INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUOXETINE

Composition:

Active substance: fluoxetine;

1 tablet contains 20 mg of fluoxetine hydrochloride;

Excipients: lactose monohydrate; corn starch; sucrose; talc; calcium stearate; gelatin; Opadry II white, containing: titanium dioxide (E 171), talc, polyethylene glycol, polyvinyl alcohol; Sepispers dry yellow R.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, from light-yellow to dark-yellow in color.

Pharmacotherapeutic group. Antidepressants. ATC code N06AB03.

Pharmacological properties.

Pharmacodynamics. Fluoxetine is an antidepressant whose mechanism of action is based on selective inhibition of neuronal reuptake of serotonin in the central nervous system. Fluoxetine is also a weak antagonist of muscarinic, histaminergic, and α-adrenergic receptors. Unlike other antidepressants, it does not reduce the functional activity of β-adrenergic receptors and has minimal effect on neuronal reuptake of norepinephrine and dopamine. It promotes improvement of mood, relieves feelings of fear, tension, and dysphoria. It has stimulatory and analgesic effects and does not produce sedative or cardiotoxic effects when administered at medium therapeutic doses.

A stable therapeutic effect develops within 1–2 weeks of continuous drug administration and persists for at least 1 week after discontinuation.

Pharmacokinetics. Fluoxetine is absorbed from the gastrointestinal tract. It undergoes weak metabolism during first-pass through the liver. Food intake does not affect the extent of absorption, although it may slow its rate. Maximum plasma concentration is reached within 6–8 hours. Steady-state plasma concentration is achieved only after continuous administration for several weeks. Plasma protein binding is 94.5%. Fluoxetine readily crosses the blood-brain barrier. It is metabolized in the liver via demethylation to form the main active metabolite, norfluoxetine. The elimination half-life of fluoxetine is 2–3 days; that of norfluoxetine is 7–9 days. Fluoxetine is excreted primarily by the kidneys (80%) and through the intestine (approximately 15%).

Clinical characteristics.

Indications. Major depressive episodes/disorders.

Obsessive-compulsive disorders.

Nervous bulimia: as part of comprehensive psychotherapy to reduce uncontrolled eating and purging behaviors.

Contraindications. Hypersensitivity to fluoxetine or to any of the other components of the medicinal product.

Severe hepatic and renal insufficiency, epilepsy, history of seizures, suicidal thoughts, glaucoma, urinary bladder atony, benign prostatic hyperplasia.

Concomitant use with monoamine oxidase inhibitors (MAOIs) (selective, non-selective), including linezolid. The interval between discontinuation of MAOI therapy and initiation of fluoxetine treatment should be at least 14 days. The interval between discontinuation of fluoxetine and initiation of MAOI therapy should be no less than 5 weeks.

Use in combination with metoprolol in patients with heart failure.

Interaction with other medicinal products and other forms of interaction. It is important to consider the long elimination half-life of both fluoxetine and norfluoxetine when evaluating pharmacodynamic and pharmacokinetic interactions with other medicinal products (e.g., when switching from fluoxetine to other antidepressants).

MAO inhibitors. The period between discontinuation of MAO inhibitors and initiation of treatment with the medicinal product should be at least 14 days. After discontinuation of fluoxetine, at least 5 weeks should elapse before starting therapy with MAO inhibitors. Severe, sometimes fatal reactions (hyperthermia, rigidity, myoclonus, autonomic instability, rapid changes in vital signs, and disturbances of mental function, including intense agitation, delirium, and coma) have been reported in patients taking fluoxetine in combination with MAO inhibitors, as well as in those who discontinued fluoxetine and subsequently started MAO inhibitor therapy. Concomitant use of fluoxetine with MAO inhibitors is contraindicated (see section "Contraindications").

Metoprolol. Concomitant use of fluoxetine with metoprolol in patients with heart failure is contraindicated (see section "Contraindications") due to increased risk of metoprolol side effects, such as severe bradycardia, caused by inhibition of its metabolism by fluoxetine.

