Fevarin, 50 mg 15 pcs.

Pharmacodynamics

The mechanism of action of Fevarin is associated with selective inhibition of serotonin reuptake by brain neurons and is characterized by minimal effect on the noradrenergic system. Phevarin has a weak ability to bind to a-adrenergic, b-adrenergic, histaminergic, m-cholinoreceptors, dopaminergic or serotoninergic receptors.

Pharmacokinetics

Intake:
After oral administration, fluvoxamine is completely absorbed from the gastrointestinal tract. Maximum plasma concentrations of the drug are noted 3-8 hours after ingestion. 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 primarily in the liver. Although cytochrome P 450 isoenzyme 2D6 is major in the metabolism of fluvoxamine, plasma concentrations of the drug are not much higher in persons with decreased function of this isoenzyme 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 the equilibrium plasma concentration is usually reached 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 major metabolites have negligible pharmacological activity. The other metabolites are probably pharmacologically inactive. Fluvoxamine significantly inhibits cytochrome P450 1A2, moderately inhibits cytochromes P450 2C and P450 WA4, and slightly inhibits cytochrome P450 2D6. Pharmacokinetics of a single dose of fluvoxamine is linear. The equilibrium concentration of fluvoxamine is higher than that of single dose and is disproportionately higher at higher daily doses.

Special 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. Equilibrium plasma concentrations of fluvoxamine are 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.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

the active ingredient:

fluvoxamine maleate – 50 mg

excipients:

Mannitol – 152.0 mg,

corn starch – 40.0 mg,

Pregelatinized starch – 6.0 mg,

sodium stearyl fumarate – 1.8 mg,

colloidal silicon dioxide – 0.8 mg

coating:

hypromellose – 4.1 mg,

macrogol 6000 – 1.5 mg,

talc – 0.3 mg,

titanium dioxide (E171) – 1.5 mg.

How to take, the dosage

Inhaled without chewing and with a small amount of water.

Depression. The recommended starting dose is 50 or 100 mg (once in the evening). A gradual increase in the starting dose to the 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 intakes. According to the official recommendations of the WHO, treatment with antidepressants should be continued for at least 6 months of remission after a depressive episode. To prevent relapses of depression, it is recommended to take 100 mg of Fevarin once a day.

Obsessive-compulsive disorder. It is recommended to start with a dose of 50 mg Fevarin per day for 3-4 days. The effective daily dose is usually 100 to 300 mg. Doses should be increased gradually until an effective daily dose is reached, which should not exceed 300 mg in adults. Doses up to 150 mg can be taken as a single dose, preferably in the evening. Daily doses over 150 mg are recommended to be divided into 2 or 3 doses.

Doses for children over 8 years of age and adolescents: initial 25 mg/day for 1 administration, maintenance 50-200 mg/day. The daily dose should not exceed 200 mg. Daily doses over 100 mg are recommended to be divided into 2 or 3 doses.

If there is a good response to the drug, treatment may be continued in an individually adjusted daily dose. If improvement is not achieved after 10 weeks of treatment, fluvoxamine should be discontinued. 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, and therefore it may be considered reasonable to extend treatment with Fevarin beyond 10 weeks in patients who respond well to the drug. The selection of the minimum effective maintenance dose should be done with caution on a case-by-case basis. Some clinicians recommend concomitant psychotherapy in patients who respond well to pharmacotherapy.

The treatment of patients with hepatic or renal impairment should be started with the lowest dose under strict medical supervision.

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

Interaction

Fevarin should not be used in combination with MAO inhibitors.

Fluvoxamine is a potent inhibitor of cytochrome P450 1A2, and to a lesser extent of P450 2C and P450 3A4. Drugs that are largely metabolized by these isoenzymes are more slowly excreted and may have higher plasma concentrations if concomitantly prescribed with fluvoxamine. This is particularly important for drugs that are characterized by low therapeutic latency. Patients need close monitoring, and dosage adjustments are recommended if necessary.

Fluvoxamine has minimal inhibitory effect on cytochrome P450 2D6 and probably has no effect on non-oxidative metabolism and renal excretion.

