Rokona, 100 mg 30 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
and in vivo with minimal affinity for serotonin receptors. Its ability to
bind to a- and α-adrenoceptors, histamine, m-choline or
dopamine receptors is negligible.

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

Pharmacokinetics

Intake

Intake

.p>After oral administration, fluvoxamine is completely absorbed from the gastro-
intestinal tract. 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
fluvoxamine with food does not affect pharmacokinetics.

Distribution

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

Metabolism

The metabolism of fluvoxamine occurs primarily in the liver. Although
cytochrome P 450 isoenzyme 2D6 is the major enzyme in the metabolism of
fluvoxamine, plasma concentrations of the drug in persons with decreased
function of this isoenzyme are not much higher than in persons with normal
metabolism.

The average plasma 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 main metabolites have
insignificant pharmacological activity. Other metabolites are probably
pharmacologically inactive.

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

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

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) as in adolescents (ages 12-17 years). Plasma concentrations in adolescents are similar to those in adults.

Indications

Active ingredient

Composition

Interaction

MAO inhibitors
Fluvoxamine should not be used in combination with MAO inhibitors,
linezolid because of the risk of serotonin syndrome (see.
Contraindications),
Fluvoxamine’s effect on the oxidative process of other drugs
Fluvoxamine may inhibit the metabolism of drugs,
metabolized by certain cytochrome P450 isoenzymesIn in vitro and in vivo studies have shown powerful inhibitory
fluvoxamine on cytochrome P450 isoenzymes 1A2 and P450 2C19 and to a lesser
degree 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 particularly 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 ramelteon at a dose of 16 mg, the AUC (area under the concentration-time curve) for ramelteon increased by approximately
190 times and the Stach (maximum concentration) increased by approximately 70 times compared to these parameters when ramelteon alone was administered.
Narrow-Range Drugs
Patients concurrently taking fluvoxamine and narrow-range drugs that are metabolized exclusively or by a combination of cytochrome isoenzymes that inhibit fluvoxamine (such astacrine, theophylline, methadone, mexiletine, phenytoin, carbamazepine, and cyclosporine) should be closely monitored. Dose adjustments for these drugs are recommended if necessary.
Tricyclic antidepressants and neuroleptics
An increased concentration of tricyclic antidepressants (e.g., clomipramine,

Directions for use

Special Instructions

As with other psychotropic medications, alcohol consumption is not recommended during treatment with fluvoxamine.
Suicidal thoughts/suicidal thoughts or clinical deterioration
Depression is associated with an increased risk of suicidal thoughts,
suicidal thoughts 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.
In clinical practice, it is common 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 thoughts or suicide attempts 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.
Warn patients (and their caregivers) 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.
Children 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 (suicidal
tries 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 lacking.
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 correlated with the benefit of its use.
Elderly Patients
Data from the treatment of elderly and younger patients suggest that there are 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 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.
Hepatic and/or renal disorders
The treatment of patients with hepatic or renal impairment should be started with low doses and 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, in which case 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 under close supervision. 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 stiffness, myoclonus, labile autonomic nervous system with possible rapid changes in vital parameters (pulse, respiration, BP, 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 started.
Metabolic and nutritional disorders
As with other selective serotonin reuptake inhibitors, hyponatremia may occur in rare cases, which is reversed 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.
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, the dose of antidiabetic drugs may need to be adjusted.
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.
Patients with increased intraocular pressure or those at high risk of acute closed-angle glaucoma should therefore be prescribed fluvoxamine with caution.
Hematological disorders
There have been reports of intradermal hemorrhages such as ecchymoses and purpura as well as other hemorrhagic manifestations (such as gastrointestinal bleeding or gynecological bleeding) observed when
using selective serotonin reuptake inhibitors. Caution should be exercised when prescribing these medications to elderly patients and, patients receiving concomitant medications acting on platelet function (e.g., atypical antipsychotics and phenothiazines, many tricyclic antidepressants, acetylsalicylicacetylacetic 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
An increased risk of QT interval prolongation/paroxysmal ventricular pirouette tachycardia when combining fluvoxamine
with terfenadine or astemizole or cisapride, due to an increase in plasma concentrations 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)
The experience of clinical use of fluvoxamine against ECT is limited, so such therapy should be used with caution.
Cancellation reactions
Cancellation of fluvoxamine may occur, although available data from preclinical and clinical studies have not demonstrated
the emergence of dependence on fluvoxamine treatment. The most common symptoms observed in case of drug withdrawal are: dizziness, sensory disturbances (including paresthesias, visual disturbances and a
current sensation), sleep disturbances (including insomnia and vivid dreams) agitation, irritability, mental confusion, emotional lability, headache, nausea and/or vomiting, diarrhea, sweating, palpitations, tremors and anxiety (see Most of these symptoms are mild to moderate in severity 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 “Dosage and administration”).
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.