MAO-A inhibitors. It is not recommended to use fluoxetine in combination with MAO-A inhibitors, including linezolid and methylene blue, due to the risk of developing serotonin syndrome, which includes diarrhea, tachycardia, sweating, tremor, confusion, or coma. If concomitant use of these medicinal products with fluoxetine cannot be avoided, treatment should be initiated at the lowest recommended dose and the patient's clinical status should be closely monitored.

Mequitazine. The risk of mequitazine side effects increases due to inhibition of its metabolism by fluoxetine.

Phenytoin. Changes in blood levels of both fluoxetine and phenytoin have been observed during combined use. In some cases, signs of toxicity have occurred. Doses of both drugs should be titrated carefully, and the patient's clinical status should be monitored.

Serotonergic medicinal products. Concomitant use with other serotonergic medicinal products (e.g., tramadol, triptans) may increase the risk of serotonin syndrome. When triptans are used, there is an additional increased risk of coronary vasoconstriction and hypertension.

Lithium and tryptophan. Fluoxetine should be used with caution with lithium or tryptophan, as cases of serotonin syndrome have been reported with concomitant use of serotonin reuptake inhibitors and these medicinal products. When fluoxetine is used with lithium, the patient's clinical status should be monitored more frequently.

Cytochrome CYP2D6 isoenzyme. Since the metabolism of fluoxetine (as well as tricyclic antidepressants and other selective serotonin reuptake inhibitors) involves the hepatic cytochrome P450 isoenzyme CYP2D6, concomitant use with medicinal products that are also metabolized by these enzymes may lead to interaction reactions. Therefore, treatment with medicinal products that are metabolized by this system and have a narrow therapeutic index (such as flecainide, encainide, carbamazepine, and tricyclic antidepressants) should be initiated at the lowest doses if the patient is concurrently receiving fluoxetine or has received it within the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already taking such a medicinal product, a reduction in the dose of the first medicinal product should be considered.

Tamoxifen. Pharmacokinetic interactions between CYP2D6 inhibitors and tamoxifen have been described in the literature, with a reported 65–75% reduction in one of the more active metabolites of tamoxifen, such as endoxifen. Several studies have reported reduced efficacy of tamoxifen when used concomitantly with certain serotonin reuptake inhibitors. Reduced efficacy of tamoxifen cannot be excluded; therefore, concomitant use of potent CYP2D6 inhibitors, including fluoxetine, should be avoided if possible (see section "Special precautions for use").

Fluoxetine may potentiate the effects of alprazolam and diazepam; therefore, these should be used with caution.

Concomitant use with fluoxetine has been associated with altered blood concentrations of clozapine, diazepam, alprazolam, imipramine, and desipramine, and in some cases, signs of toxic effects have been observed. When fluoxetine is used with these medicinal products, the conservative selection of dosage should be reviewed, and the patient's condition should be closely monitored.

Fluoxetine is highly bound to plasma proteins; therefore, when fluoxetine is co-administered with another medicinal product that is also highly protein-bound, changes in plasma concentrations of both medicinal products may occur.

Oral anticoagulants. Prolonged bleeding time has been observed when fluoxetine is used concomitantly with warfarin. Changes in anticoagulant effect (laboratory parameters and/or clinical symptoms) were inconsistent. As with initiating or discontinuing fluoxetine during warfarin therapy, careful monitoring of blood coagulation parameters is required. When prescribing other medicinal products after discontinuation of fluoxetine, the long elimination half-life of fluoxetine and its active metabolite norfluoxetine should be considered, and the possibility of drug interactions should be taken into account (see section "Special precautions for use").

Electroconvulsive therapy. Rare cases of prolonged seizures have been reported in patients taking fluoxetine during electroconvulsive therapy. Therefore, caution should be exercised in such patients.

