Prodip

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRODEP (PRODEP)

Composition:

Active substance: fluoxetine;

One capsule contains fluoxetine hydrochloride equivalent to fluoxetine 20 mg;

Excipients: lactose monohydrate; corn starch; talc; magnesium stearate; colloidal anhydrous silicon dioxide; sodium starch glycolate (type A);

gelatin capsule contains: titanium dioxide (E171), indigo carmine (E133).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules No. 2 with blue body and blue cap, marked with “PRODEP” in white lettering around the body and black lettering around the cap, containing white powder.

Pharmacotherapeutic group.

Antidepressants. ATC code N06AB03.

Pharmacological properties.

Pharmacodynamics. Fluoxetine – the active component of the medicinal product Prodep – is an antidepressant. Chemically, it does not belong to either tricyclic or tetracyclic antidepressants. Fluoxetine has significant antidepressant activity, which is probably related to potent, specific inhibition of serotonin reuptake in synapses of neurons in the central nervous system. Unlike tricyclic antidepressants, fluoxetine is a weak antagonist of muscarinic, histaminergic, and adrenergic receptors; when used, adverse effects on the cardiovascular system, as well as other phenomena caused by anticholinergic action typical of tricyclic antidepressants, are not observed. There is no evidence of carcinogenic or mutagenic effects of the drug.

Pharmacokinetics.

Absorption: fluoxetine is well absorbed after oral administration. Food intake does not affect the bioavailability of the drug, although it may somewhat delay absorption.

Distribution: fluoxetine is highly bound to plasma proteins (about 95%) and has a large volume of distribution (20–40 l/kg). Equilibrium concentrations in plasma are reached after several weeks of drug administration. Equilibrium concentrations after prolonged use are similar to those observed during the 4th–5th week of treatment.

Metabolism: fluoxetine has a nonlinear pharmacokinetic profile with a first-pass effect through the liver. After a single 40 mg dose of fluoxetine, maximum plasma concentration (15–55 ng/ml) is observed within 6–8 hours. In the liver, it is metabolized by the polymorphic enzyme CYP2D6 into the active metabolite norfluoxetine and several other unidentified metabolites.

Elimination: the elimination half-life of fluoxetine ranges from 4 to 6 days, and that of its active metabolite ranges from 4 to 16 days. It is primarily excreted by the kidneys (60%). The drug is excreted into breast milk.

Elderly patients: the pharmacokinetics of fluoxetine in healthy elderly individuals is similar to that in younger adult volunteers.

Clinical characteristics.

Indications.

Major depressive episodes/disorders.

Obsessive-compulsive disorders.

Bulimia nervosa: as part of comprehensive psychotherapy to reduce binge 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 ideation, glaucoma, urinary bladder atony, benign prostatic hyperplasia.

Concomitant use with monoamine oxidase inhibitors (MAOIs) (selective and non-selective), including linezolid. There must be a minimum interval of 14 days between discontinuation of MAOI therapy and initiation of fluoxetine treatment. The interval between discontinuation of fluoxetine and initiation of MAOI therapy must be at least 5 weeks.

Concomitant use with metoprolol in patients with heart failure.

Interaction with other medicinal products and other forms of interaction.

The long elimination half-life of both fluoxetine and norfluoxetine should be taken into account when considering pharmacodynamic and pharmacokinetic drug interactions (e.g., when switching from fluoxetine to other antidepressants).

MAO inhibitors

The period between discontinuation of MAO inhibitors and initiation of Prodep therapy must be at least 14 days. After discontinuation of Prodep, at least 5 weeks must elapse before starting therapy with MAO inhibitors. Severe, sometimes fatal reactions (hyperthermia, rigidity, myoclonus, autonomic instability with rapid changes in vital signs, and mental status changes including agitation, delirium, and coma) have been reported in patients who received Prodep in combination with MAO inhibitors, as well as in those who discontinued Prodep and then 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 condition should be closely monitored.

Mirtazapine

The risk of mirtazapine 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 should be titrated carefully, and patients' clinical status should be monitored.

Serotonergic medicinal products. The risk of serotonin syndrome increases when fluoxetine is used concomitantly with other serotonergic agents (e.g., tramadol, triptans). When triptans are used, there is an additional increased risk of coronary vasoconstriction and hypertension.

Lithium and tryptophan. Fluoxetine should be used with caution together with lithium or tryptophan, as cases of serotonin syndrome have been reported when SSRIs are used concomitantly with these medicinal products. When fluoxetine is used with lithium, the patient's clinical condition should be monitored more frequently.

CYP2D6 isoenzyme. Since fluoxetine metabolism (as well as tricyclic antidepressants and other SSRIs) involves the hepatic cytochrome P450 isoenzyme CYP2D6, concomitant use with medicinal products that are also metabolized by these enzymes may lead to drug interactions. Therefore, treatment with drugs metabolized by this system and having 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. When fluoxetine is added to the treatment regimen of a patient already taking such a drug, a dose reduction of the first drug should be considered.

Tamoxifen

Pharmacokinetic interactions between CYP2D6 inhibitors and tamoxifen have been described in scientific 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 SSRIs. Reduced tamoxifen efficacy 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 drugs should be used with caution.

Concomitant use of fluoxetine has been associated with altered plasma 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 drugs, careful dose adjustment and monitoring of the patient's condition are required.

Fluoxetine is highly protein-bound in plasma; therefore, when fluoxetine is co-administered with another highly protein-bound drug, changes in plasma concentrations of both drugs 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 signs and symptoms) were inconsistent. As with warfarin therapy combined with other drugs, careful monitoring of coagulation parameters is required both at the start and after discontinuation of fluoxetine. When prescribing other drugs after fluoxetine discontinuation, 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 (ECT).

