Fevarin, 100 mg 30 pcs.

Interaction

Fluvoxamine significantly inhibits the cytochrome P450 isoenzyme 1A2 and to a lesser extent the P450 2C and P 450 ZA4 isoenzymes. Drugs that are largely metabolized by these isoenzymes are more slowly excreted and may have higher plasma concentrations when concomitantly prescribed with fluvoxamine. This is particularly significant for drugs that have a narrow range of therapeutic action. Patients need close monitoring and dose adjustments of these drugs are recommended if necessary.

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

Cytochrome Р450 1A2 isoenzyme
Increased concentrations of tricyclic antidepressants (clomipramine, imipramine, amitriptyline) and neuroleptics (clozapine, olanzapine) that are largely metabolized by cytochrome Р450 1A2 isoenzyme have been observed when fluvoxamine was used concomitantly. Therefore, if treatment with fluvoxamine is initiated, a dose reduction of these drugs should be considered.

Patients taking fluvoxamine and drugs with a narrow therapeutic range metabolized by cytochrome P450 1A2 isoenzymes (such as tacrine, theophylline, methadone, mexiletine) simultaneously should be monitored closely. If necessary, it is recommended that the dose of these drugs be adjusted. Single cases of cardiotoxicity have been reported when fluvoxamine and thioridazine are concomitantly administered. When fluvoxamine interacted with propranolol, increased plasma concentrations of propranolol were observed. Therefore, it may be recommended to reduce the dose of propranolol if concomitantly taken with fluvoxamine. While taking fluvoxamine, plasma concentrations of caffeine may increase. Thus, patients who consume large amounts of beverages containing caffeine should decrease their consumption while taking fluvoxamine, and when adverse effects of caffeine, such as tremor, palpitations, nausea, restlessness, and insomnia, are observed.

Concomitant administration 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 withdrawing ropinirole during treatment with fluvoxamine is recommended.

Cytochrome P450 2C isoenzyme

Patients taking fluvoxamine and drugs with a narrow therapeutic range that are metabolized by cytochrome P450 2C isoenzyme (such as phenytoin) at the same time should be monitored closely, and dose adjustments of these drugs are recommended if necessary.

When fluvoxamine is used in combination with warfarin, significant increases in plasma warfarin concentrations and prolongation of prothrombin time have been observed.

Cytochrome P450 isoenzyme WA4

Terfenadine, astemizole, cisapride: When combined 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.

Patients concomitantly taking fluvoxamine and drugs with a narrow therapeutic range that are metabolized by cytochrome P450 CA4 isoenzymes (such as carbamazepine, cyclosporine) should be closely monitored and dose 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 dose 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 atenololol.

Pharmacodynamic interactions

In case of combined administration of fluvoxamine 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 (see “Special Instructions”). 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 administration of oral anticoagulants and fluvoxamine may increase the risk of hemorrhagia.

These 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®.

Suicidal/suicidal thoughts or clinical deterioration
Depression is associated with an increased risk of suicidal thoughts or suicidal behavior (self-harm or suicide). 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.

Obsessive-compulsive disorders may also be associated with an increased risk of suicidal events. In addition, these conditions may accompany major depression. Therefore, the same precautions should be taken when treating patients with obsessive-compulsive disorders as when treating patients with major depression.

Patients with a history of suicide-related events or who exhibit significant suicidal ideation are known to have a greater risk of suicidal thoughts or suicidal behaviors 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.

Pediatric population
Fluvoxamine should not be used to treat children and adolescents under 18 years of age with the exception of patients with obsessive-compulsive disorder. Because of a lack of clinical experience, the use of fluvoxamine in children for the treatment of depression cannot be recommended. In clinical studies in children and adolescents, suicidal-conditioned behavior (suicide attempts and thoughts) and hostility (mainly aggression, oppositional behavior, and anger) were observed more frequently in patients who received an antidepressant compared to those who received a placebo. If, based on clinical need, the decision to treat is made, the patient should be closely monitored for the occurrence of suicidal symptoms.

In addition, long-term safety data for children and adolescents regarding growth, development, and establishment of cognitive behavior are not available.

Adults (18 to 24 years old)
A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders found an increased risk of suicidal behavior with antidepressants compared to placebo in patients younger than 25 years old. When prescribing fluvoxamine, the risk of suicide should be weighed against the benefit of its use.

Elderly patients
Data from the treatment of elderly patients and younger patients suggest that there are no clinically significant differences between their commonly used daily doses. However, dosage escalation in older patients should always be done more slowly and with more caution.

Akathisia/psychomotor agitation
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.

The treatment of patients suffering from hepatic or renal insufficiency should be started with low doses and such patients should be under close medical supervision. In rare cases, treatment with fluvoxamine may lead to increased hepatic enzyme activity, most often accompanied by associated clinical symptoms, and in these cases Fevarin® should be discontinued.

Nervous system disorders
Caution should be exercised when prescribing the drug in 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 a condition similar to malignant neuroleptic syndrome have been described that may be associated with the administration of fluvoxamine, especially in combination with other serotonergic and/or neuroleptic drugs. Since these syndromes can lead to potentially life-threatening conditions manifested by hyperthermia, muscle stiffness, myoclonus, labile autonomic nervous system with possible rapid changes of vital parameters (pulse, respiration, BP, etc.etc.), changes in mental status, including confusion, irritability, extreme agitation up to delirium or coma – in such cases, treatment with fluvoxamine should be stopped and appropriate symptomatic treatment should be initiated.

