Rokona, 100 mg 15 pcs.

Pharmacotherapeutic group: antidepressant

ATX code: N06AB08

Pharmacological action

Pharmacodynamics

Receptor binding studies have shown that fluvoxamine
is a potent inhibitor of serotonin reuptake both in vitro
and in vivo with minimal affinity for serotonin receptors. Its ability
to bind to a- and α-adrenoreceptors, histamine, m-choline or
dopamine receptors is negligible.

Fluvoxamine has a high affinity for α – receptors, acting as
their agonist.

Pharmacokinetics

Absorption

.p>Fluvoxamine is completely absorbed from the gastro-
intestinal tract after oral administration. Maximum concentrations of fluvoxamine in plasma
blood are noted 3-8 hours after ingestion. Absolute bioavailability
is 53% after primary metabolism in the liver. Concomitant intake
of fluvoxamine with food does not affect the pharmacokinetics.

Distribution

The binding of fluvoxamine to plasma proteins is 80% (in vitro). The volume
of distribution is 25 l/kg.

Metabolism

The metabolism of fluvoxamine occurs primarily in the liver. Although
cytochrome P 450 isoenzyme 2D6 is the major metabolism
of fluvoxamine, plasma concentrations of the drug in individuals with decreased
function of this isoenzyme are not much higher 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 eliminated via the kidneys. The two major metabolites have
negligible pharmacological activity. Other metabolites are probably
pharmacologically inactive.

Fluvoxamine significantly inhibits cytochrome P450 1A2 and P450 2C19, moderately
inhibits cytochromes P450 2C9, P450 2D6 and P450 WA4.

The pharmacokinetics of a single dose of fluvoxamine is linear. The equilibrium
concentration of fluvoxamine is higher than the single dose concentration, and this
disproportionality is more pronounced at higher daily doses.
Special patient groups

The pharmacokinetics of fluvoxamine are similar in healthy subjects, elderly
patients with renal impairment. The metabolism of fluvoxamine is reduced
patients with liver disease.

The equilibrium plasma concentration of fluvoxamine is 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

Depression of various genesis; -Obsessive-compulsive disorders.

Active ingredient

Fluvoxamine

Composition

Composition per tablet: Active substance: fluvoxamine maleate (in terms of anhydrous substance) 50 mg or 100 mg. Excipients: mannitol, corn starch, pregelatinized starch, sodium stearyl fumarate, colloidal silica. Contents of the coating: hypromellose, titanium dioxide, macrogol (polyethylene glycol 6000), talc.