Cytochrome P450 1A2. Concomitant administration of Fevarin has been observed to increase previously stable levels of tricyclic antidepressants (clomipramine, imipramine, amitriptyline) and neuroleptics (clozapine, olanzapine), which are largely metabolized by cytochrome P450 1A2. In this regard, a dose reduction of these drugs may be recommended.

Patients concomitantly taking fluvoxamine and drugs with low therapeutic activity that are metabolized by cytochrome P450 1A2 (such as tacrine, theophylline, methadone, mexiletine) should be monitored closely. Dosages of these drugs should be adjusted if necessary.

When used in combination with warfarin, a significant increase in plasma warfarin concentrations and prolongation of PV have been observed.

A single case of cardiotoxicity has been reported with concomitant use of fluvoxamine with thioridazine.

In studies examining Fevarin interactions, increased concentrations of propranolol have been reported after administration of Fevarin. Therefore, a reduction in the dose of propranololol may be recommended in case of additional administration of Pevarin.

The plasma levels of caffeine may increase during administration of fluvoxamine. Therefore, if large amounts of caffeine-containing beverages are consumed and if adverse effects of caffeine, such as tremor, palpitations, nausea, restlessness, and insomnia develop, caffeine intake should be reduced while taking fluvoxamine.

Concomitant administration of fluvoxamine and ropinirole may increase the plasma concentration of the latter, thereby increasing the risk of overdose. In these cases, it is recommended that the dose of ropinirole be monitored or reduced during treatment with fluvoxamine.

Cytochrome P450 2C. Patients concomitantly taking fluvoxamine and drugs with low therapeutic potency that are metabolized by cytochrome P450 2C (phenytoin) should be closely monitored and dosage adjustments of these drugs are recommended.

Patients concomitantly taking fluvoxamine and drugs with low therapeutic potency that are metabolized by cytochrome P450 3A4 (such as carbamazepine, cyclosporine) should be closely monitored and dosage adjustments of these drugs are recommended.

When benzodiazepines that undergo oxidative metabolism, such as triazolam, midazolam, alprazolam and diazepam, are concomitantly prescribed with fluvoxamine, their plasma concentrations may increase. The dosage of these benzodiazepines should be reduced while fluvoxamine is being taken.

Glucuronidation. Fluvoxamine has no effect on the plasma concentration of digoxin.

Renal excretion. Fluvoxamine has no effect on the plasma concentration of atenolol.

Pharmacodynamic reactions. When fluvoxamine is combined with serotonergic drugs (triptans, serotonin reuptake inhibitors), tramadol, the serotonergic effects of fluvoxamine may be enhanced.

Fluvoxamine is used with lithium preparations to treat severe patients who do not respond well to pharmacotherapy. Lithium and possibly tryptophan enhance the serotonergic effects of Febarin and therefore treatment with this combination should be used with caution.

The simultaneous administration of oral anticoagulants and fluvoxamine may increase the risk of hemorrhages. Such patients should be monitored by a physician.

Special Instructions

The use of alcohol is not recommended during treatment with the drug.

Patients suffering from depression usually have a high probability of suicide attempt, which may persist until sufficient remission is achieved. Such patients should be monitored.

The treatment of patients suffering from hepatic or renal insufficiency should be started with minimally effective doses of Fevarin under strict medical supervision. In rare cases, treatment with Fevarin may lead to increase in liver transaminases, most often accompanied by corresponding clinical symptoms. In these cases, Fevarin should be discontinued.

The control of blood glucose levels may be impaired, especially in the early stages of treatment. Adjustment of the dosage of antidiabetic drugs may be necessary.

Caution should be exercised when prescribing the drug to patients with a history of seizures. Administration of Fevarin to patients with unstable epilepsy should be avoided, and patients with stable epilepsy should be under close medical supervision. Treatment with Fevarin should be discontinued in case of development of epileptic seizures or increase in their frequency.