Metabolic and nutritional disorders.
As with other selective serotonin reuptake inhibitors, in rare cases, hyponatremia may occur, which reverses after withdrawal of fluvoxamine. Some cases have been caused by insufficient antidiuretic hormone secretion syndrome. These cases were mostly observed in elderly patients.

The control of blood glucose levels (i.e., hyperglycemia, hypoglycemia, impaired glucose tolerance) may be impaired, especially in the early stages of treatment. If fluvoxamine is prescribed to patients with a history of diabetes mellitus, an adjustment of the dose of antidiabetic 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 two weeks of treatment.

Hematologic disorders
There have been reports of intradermal hemorrhages such as ecchymoses and purpura as well as hemorrhagic manifestations (such as gastrointestinal 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, non-steroidal anti-inflammatory drugs) or drugs that increase the risk of bleeding, and in patients with a history of bleeding or who are prone to bleeding (e.g., thrombocytopenia).

Heart disorders
Increased risk of QT interval prolongation/paroxysmal ventricular pirouette tachycardia when combining 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 beats per minute).

Withdrawal reactions
Withdrawal symptoms may occur when discontinuing fluvoxamine, although available data from preclinical and clinical studies have not shown dependence on fluvoxamine treatment. Symptoms noted in the event of drug withdrawal include dizziness, paresthesias, headache, nausea, and anxiety. Most of these symptoms are mildly pronounced and are self-limited. Gradual reduction of the dose is recommended when treatment with the drug is stopped.
Phevarin administered to healthy volunteers in doses up to 150 mg had no or negligible effect on driving ability and operating machinery. At the same time, there have been reports of drowsiness during treatment with fluvoxamine. Therefore, caution is advised until a final determination of the individual response to the drug is made.

Contraindications

Severe liver dysfunction, concomitant use of MAO inhibitors, children under 8 years of age, hypersensitivity to fluvoxamine.

Side effects

Some side effects observed in clinical trials were often associated with symptoms of depression rather than treatment with Fevarin®.

Frequent (> 1% and
General disorders: asthenia, malaise.
Cardiac disorders: palpitations,tachycardia.
Gastrointestinal disorders: abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, nausea, vomiting.
Nervous system disorders: increased excitability, anxiety, agitation, dizziness, insomnia or drowsiness, tremor, headache.
Skin and subcutaneous tissue disorders: increased sweating.
Metabolic and nutrition disorders: anorexia.

Infrequent (>0.1% and
Vascular disorders: orthostatic hypotension
Musculoskeletal and connective tissue disorders: arthralgia, myalgia.
Nervous system disorders: ataxia, extrapyramidal disorders.
Mental disorders: confusion, hallucinations.
Genital and mammary gland disorders: violation (delay) of ejaculation.
Skin and subcutaneous tissue disorders: skin hypersensitivity reactions, (including rash, itching, angioedema).

Rare (>0.01% and
Liver disorders: liver dysfunction (increased activity of liver enzymes).
Nervous system disorders: seizures.
Mental disorders: mania
Genital and mammary gland disorders: galactorrhea.
Skin and subcutaneous tissue disorders: photosensitivity reactions.

In addition to the adverse events described during clinical trials, the following side effects have been reported during the post-marketing use of fluvoxamine. The exact frequency cannot be provided and is therefore classified as “unknown”.

Blood and lymphatic system disorders: hemorrhages (e.g., gastrointestinal bleeding, ecchymosis, purpura).

Endocrine system disorders: insufficient secretion of antidiuretic hormone.

Metabolic and nutrition disorders: hyponatremia, weight gain, weight loss.

Nervous system disorders: serotonin syndrome; phenomena similar to malignant neuroleptic syndrome; akathisia/psychomotor agitation; paresthesias; dysgeusia.

Mental disorders: suicidal thoughts and suicidal behavior have been reported during treatment with fluvoxamine or shortly thereafter.

Kidney and urinary tract disorders: urinary disorders (including urinary retention, urinary incontinence, frequent urination, nycturia, and enuresis).

Gender and mammary disorders: anorgasmia.

General disorders: drug withdrawal syndrome, including withdrawal syndrome in infants.

Overdose

Symptoms

The most characteristic symptoms include gastrointestinal disturbances (nausea, vomiting and diarrhea), drowsiness and dizziness. In addition, there have been reports of cardiac abnormalities (tachycardia, bradycardia, arterial hypotension), hepatic dysfunction, seizures, and coma.

Fluvoxamine has a wide therapeutic dose range with respect to overdose safety. Since its release to the market, reports of deaths attributed to overdose with fluvoxamine alone have been extremely rare. The highest reported dose of fluvoxamine taken by one patient was 12 g. This patient was completely cured. More serious complications were observed in cases of intentional overdose of fluvoxamine in combination with other drugs.

Treatment

There is no specific antidote for fluvoxamine: In case of overdose, gastric lavage is recommended and should be performed as soon as possible after taking the drug, as well as symptomatic treatment. In addition, repeated administration of activated charcoal is recommended, if necessary prescription of osmotic laxatives. Forced diuresis or dialysis is not effective.

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 had 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

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