QT interval prolongation. Pharmacokinetic and pharmacodynamic studies of fluoxetine with other medicinal products that prolong the QT interval have not been conducted. An additive effect of fluoxetine and such medicinal products cannot be excluded. Therefore, caution should be exercised when using fluoxetine concomitantly with medicinal products that prolong the QT interval, such as class IA and III antiarrhythmics, antipsychotic medicinal products (e.g., phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g., sparfloxacin, moxifloxacin, intravenous erythromycin, pentamidine), antimalarial drugs, particularly halofantrine, and certain antihistamines (astemizole, mizolastine).

Alcohol. During clinical studies, fluoxetine did not increase blood alcohol levels or enhance the effects of alcohol. However, concomitant use of serotonin reuptake inhibitors and alcohol is not recommended.

St. John's wort. When fluoxetine is used concomitantly with St. John's wort, the risk of serotonergic effects, such as serotonin syndrome, increases. Serotonin syndrome may occur with the use of serotonin reuptake inhibitors and herbal preparations containing St. John's wort.

Antidiabetic agents. Fluoxetine enhances the effects of antidiabetic agents.

Cyproheptadine. Isolated cases of reduced antidepressant activity of fluoxetine have been reported when used in combination with cyproheptadine.

Medicinal products causing hyponatremia. The use of fluoxetine in combination with other medicinal products that cause hyponatremia (e.g., diuretics, desmopressin, carbamazepine, oxcarbazepine) increases the risk of hyponatremia.

Medicinal products that lower the seizure threshold. The use of fluoxetine in combination with other medicinal products that may lower the seizure threshold (e.g., tricyclic antidepressants, other selective serotonin reuptake inhibitors, phenothiazines, butyrophenones, mefloquine, chloroquine, bupropion, tramadol) increases the risk of seizures.

Special precautions for use.

Suicide/suicidal thoughts or clinical worsening. Depression is associated with an increased risk of suicidal thoughts and suicide attempts. This risk persists until remission occurs. Improvement may not occur for several weeks or longer after initiation of treatment; patients should be closely monitored until improvement is observed. Clinical experience indicates that the risk of suicide may increase during the early stages of recovery.

Patients with major depressive disorders and other psychiatric disorders should be continuously monitored, as other psychiatric disorders may develop.

Particular attention should be paid to patients at high risk of developing suicidal ideation or attempts, especially at the beginning of treatment or when the dose is changed.

The medicinal product is contraindicated in patients with suicidal thoughts.

Use of antidepressant agents in adults with psychiatric disorders has been associated with an increased risk of suicidal behavior in patients under 25 years of age. Appropriate measures should be taken if clinical worsening, suicidal attempts, or behavioral changes occur.

Cardiovascular disorders. Cases of QT interval prolongation and ventricular arrhythmia have been reported (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose"). The medicinal product should be used with caution in patients with congenital QT prolongation or a history of QT prolongation, or in patients with other clinical conditions that may lead to arrhythmia (e.g., hypokalemia and hypomagnesemia, bradycardia, acute myocardial infarction, decompensated heart failure), or in cases of increased fluoxetine concentration (e.g., hepatic impairment). An ECG should be performed before initiating fluoxetine treatment. If symptoms of cardiac arrhythmia occur during fluoxetine therapy, fluoxetine should be discontinued and an ECG should be performed.

Serotonin syndrome or neuroleptic malignant syndrome. Rare cases of serotonin syndrome or neuroleptic malignant syndrome have been reported in patients receiving fluoxetine, particularly when used in combination with other serotonergic agents (including L-tryptophan) and/or neuroleptic drugs. Since these symptoms may be life-threatening, fluoxetine treatment should be discontinued and supportive and symptomatic therapy should be initiated if symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible vital function disturbances, or changes in mental status (including confusion, agitation progressing to delirium, and coma) occur.

