In addition, there is no evidence of long-term safety in children regarding the growth, maturation and development of cognitive behavior.

The drug can not be used to treat depression in children due to lack of sufficient experience.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Fevarin in a daily dose of 150 mg does not affect or almost does not affect the ability to drive vehicles and work with potentially dangerous machines and mechanisms. However, drowsiness may occur during treatment with Fevarin, which must be considered before establishing an individual reaction to the drug.

Interactions

Fevarin cannot be 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 metabolized predominantly with the participation of these isoenzymes are excreted more slowly and can create higher plasma concentrations when used simultaneously with fevarin. this is especially true for medicines with a narrow range of indications for use. careful monitoring of the condition of patients is necessary and, if necessary, dose adjustment of drugs.

Fluvoxamine has a moderate inhibitory effect on CYP 2D6. It probably does not affect non-oxidative metabolism and renal excretion.

CYP 1A2

When used together with Fevarin, an increase in the plasma concentration of a previously stable concentration of tricyclic antidepressants (e.g. clomipramine, imipramine, amitriptyline) and antipsychotics (e.g. closepine, olanzapine), which are metabolized primarily by cytochrome P450 1A2, was noted. You should consider the need to reduce the dose of these drugs before starting Fevarin treatment.

Careful monitoring of the condition of patients who are taking fluvoxamine and drugs with a narrow range of indications for use, metabolized by CYP 1A2 (such as tacrine, theophylline, methadone, mexiletine), and if necessary, adjusting their doses is necessary.

When used together with Fevarin, the concentration of warfarin in the blood plasma increases significantly and the prothrombin time increases.

There are reports of particular cases of cardiotoxic effect of the combination of fluvoxamine with thioridazine.

The concentration of propranolol in blood plasma may increase while taking Fevarin and there may be a need to reduce its dose.

Plasma caffeine levels may increase. Therefore, it is recommended that patients who consume a significant amount of caffeinated drinks while using Fevarin reduce their amount in the diet, especially if side effects of caffeine are noted (such as tremors, palpitations, nausea, anxiety, and insomnia).

When taking ropinirole in combination with Fevarin, the concentration of the first in the blood plasma and the risk of its overdose increase. Therefore, it is necessary to observe patients and, possibly, reduce the dose of ropinirole during treatment with Fevarin and after its withdrawal.

CYP 2C

Careful monitoring of the condition of patients taking fluvoxamine and drugs with a narrow range of indications for use, metabolized by CYP 2C (such as phenytoin), and, if necessary, adjusting their doses, is necessary.

CYP 3A4

Terfenadine, astemizole, cisapride - see SPECIAL INSTRUCTIONS.

Careful monitoring of the condition of patients taking fluvoxamine and drugs with a narrow range of indications for use, metabolized by CYP 3A4 (such as carbamazepine, cyclosporine), and, if necessary, adjusting their doses, is necessary.

With concomitant use with Fevarin, plasma concentrations of benzodiazepines metabolized by oxidation (for example, triazolam, midazolam, alprazolam and diazepam) may increase. Doses of these drugs with simultaneous use with Fevarin should be reduced.

Fluvoxamine does not affect the plasma concentration of digoxin or atenolol.

Serotonergic effects may be enhanced by the administration of Fevarin in combination with other serotonergic drugs (including triptans, tramadol, selective serotonin reuptake inhibitors, and Hypericum perforatum).

Fevarin was prescribed in combination with lithium preparations for patients with severe forms of the disease resistant to drug treatment. However, lithium (and possibly also tryptophan) can enhance the serotonergic effect of Fevarin, therefore, they should be prescribed at the same time with caution.

In patients taking oral anticoagulants and Fevarin, the risk of bleeding may increase, so you should carefully monitor the condition of such patients.

During treatment with Fevarin, like other psychotropic drugs, alcohol should be avoided.

Overdose

Most often noted nausea, vomiting, diarrhea, drowsiness and dizziness; possible tachycardia, bradycardia, arterial hypotension; impaired liver function; convulsions and coma.

Fevarin has a sufficiently wide range of safety in case of overdose. Reports of deaths in connection with an overdose of Fevarin only are single. The highest fixed dose of the drug in case of an overdose was 12 g. The patient who took it fully recovered. More serious complications were noted in the case of a deliberate overdose of fluvoxamine in combination with other drugs.

The treatment is symptomatic. There is no special antidote.In case of overdose, you should rinse your stomach as soon as possible and take activated charcoal, carry out maintenance therapy. If necessary, osmotic laxatives are prescribed. The effectiveness of forced diuresis or dialysis is doubtful.

Storage conditions

In a dry, dark place at temperatures up to 25 ° C.