Influence on driving ability,
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

Contraindications

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

Treatment with fluvoxamine may be initiated:

The time interval between stopping fluvoxamine and starting
treatment with any MAOI inhibitor should be at least one week,
-simultaneous use with ramelteon (see “Interactions
.

Cautions

Hepatic and renal failure, history of seizures, epilepsy,

Side effects

Some of the adverse effects observed in clinical trials were often related to the disease and not to the ongoing treatment with fluvoxamine.
All reactions are categorized 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 determined – bleeding (e.g., gastrointestinal bleeding, gynecological bleeding, ecchymosis, purpura).
Endocrine system disorders: frequency is not determined – hyperprolactinemia, inadequate antidiuretic hormone production syndrome.
Mechanism and nutrition disorders: frequently – anorexia, frequency is not determined – hyponatremia, weight loss, weight gain.
Psychiatric 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.
Hepatic disorders: rarely – functional disorders (increased liver enzymes activity).
Skin and subcutaneous tissue disorders: frequently – increased sweating, infrequently – skin hypersensitivity reactions (including rash,
zud, angio-neurotic edema), rarely – photosensitivity.
Muscular and connective tissue disorders: infrequent – arthralgia, myalgia, the frequency is not known – bone fracture**. Renal and urinary tract disorders: frequency is not known – urinary disorders (including urinary retention, urinary incontinence, pollacciuria, nocturia and enuresis).
Gender and mammary gland disorders: infrequent – disruption
(delayed) 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 have taken fluvoxamine late in pregnancy.
* – Nausea, sometimes accompanied by vomiting, is the most commonly
observed side effect associated with treatment with fluvoxamine.
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 fracture in patients receiving SSRIs and tricyclic antidepressants. The mechanism of the increased risk is unknown.
Cancellation syndrome after discontinuation of fluvoxamine
Cancellation of fluvoxamine (especially abrupt) often results in the development of withdrawal syndrome. The most common symptoms noted in case of withdrawal of the drug are: Dizziness, sensory disturbances
(including paresthesias, visual disturbance, and a shock sensation),
disorders of sleep (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 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
In a 10-week placebo-controlled study in children and adolescents with OCD, adverse events such as insomnia, asthenia,
high excitability, hyperkinesia, somnolence, and dyspepsia occurred more frequently in patients who received the drug compared to patients who received the placebo. Serious adverse events in this study included hyperexcitability and hypomania.
Convulsions in children and adolescents have been reported outside the clinical
study.

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
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 administration of activated charcoal is recommended, and if necessary osmotic laxatives should be prescribed. Forced diuresis or dialysis is not effective.

In addition, repeated administration of activated charcoal is recommended.

Pregnancy use

Pregnancy
Epidemiological evidence suggests 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.
There is evidence 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
SIOZS in the last months of pregnancy).
No fluvoxamine use during pregnancy is recommended unless the woman’s clinical condition indicates that it should be used.
Some 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,

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