Mania. Antidepressants should be used with caution in patients with mania or hypomania. Fluoxetine should be discontinued in patients experiencing a manic episode.

Bleeding. Subcutaneous bleeding, such as ecchymoses or purpura, has been reported during treatment with antidepressant medicinal products. Ecchymoses occur rarely with fluoxetine therapy. Other hemorrhagic manifestations (gynecological bleeding, gastrointestinal bleeding, and other skin or mucosal hemorrhages) have also been observed rarely. The product should be used with caution in patients who are concurrently taking oral anticoagulants or agents affecting platelet function (atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs), or other drugs that may increase the risk of bleeding, as well as in patients with a history of bleeding.

Selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) increase the risk of postpartum hemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions").

Seizures. There is a potential risk of seizures with the use of antidepressant medicinal products. Fluoxetine should be discontinued in patients who develop seizures or who are at increased risk of seizures. Fluoxetine should be avoided in patients with unstable seizure disorders/epilepsy.

Tamoxifen. The use of fluoxetine, a potent CYP2D6 inhibitor, may reduce the concentration of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, concomitant use of tamoxifen and fluoxetine should be avoided if possible.

Akathisia/psychomotor agitation. Fluoxetine use has been associated with the development of akathisia, which is subjectively characterized by a need to move, often with an inability to stand or sit still. This disorder is most commonly observed during the first weeks of treatment. Dose increases are not recommended in patients who develop these symptoms.

Diabetes mellitus. Changes in blood glucose levels have been observed in diabetic patients during fluoxetine treatment. Hypoglycemia occurred during treatment with fluoxetine, while hyperglycemia occurred after discontinuation of treatment. Dose adjustments of insulin and/or oral hypoglycemic agents may be necessary at the beginning and after discontinuation of fluoxetine therapy.

Hepatic/renal function. Fluoxetine is extensively metabolized in the liver and excreted by the kidneys. Lower doses as alternative daily doses are recommended for patients with hepatic impairment. After administration of 20 mg daily for 2 months, plasma levels of fluoxetine or norfluoxetine in patients with renal impairment (creatinine clearance < 10 ml/min) and in patients requiring hemodialysis were similar to those in patients with normal renal function. The medicinal product is contraindicated in severe hepatic and renal impairment.

Skin rashes and allergic reactions. Cases of skin rashes, anaphylactic reactions, and progressive systemic disorders involving the skin, lungs, and liver have been reported during fluoxetine use. Fluoxetine should be discontinued if skin rashes or other allergic reactions of undetermined etiology occur.

Weight loss. Patients receiving fluoxetine may experience weight loss.

Withdrawal symptoms. Withdrawal symptoms frequently occur in patients when treatment is abruptly discontinued (see section "Adverse reactions"). In clinical trials, adverse reactions upon discontinuation occurred in approximately 60% of patients, both in those receiving fluoxetine and those receiving placebo. The risk of developing withdrawal symptoms depends on several factors, including duration of treatment, dose, and rate of dose reduction. Dose tapering should be performed over 1 to 2 weeks according to patient needs.

Withdrawal symptoms include: dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and headache. Generally, withdrawal symptoms are mild to moderate in severity but may be severe in some cases. These symptoms usually begin within the first few days after discontinuation of fluoxetine and resolve spontaneously within the first 2 weeks, although in some cases they may persist for 2–3 months or longer. Therefore, it is recommended to gradually reduce the dose of fluoxetine over at least 1–2 weeks according to patient needs.

Mydriasis. Cases of mydriasis have been reported in patients taking fluoxetine. Therefore, caution should be exercised in patients with elevated intraocular pressure or at risk of acute angle-closure glaucoma. The product is contraindicated in patients with glaucoma.

Electroconvulsive therapy. Rare cases of prolonged seizures have been reported in patients receiving fluoxetine during electroconvulsive therapy. Therefore, caution should be exercised in such patients.