Interaction

MAO inhibitors
Fluvoxamine should not be used in combination with MAO inhibitors,
linezolid because of the risk of serotonin syndrome (see.
Contraindications),
The effect of fluvoxamine on the oxidative process of other drugs
Fluvoxamine can inhibit the metabolism of drugs,
metabolized by certain cytochrome P450 isoenzymes
In in vitro and in vivo studies, fluvoxamine has been shown to be a potent inhibitor
on cytochrome P450 isoenzymes 1A2 and P450 2C19 and to a lesser extent
on cytochrome P450 2C9, P450 2D6 and P450 WA4 isoenzymes.
Drugs that are largely metabolized by these isoenzymes are more slowly excreted and may have higher plasma concentrations when concomitantly used with fluvoxamine. Such drugs
should be prescribed at a minimum dose or reduced to a minimum dose when concomitantly used with fluvoxamine. Close monitoring of plasma concentrations, effects or side effects is required, as well as dose adjustments of these medications, if necessary. This is especially significant for drugs that have a narrow therapeutic range.
Ramelteon
When fluvoxamine was taken twice daily at 100 mg for 3 days before concomitant use of 16 mg ramelteon, the AUC (area under the concentration-time curve) for ramelteon increased approximately
190 times and the Stah (maximum concentration) increased approximately 70 times as compared to these parameters when ramelteon alone was prescribed.
Narrow therapeutic range drugs
Patients concurrently taking fluvoxamine and narrow therapeutic range drugs that are metabolized exclusively or by a combination of cytochrome isoenzymes that inhibit fluvoxamine (such as tacrine, theophylline, methadone, mexiletine, phenytoin, carbamazepine, and cyclosporine) should be closely monitored. Dose adjustments for these drugs are recommended if necessary
.
Tricyclic antidepressants and neuroleptics
Increased concentrations of tricyclic antidepressants (e.g., clomipramine, Benzodiazepines
When benzodiazepines that undergo oxidative metabolism, such as triazolam, midazolam,
alprazolam and diazepam, are used simultaneously with fluvoxamine, their plasma concentrations may increase. The dose of these benzodiazepines should be reduced while fluvoxamine is being taken.
Cases of increased plasma concentrations
When fluvoxamine and ropinirole are used simultaneously, plasma concentrations of ropinirole may increase, thereby increasing the risk of an
overdose. In such cases, it is recommended that the plasma concentrations of propranololol be monitored or, if
necessary, the dose of ropinirole be reduced or withdrawn during treatment with fluvoxamine.
When fluvoxamine interacted with propranolol, increased plasma concentrations of propranolol were noted. In this regard, it can be recommended
reduction of propranolol dose in case of concomitant use with
fluvoxamine.
When fluvoxamine is used in combination with warfarin a significant increase in plasma warfarin concentrations and prolongation of
prothrombin time were observed.
Cases of increased incidence of adverse effects
Single cases of cardiotoxicity have been reported with concomitant use of fluvoxamine and thioridazine.
During administration of fluvoxamine, plasma caffeine concentrations may increase. Thus, patients who consume large amounts of beverages containing caffeine should reduce their intake while taking
fluvoxamine, and when adverse effects of caffeine such as tremor, palpitations, nausea, anxiety, insomnia are observed. be administered together with these drugs.
Glucuronidation
Fluvoxamine has no effect on the plasma concentration of digoxin.
Renal excretion
Fluvoxamine has no effect on the plasma concentration of atenolol.
Pharmacodynamic interactions
In case of concomitant use of fluvoxamine with serotonergic drugs (such as triptans, tramadol, selective serotonin reuptake inhibitors