Rare cases of serotonergic syndrome or a condition similar to malignant neuroleptic syndrome have been described that may be associated with administration of fluvoxamine, in combination with other serotonergic antidepressants and neuroleptic agents. Since these syndromes may lead to potentially life-threatening conditions manifested by hyperthermia, muscle stiffness, myoclonus, autonomic nervous system lability with possible rapid changes in vital parameters, changes in mental status, including increased irritability, agitation, confusion, delirium and coma – treatment with fluvoxamine should be stopped. Appropriate treatment should be initiated if necessary.

As with other selective serotonin reuptake inhibitors, in rare cases fluvoxamine may cause hyponatremia, which reverses after drug withdrawal. Some cases have been caused by the syndrome of insufficient secretion of antidiuretic hormone. Mostly these cases have been observed in elderly patients.

There have been reports of intradermal hemorrhages such as ecchymosis and purpura, as well as hemorrhagic manifestations (such as gastrointestinal bleeding) observed with the use of selective serotonin reuptake inhibitors. Caution should be exercised when prescribing these drugs in elderly patients and patients concomitantly receiving drugs acting on platelet function (atypical antipsychotics and phenothiazines, many tricyclic antidepressants, aspirin, NSAIDs) or drugs that increase the risk of bleeding, as well as in patients with a history of bleeding and prone to bleeding (for example, in patients with thrombocytopenia).

In 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 administered with these drugs.

The data from the treatment of elderly and younger patients suggest that there are no clinically significant differences between the commonly used daily doses in them. Nevertheless, increasing doses in elderly patients should always be done more slowly and with more caution. Phevarin may lead to a slight decrease in HR (by 2-6 beats per minute).

Phevarin is not recommended for the treatment of depression in children due to lack of clinical experience.

Phevarin administered to healthy volunteers in doses up to 150 mg had no or negligible effect on driving or operating machinery. However, there have been reports of drowsiness during treatment with the drug. Therefore, caution is advised until a final determination of the individual response to the drug is made.

Synopsis

Contraindications

With caution:

Side effects

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.

Some of the side effects observed in clinical trials were often related to symptoms of depression rather than to treatment with Fevarin.

General: frequent (1-10%) – asthenia, headache, malaise.

Cardiovascular system: frequently (1-10%) – palpitations, tachycardia; sometimes (less than 1%) – postural hypotension.

Gastrointestinal system disorders: frequently (1-10%) – abdominal pain, anorexia, constipation, diarrhea, dry mouth, dyspepsia; rarely (less than 0.1%) – liver dysfunction (increased liver transaminases).

CNS disorders: frequently (1-10%) – nervousness, anxiety, agitation, dizziness, insomnia or somnolence, tremor; sometimes (less than 1%) – ataxia, confusion, extrapyramidal disorders, hallucinations; rarely (less than 0.1%) – seizures, manic syndrome.

Skin disorders: frequently (1-10%) – sweating; sometimes (less than 1%) – skin hypersensitivity reactions (rash, itching, angioedema); rarely (less than 0.1%) – photosensitization.

Skeletal and muscular system: sometimes (less than 1%) – arthralgia, myalgia.

As to the sexual system: sometimes (less than 1%) – delayed ejaculation; rarely (less than 0.1%) – galactorrhea.

Others: rare (less than 0.1%) – change in body weight; serotoninergic syndrome, condition similar to neuroleptic malignant syndrome, hyponatremia and syndrome of insufficient secretion of antidiuretic hormone; very rare – paresthesias, anorgasmia and perversion of taste.

When discontinuing fluvoxamine, withdrawal symptoms may develop – dizziness, paresthesias, headache, nausea, anxiety (most symptoms are mild and are self-limited). Gradual reduction of the dose is recommended when withdrawing the drug.

Hemorrhagic manifestations – ecchymoses, purpura, gastrointestinal bleeding.

Overdose

Pregnancy use

Few observational data indicate any adverse effects of fluvoxamine in pregnancy. To date, no other epidemiological data are available.

The potential risk to humans is unknown. The drug should be administered to pregnant women with caution.

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, tremors, muscle tone disorders, increased neuroreflexive excitability syndrome, and continuous crying after exposure to selective serotonin reuptake inhibitors in the third trimester of pregnancy, which may have required longer hospitalizations. Fluvoxamine penetrates into breast milk. Therefore, the drug should not be used during lactation.

Similarities