Hyponatremia. Hyponatremia may occur during fluoxetine treatment. This is mainly observed in elderly patients and in patients receiving diuretics, due to reduced circulating blood volume (CBV).

St. John's wort. Concomitant use of fluoxetine and St. John's wort increases the risk of serotonergic effects, such as serotonin syndrome, which may occur with the use of serotonin reuptake inhibitors (SSRIs) and herbal preparations containing St. John's wort.

Sexual dysfunction. SSRIs may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Persistent sexual dysfunction, with symptoms continuing despite discontinuation of SSRIs, has been reported.

The product contains sugar and lactose monohydrate. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Some epidemiological studies have reported an increased risk of cardiovascular malformations in infants associated with maternal use of fluoxetine during the first trimester of pregnancy. The mechanism of this phenomenon is unknown. Overall, study data indicate that the risk of cardiovascular malformations in infants whose mothers used fluoxetine during pregnancy is 2/100, compared with an expected frequency of 1/100 in the general population.

According to epidemiological data, use of serotonin reuptake inhibitors during pregnancy, particularly in late pregnancy, increases the risk of persistent pulmonary hypertension in newborns. This risk is approximately 5 cases per 1000 pregnancies, compared with a frequency of 1 to 2 cases per 1000 pregnancies in the general population.

Observational data indicate an increased (approximately twofold) risk of postpartum hemorrhage when SSRIs/SNRIs are used during the last month of pregnancy (see sections "Special precautions for use" and "Adverse reactions").

Fluoxetine is contraindicated during pregnancy.

Breastfeeding. Fluoxetine is contraindicated during breastfeeding.

Fluoxetine and its metabolite norfluoxetine are excreted in breast milk, and adverse reactions in breastfed infants have been reported. If fluoxetine treatment is considered necessary, breastfeeding should be discontinued.

Fertility. Animal studies have demonstrated that fluoxetine may affect sperm quality.

It has been reported that the effect of some serotonin reuptake inhibitors on sperm quality is reversible. There are no data on the effect on human fertility.

Ability to influence reaction speed when driving or operating machinery. During fluoxetine treatment, patients should refrain from driving or operating machinery.

Dosage and Administration

The drug is taken orally, regardless of meal times.

Major Depressive Episodes/Disorders. Fluoxetine therapy should be initiated at a dose of 20 mg once daily in the morning—this dose is sufficient to achieve an antidepressant effect. If clinically necessary, after 3–4 weeks from the start of therapy, the dose may be increased to 20 mg twice daily. Although dose escalation may intensify adverse effects, for some patients with inadequate response to the 20 mg dose, the dose may be gradually increased up to 60 mg per day. Dose increases should be individualized and performed cautiously. Therapy should be initiated with the lowest effective dose.

Patients with depressive disorders should be treated for a sufficient duration, at least 6 months, to ensure the absence of disease symptoms.

Obsessive-Compulsive Disorder. The usual recommended dose is 20 mg daily. Although increasing the dose may intensify adverse effects, for some patients with inadequate response to 20 mg within 2 weeks, the dose may be gradually increased up to 60 mg per day.

If no clinical effect is observed within 10 weeks of treatment, fluoxetine therapy should be reevaluated. If a positive therapeutic response has been achieved, fluoxetine therapy should be continued at an individually adjusted dose. Doses should be increased individually and cautiously, and therapy should be maintained at the lowest effective dose. The patient's need for continued treatment should be periodically reassessed.

Long-term pharmacotherapy (beyond 24 weeks) in patients with obsessive-compulsive disorder has not been studied.

Neurotic Bulimia. For adults and elderly patients, the dose is 20 mg daily. Long-term pharmacotherapy (beyond 3 months) in patients with bulimia has not been studied.

General Recommendations. The usual recommended dose of the drug is 20 mg daily, which may be increased if necessary. The maximum daily dose is 80 mg. Doses exceeding 80 mg daily have not been studied. If a single dose less than 20 mg is required, another formulation with appropriate dosage strength should be used.