and preparations of St. John’s wort) the serotonergic effects of fluvoxamine may be enhanced (see “Special Precautions. “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 carried out with caution.
The risk of hemorrhages may increase when indirect anticoagulants and fluvoxamine are used simultaneously. Such patients should be under medical supervision.

Directions for use

Fluvoxamine tablets should be taken orally, without chewing, with water.
The tablet may be divided into two equal parts.
Depression
Adults
The recommended starting dose for adults is 50 mg or 100 mg
(once in the evening). After 3-4 weeks of therapy, the dose should
be reviewed and adjusted according to clinical experience
with the drug. A gradual increase in dose to effective levels is recommended.
The effective daily dose, usually 100 mg, is selected
individually depending on the patient’s response to treatment. The daily dose can be as high as 300 mg. It is recommended that daily doses over 150 mg be divided into 2 or 3 doses. The selection of the minimum effective maintenance dose
should be done with caution on an individual basis.
In accordance with official WHO recommendations, 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 the drug once daily.
Children
Due to a lack of clinical experience, fluvoxamine is not recommended
for the treatment of depression in children under 18 years.
Obsessive-compulsive disorder (OCD)
Adults
The recommended starting dose for adults is 50 mg of the drug daily
for 3-4 days. The effective daily dose is usually from
100 mg to 300 mg. Doses should be increased gradually until an effective daily dose is achieved, which should not exceed 300 mg in adults. Doses of up to 150 mg may be taken once daily, preferably in the evening. Daily doses over
150 mg are recommended to be divided into 2 or 3 doses.
If there is a good therapeutic response to the drug, treatment may be continued
with an individually adjusted daily dose. If improvement is not
achieved after 10 weeks, treatment with fluvoxamine should be reconsidered.
So far, no systemic studies have been organized to
answer the question of how long treatment with fluvoxamine can be continued,
but obsessive-compulsive disorders are chronic in nature,
and therefore it may be considered appropriate to extend treatment with fluvoxamine
beyond 10 weeks in patients who respond well to the drug. The selection of
a minimum effective maintenance dose should be done
with caution on a case-by-case basis. The need for treatment should be reassessed periodically. Some clinicians recommend
concomitant psychotherapy in patients who respond well to
pharmacotherapy. Long-term efficacy (>24 weeks) has not
been confirmed.
Children over 8 years of age and adolescents
In children over 8 years of age and adolescents, there are limited data on use at doses over 100 mg two
times daily for 10 weeks. The starting dose for children
over 8 years of age and adolescents is 25 mg/day on one visit, preferably
before bedtime. The dose should be increased by 25 mg to the tolerance every 4-7 days
until an effective daily dose is reached. The effective daily dose is usually
50 to 200 mg/day, the maximum dose in children should not exceed 200 mg/day.
Daily doses over 50 mg should be divided into 2 doses, and
if the two doses received are unequal, the larger dose should be taken before bedtime.
Withdrawal syndrome after discontinuation of fluvoxamine
Abrupt withdrawal of the drug should be avoided. When discontinuing treatment with fluvoxamine, the dose should be gradually reduced over at least 1-2
weeks to reduce the risk of withdrawal (see Side effects
and Cautions), If there are intolerable symptoms
after reducing the dose or after withdrawing treatment, consideration may be given to
resuming treatment at the previously recommended dose. At a later time, the physician may reduce the dose again, but more gradually.
Treatment of patients with hepatic or renal impairment should
be started at low doses under close medical supervision.

Special Instructions

As with other psychotropic medications, alcohol consumption is not recommended during treatment with fluvoxamine.
Suicidal/suicidal ideation or clinical deterioration
Depression is associated with an increased risk of suicidal ideation,
self-harm and suicide attempts (suicidal behavior). This risk persists until significant improvement. Because improvement may not occur during the first few weeks of treatment or longer, patients
should be closely monitored until such improvement occurs.
It is common in clinical practice to see an increased risk of suicide in the early stages of recovery.
Other psychiatric disorders for which fluvoxamine is prescribed may also be associated with an increased risk of suicidal behaviors. In addition,
these conditions may accompany major depression. Therefore, patients with other psychiatric disorders should be closely monitored.
Patients with a history of suicidal behavior or significant suicidal ideation are known to have a greater risk of suicidal ideation or suicide attempts before starting treatment and
should be closely monitored during treatment.
Close 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 changes in
behavior, and to consult a specialist immediately 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, fluvoxamine cannot be recommended for the treatment of
depression in children. 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 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 when taking antidepressants compared to placebo in patients younger than 25 years old. When prescribing fluvoxamine
the risk of suicide should be correlated with the benefit of its use.
Elderly patients
Data from the treatment of elderly and younger patients indicate no clinically significant differences between their commonly used daily doses. However, increasing
doses in elderly patients should always be done more slowly and with greater caution.
Akathisia/psychomotor agitation
The development of akathisia associated with fluvoxamine administration is characterized by subjectively unpleasant and distressing restlessness. 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.
Disorders of liver and/or renal function
Treatment of patients with hepatic or renal impairment should be started with low doses, 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 such cases the drug should
be withdrawn.
Nervous system disorders
Caution should be exercised when prescribing the drug to patients with a history of seizures. Administration of fluvoxamine in patients with unstable epilepsy should be avoided, and patients with stable epilepsy should
be closely monitored. Treatment with the drug should be discontinued if epileptic seizures occur or increase in frequency.
Rare cases of serotonergic syndrome or a condition similar to malignant neuroleptic syndrome have been described that may be associated with fluvoxamine administration, especially in combination with other serotonergic and/or neuroleptic medications.
Since these syndromes can lead to potentially life-threatening conditions manifested by hyperthermia, muscle rigidity, myoclonus, labile autonomic nervous system with possible rapid changes in vital parameters (pulse, respiration, BP, etc.
mental status changes, 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 a syndrome of insufficient secretion of antidiuretic
hormone. These cases have mainly been observed in elderly patients.
Blood glucose control may be impaired (i.e., hyperglycemia, hypoglycemia, impaired glucose tolerance), especially in the early stages
of treatment. If fluvoxamine is prescribed to patients with a history of diabetes mellitus, adjustments to the dose of antidiabetic drugs may be required.
The most commonly observed symptom associated with the use of fluvoxamine is nausea, sometimes accompanied by vomiting. This
side effect usually disappears within the first two weeks of treatment.
Visual disturbances
Cases of mydriasis have been reported with SSRIs such as fluvoxamine.
Therefore, patients with elevated intraocular pressure or patients at increased risk of acute closed-angle glaucoma should be prescribed with caution.
Hematologic disorders
There have been reports of intradermal hemorrhages such as ecchymoses and purpura as well as other hemorrhagic manifestations (e.g., gastrointestinal bleeding or gynecologic bleeding) observed with
the use of selective serotonin reuptake inhibitors. Caution should be exercised when prescribing these medications to elderly patients and, patients concomitantly receiving medications acting on platelet function (e.g., atypical antipsychotics and phenothiazines, many tricyclic antidepressants, acetylsalicylicbr> acid, non-steroidal anti-inflammatory drugs) or drugs that increase the risk of bleeding, as well as patients with a history of bleeding or those prone to bleeding (e.
with thrombocytopenia or coagulation disorders).
Cardiac disorders
Increased risk of QT interval prolongation/paroxysmal ventricular tachycardia of the “pirouette” type when combining fluvoxamine
therapy with terfenadine or astemizole or cisapride, due to the increase in plasma concentration of the latter. Therefore, fluvoxamine should not be administered together with these drugs.
Fluvoxamine may cause a slight decrease in HR (by 2-6 beats per minute).
Electroconvulsive therapy (ECT)
Experience of clinical use of fluvoxamine against ECT is limited, so such therapy should be used with caution.
Withdrawal reactions
Withdrawal from fluvoxamine may occur, although available data from preclinical and clinical studies have not demonstrated
dependence on fluvoxamine treatment. The most common symptoms noted in case of withdrawal of the drug are: dizziness, sensory disturbances (including paresthesias, visual disturbances and a
shock sensation), sleep disturbances (including insomnia and vivid dreams) agitation, irritability, confusion, emotional lability, headache, nausea and/or vomiting, diarrhea, sweating, palpitations, tremors and anxiety (see Most of these symptoms are mild to moderate and resolve on their own, but in some patients they may be severe and/or prolonged. These symptoms usually occur in the first few days after discontinuation of treatment. For this reason, it is recommended that the dose of fluvoxamine be gradually reduced before complete withdrawal according to the patient’s condition (see section “Administration and Doses”),
Mania/hypomania
Fluvoxamine should be used with caution in patients with a history of mania/hypomania. If a patient develops a manic phase, fluvoxamine should be discontinued.