Fluoxetine may be administered 1–2 times daily, regardless of meal times.

After discontinuation of the drug, the active substance continues to circulate in the body for another 2 weeks; this should be taken into account when prescribing other medications or discontinuing treatment.

Maintenance Therapy. As with other antidepressants, it may take 3–4 weeks to observe the full effect of fluoxetine.

Dosage should be reduced in patients with renal or hepatic impairment, elderly patients with concomitant diseases, and patients taking other medications.

Elderly Patients: Dose increases should be cautious. The usual daily dose generally does not exceed 40 mg.

The maximum daily dose is 60 mg.

A reduced dose or intermittent dosing (e.g., every other day) may be recommended for patients with hepatic disorders or those receiving concomitant therapy with drugs that may interact with fluoxetine.

Abrupt discontinuation of fluoxetine therapy should be avoided. To discontinue the drug, the dose should be gradually reduced over 1–2 weeks to prevent discontinuation syndrome. If symptoms of clinical worsening occur during dose reduction or after discontinuation, therapy should be resumed at the previously effective therapeutic dose. After some time, the physician may resume gradual dose reduction.

Children. Not recommended for children due to insufficient clinical experience with the drug in this age group.

Overdose.

Symptoms: nausea, vomiting, seizures, cardiovascular disturbances (including sinus rhythm disturbances and ventricular arrhythmias) or ECG changes indicating QT interval prolongation, cardiac events including rare cases of torsades de pointes, respiratory disturbances, central nervous system changes ranging from agitation to coma, hypomania.

Treatment: induced vomiting or gastric lavage, administration of activated charcoal and sorbents, symptomatic and supportive therapy. There is no specific antidote. Forced diuresis or dialysis are poorly effective in fluoxetine overdose.

Cardiorespiratory monitoring is recommended.

Adverse Reactions

The most commonly reported adverse reactions during fluoxetine treatment are headache, nausea, insomnia, fatigue, and diarrhea. The intensity and frequency of adverse reactions decrease with continued treatment and usually do not lead to discontinuation of therapy.

Summary of adverse reactions

Frequency of adverse reactions is categorized as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:
Rare – thrombocytopenia, neutropenia, leukopenia.

Immune system disorders:
Rare – hypersensitivity reactions, including angioedema, anaphylactic shock; anaphylactoid reactions, serum sickness.

Endocrine system disorders:
Rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders:
Common – decreased appetite, including anorexia; rare – hyponatremia.

Psychiatric disorders:
Very common – insomnia, including early morning awakening, difficulty falling asleep, nocturnal insomnia;
Common – agitation, nervousness, anxiety, tension, decreased libido, including loss of libido, sleep disturbances, including abnormal dreams, night terrors;
Uncommon – depersonalization, mood elevation, euphoric mood, thought disturbances, orgasmic disturbances, including anorgasmia, bruxism, suicidal ideation and behavior, including suicide attempts and suicide, suicidal depression, self-harm, autoaggressive thoughts and behavior (may be related to the underlying condition);
Rare – hypomania, mania, hallucinations, agitation, panic attacks, confusion, dysphemia, aggression.

Nervous system disorders:
Very common – headache;
Common – attention disturbances, dizziness, dysgeusia, lethargy, somnolence, including hypersomnia, sedation, tremor;
Uncommon – psychomotor hyperactivity, dyskinesia, ataxia, coordination disturbances, myoclonus, memory impairment;
Rare – seizures, akathisia, buccoglossal syndrome, serotonin syndrome.

Eye disorders:
Common – blurred vision;
Uncommon – mydriasis.

Ear and labyrinth disorders:
Uncommon – tinnitus.

Cardiac disorders:
Common – palpitations, QT interval prolongation, sensation of flushing, including hot flushes;
Uncommon – hypotension;
Rare – ventricular arrhythmia, including torsades de pointes, vasculitis, vasodilation.

Respiratory, thoracic and mediastinal disorders:
Common – yawning;
Uncommon – dyspnea, epistaxis;
Rare – pharyngitis, pulmonary disorders (inflammatory processes or various histopathological changes and/or fibrosis, including atelectasis, interstitial lung disease, pneumonia).

Gastrointestinal disorders:
Very common – diarrhea, nausea;
Common – vomiting, dyspepsia, dry mouth;
Uncommon – dysphagia, gastrointestinal hemorrhage, including gingival bleeding, hematemesis, bloody stools, rectal bleeding, hemorrhagic diarrhea, melena, and gastric ulcer hemorrhage;
Rare – esophageal pain.

Hepatobiliary disorders:
Rare – idiosyncratic hepatitis.

Skin and subcutaneous tissue disorders:
Common – rash, including erythema, exfoliative rash, miliaria, erythematous, follicular, generalized, macular, maculopapular, papular, morbilliform rash, pruritic rash, vesicular rash, periumbilical rash, pruritus, urticaria, hyperhidrosis;
Uncommon – alopecia, increased tendency to bruising, cold sweat;
Rare – angioedema, ecchymoses, photosensitivity reactions, purpura, erythema multiforme, which may progress to Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell's syndrome).

Musculoskeletal and connective tissue disorders:
Common – arthralgia;
Uncommon – muscle twitching;
Rare – myalgia.

Renal and urinary disorders:
Common – frequent urination, including pollakiuria;
Uncommon – dysuria;
Rare – urinary retention, urinary disorders.

Reproductive system and breast disorders:
Common – uterine dysfunction, gynecological bleeding, including cervical bleeding, uterine bleeding, genital bleeding, menometrorrhagia, polymenorrhea, postmenopausal bleeding, vaginal bleeding; erectile dysfunction, ejaculation disorders, including anejaculation, ejaculatory dysfunction, premature ejaculation, delayed ejaculation, retrograde ejaculation;
Uncommon – sexual dysfunction;
Rare – galactorrhea, hyperprolactinemia, priapism;
Frequency not known – postpartum hemorrhage*.

General disorders and administration site conditions:
Very common – weakness, including asthenia;
Common – sensation of trembling, chills;
Uncommon – fatigue, malaise, sensation of cold or heat;
Rare – mucosal bleeding.

Investigations:
Common – weight loss;
Uncommon – increased levels of transaminases and gamma-glutamyl transferase.

Description of selected adverse reactions

Suicidal thoughts. Cases of suicidal ideation and behavior have been reported during fluoxetine treatment or immediately after discontinuation (see section "Special precautions").

Bone fractures: Epidemiological studies, conducted primarily in patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving SSRIs and antidepressants. The mechanism underlying this risk is unknown.

Withdrawal symptoms. Discontinuation of fluoxetine treatment usually leads to withdrawal symptoms. The most common symptoms include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), asthenia, agitation or irritability, nausea and/or vomiting, tremor, and headache. In general, withdrawal symptoms are mild to moderate in severity, but may be severe and prolonged (see section "Special precautions"). Symptoms typically occur within the first few days after discontinuation of fluoxetine. Therefore, it is recommended to gradually reduce the dose of fluoxetine over at least 1–2 weeks according to individual patient needs (see sections "Dosage and administration" and "Special precautions").

* This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections "Special precautions" and "Use in pregnancy or breastfeeding").

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging. Tablets, 10 or 10×2 in blisters, in a carton.

Prescription status. Prescription only.

Manufacturer.

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Limited Liability Company "Research Plant "GNCLS".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and place of business.

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")

Ukraine, 61057, Kharkiv region, city of Kharkiv, Vorobiova Street, 8.

(Limited Liability Company "Research Plant "GNCLS")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(Limited Liability Company "FARMEKS GROUP")