The effect on driving ability,
machinery
Fluvoxamine administered to healthy volunteers in doses up to 150 mg had no or negligible effect on driving ability and operating machinery. However, 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.

Synopsis

For dosage 100 mg: round biconvex film-coated tablets, white or almost white, with a ridge on both sides and engraving “FLM100” on one side. On the cross section the core is white or almost white.

Contraindications

Simultaneous use with tizanidine and monoamine oxidase inhibitors
(MAO inhibitors).

Treatment with fluvoxamine may be initiated:

• 2 weeks after discontinuation of an irreversible MAO inhibitor;
• the day after discontinuation of a reversible MAO inhibitor
  (e.g., moclobemide, linezolid).

The time interval between stopping fluvoxamine and starting
therapy with any MAOI inhibitor should be at least one week,
-Simultaneous use with ramelteon (see Interactions
. concomitant use of ramelteon (see “Interaction
with other medicinal products”);

• hypersensitivity to the active ingredient or to any of the ingredients
  of the drug.

Cautions

Hepatic and renal failure, history of seizures, epilepsy,
elderly age, patients prone to bleeding (thrombocytopenia),
pregnancy, lactation.

Side effects

Some side effects observed in clinical trials were often related to the disease and not to the ongoing treatment with fluvoxamine.
All reactions are distributed by organ system and frequency of development: frequently > 1/100 to < 1/10, infrequently > 1/1000 to < 1/100, rarely > 1/10000 to < 1/1000,
frequency not determined (available data do not allow frequency determination).
Blood and lymphatic system disorders: frequency
not established – bleeding (e.g., gastrointestinal bleeding, gynecological bleeding, ecchymosis, purpura).
Endocrine system disorders: frequency is not determined – hyperprolactinemia, inadequate antidiuretic hormone production syndrome.
Metabolic and nutrition disorders: frequently – anorexia; frequency is not determined – hyponatremia, weight loss, weight gain.
Mental disorders: infrequent – hallucinations, confusion, aggression; rare – mania; frequency is not determined – suicidal ideation,
suicidal behavior (see section “Indications”).
Nervous system disorders: Frequent – anxiety, increased excitability, restlessness, insomnia, somnolence, tremor, headache,
dizziness; infrequent – extrapyramidal disorders, ataxia; rare – seizures; frequency not established – serotonin syndrome, malignant
neuroleptic syndrome, akathisia/psychomotor agitation, paresthesia, dysgeusia.
Visual disorders: frequency is not determined – glaucoma,
mydriasis.
Cardiac disorders: often – palpitations/tachycardia.
Vascular disorders: infrequent – orthostatic hypotension.
Gastrointestinal disorders: frequently – abdominal pain, constipation, diarrhea, dry mouth, dyspepsia, nausea, vomiting.
Liver disorders: rare – functional disorders (increased liver enzymes activity).
Skin and subcutaneous tissue disorders: frequently – increased sweating, infrequent – skin hypersensitivity reactions (including rash, itching, angio-neurotic edema), rarely – photosensitivity reactions.
Musculoskeletal and connective tissue disorders: infrequent – arthralgia, myalgia, the frequency is not known – bone fractures**. Renal and urinary tract disorders: frequency is not known – urinary disorders (including urinary retention, urinary incontinence, pollacciuria, nocturia and enuresis).
Genital and mammary tract disorders: infrequent – disruption
(delay) of ejaculation; rare – galactorrhea; frequency is not established – anorgasmia, menstrual disorders (such as amenorrhea, hypomenorrhea, metrorrhagia, menorrhagia).
General disorders: frequent – asthenia, malaise; frequency not established –
drug withdrawal syndrome, including withdrawal syndrome in infants whose mothers took fluvoxamine in late pregnancy.
* – Nausea, sometimes accompanied by vomiting, is the most commonly
observed side effect associated with treatment with fluvoxamine.
The frequency of occurrence usually decreases during the first two weeks
of drug use.
** – Epidemiologic studies, performed primarily with patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants. The mechanism of the increased risk is unknown.
Withdrawal syndrome after discontinuation of fluvoxamine
Discontinuation of fluvoxamine (especially abrupt) often leads to the development of withdrawal syndrome. The most common symptoms noted in case of withdrawal of the drug are: Dizziness, sensory disturbances
(including paresthesias, visual disturbances, and a shock sensation),
sleep disturbances (including insomnia and vivid dreams) agitation, irritability, confusion, emotional lability, headache
pain, nausea and/or vomiting, diarrhea, sweating, palpitations, tremors, and
anxiety (see
Most of these symptoms are mild to moderate in severity and are self-limited, but in some patients they may be severe and/or prolonged. For this reason, if treatment with fluvoxamine is no longer required, it is recommended that the dose be gradually reduced until the drug is completely withdrawn (see “Dosage and administration” and “Special Precautions”).
Children
During a 10-week placebo-controlled study in children and adolescents with OCD, adverse events such as insomnia, asthenia,
hyperexcitability, hyperkinesia, somnolence, and dyspepsia occurred more frequently in patients receiving the drug compared to patients
receiving placebo. Serious adverse events in this study included hyperexcitability and hypomania.
Seizures in children and adolescents have been reported outside clinical
studies.

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 recorded dose of fluvoxamine taken
by one patient was 12 g. This patient was completely cured. More serious complications have been 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, which should be performed as soon as possible after taking the drug, as well as symptomatic treatment.
In addition, repeated intake of activated charcoal is recommended, if necessary osmotic laxatives should be prescribed. Forced diuresis or dialysis is not effective.

Pregnancy use

Pregnancy
Epidemiologic data suggest that the use of selective serotonin reuptake inhibitors (SSRIs) in pregnancy, particularly in the last months of pregnancy, may increase the risk of persistent pulmonary hypertension (PHH) in newborns.
Available data show that PAH occurs in approximately 5 cases per 1000 births (as opposed to 1-2 cases per 1000 births if the mother did not use
SSRIs in the last months of pregnancy).
Fluvoxamine use during pregnancy is not recommended unless the woman’s clinical condition indicates the need for it.
Individual 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, tremor, muscle tone disorders, increased neuroreflex excitability syndrome after third trimester exposure to SSRIs in pregnancy, cyanosis, irritability, lethargy, somnolence, nausea, difficulty falling asleep, and continuous crying, which may require longer hospitalization.

Lactation period
Fluvoxamine penetrates into breast milk in small amounts. Therefore, the drug should not be used during lactation.
Fertility
Studies of reproductive toxicity in animals have shown that fluvoxamine affects male and female reproductive function, increases the risk of intrauterine fetal death and reduces fetal body weight at doses
approximately 4 times the maximum recommended doses for humans.
In addition, an increased incidence of perinatal mortality in pups has been observed in pre- and postnatal studies. The significance of these data in humans is unknown.
Fluvoxamine should not be administered to patients who are planning a pregnancy,
unless the patient’s clinical condition warrants the administration of fluvoxamine.

Similarities

Fevarin