Rarely, prolonged seizure duration has been observed in patients taking fluoxetine during ECT. 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. Additive effects of fluoxetine and such drugs cannot be excluded. Therefore, caution is advised when fluoxetine is used concomitantly with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g., phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g., sparfloxacin, moxifloxacin, intravenous erythromycin, pentamidine), antimalarials, 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 SSRIs and alcohol is not recommended.

St. John’s wort (Hypericum perforatum).

Concomitant use of fluoxetine and St. John’s wort increases the risk of serotonergic effects, such as serotonin syndrome, which may occur when SSRIs are used with herbal products containing St. John’s wort.

Antidiabetic agents.

Fluoxetine enhances the effect of antidiabetic drugs.

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 seizure threshold.

The use of fluoxetine in combination with other medicinal products that may lower seizure threshold (e.g., tricyclic antidepressants, other SSRIs, 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 a certain remission occurs. Improvement may not occur for several weeks or longer, and patients should be closely monitored until improvement occurs. Clinical experience generally indicates that the risk of suicide may increase in the early stages of recovery.

Patients with major depressive disorders and other psychiatric conditions require continuous monitoring, as other psychiatric disorders may develop.

Close monitoring of patients, especially those at high risk of developing suicidal ideation or attempts, is essential, particularly at the beginning of treatment or when the dose is changed.

It is contraindicated to use in patients with suicidal thoughts.

A meta-analysis of placebo-controlled studies of antidepressant use in adult patients with psychiatric disorders shows an increased risk of suicidal behavior in patients under the age of 25 taking antidepressants compared to placebo.

If clinical worsening, suicide attempts, or behavioral changes occur, appropriate measures should be taken.

Cardiovascular disorders.

During the post-marketing period, cases of QT interval prolongation and ventricular arrhythmia have been reported. (See sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects", "Overdose").

Use with caution in patients with risk factors such as congenital QT prolongation, history of QT prolongation or other clinical conditions that may lead to arrhythmia (e.g., hypokalemia and hypomagnesemia, bradycardia, acute myocardial infarction or 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 treatment, fluoxetine should be discontinued and an ECG examination should be performed.

Serotonin syndrome or neuroleptic malignant syndrome.

Rare cases of serotonin syndrome or neuroleptic malignant syndrome have been reported in patients taking fluoxetine, particularly in combination with other serotonergic agents (including L-tryptophan) and/or neuroleptic drugs. These symptoms may be life-threatening; therefore, 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, 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.

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

Seizures.

There is a potential risk of seizures with the use of antidepressant drugs. Fluoxetine treatment should be discontinued if seizures occur or if there is an 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 lead to reduced concentrations 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, subjectively characterized by a need to move, often with an inability to stand or sit still. This is particularly observed during the first weeks of treatment. Patients who develop such symptoms should not have their dose increased.

Diabetes mellitus.

In diabetic patients, changes in blood glucose levels have been observed during fluoxetine treatment. Hypoglycemia occurred during treatment with fluoxetine, and hyperglycemia occurred after discontinuation of the drug. Adjustment of insulin and/or oral hypoglycemic agent doses may be required at the beginning and after the end of fluoxetine treatment.

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. Plasma levels of fluoxetine or norfluoxetine in patients with renal impairment (creatinine clearance < 10 mL/min) and in patients requiring hemodialysis taking 20 mg daily for 2 months are similar to those in patients with normal renal function.

It 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. If skin rashes or other allergic reactions of undetermined etiology occur, fluoxetine should be discontinued.

Weight loss.

Weight reduction may be observed in patients taking fluoxetine.

Withdrawal symptoms.

Withdrawal symptoms frequently occur if treatment is abruptly discontinued (see section "Undesirable effects"). In clinical trials, withdrawal reactions occurred in approximately 60% of patients, both in those taking fluoxetine and in those taking 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 or 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 of moderate or intermediate severity, but may be severe. They usually occur within the first days after discontinuation of fluoxetine. Symptoms usually 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.

Miosis.

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

Electroconvulsive therapy.

Rare cases of prolonged seizures have been observed in patients taking 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 when using serotonin reuptake inhibitors and herbal preparations containing St. John's wort.

Lactose.

The drug contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

In some epidemiological studies, an increased risk of cardiovascular defects associated with fluoxetine use during the first trimester of pregnancy has been reported. The mechanism of this phenomenon is unknown. Overall, data indicate that the risk of cardiovascular defects in infants whose mothers used fluoxetine during pregnancy is 2 per 100, compared to an expected frequency of 1 per 100 in the general population.

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

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 on sperm quality with some serotonin reuptake inhibitors is reversible. Data on the effect on human fertility are lacking.

Ability to influence reaction speed when driving or operating machinery.

During treatment with Prodep, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

Major Depressive Episodes/Disorders.

Treatment with Prodep 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 lead to a potential increase in adverse effects, for some patients who do not respond adequately to the 20 mg dose, the dose may be gradually increased up to 60 mg per day. Dose adjustments should be individualized and made 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 Disorders.

The usual recommended dose is 20 mg daily. Although increasing the dose may lead to a potential increase in adverse effects, for some patients who do not respond adequately to 20 mg within 2 weeks, the dose may be gradually increased up to 60 mg per day.

If no clinical response is observed within 10 weeks of treatment, fluoxetine therapy should be re-evaluated. If a positive therapeutic effect is achieved, fluoxetine treatment should be continued. 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 reviewed periodically. Some clinicians recommend concomitant psychotherapy for patients who show adequate clinical response to pharmacotherapy.

Long-term pharmacotherapy (beyond 24 weeks) in patients with obsessive-compulsive disorders 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 20 mg daily may be decreased or increased. The maximum daily dose is 80 mg. Doses exceeding 80 mg daily have not been studied.

Fluoxetine may be administered 1–2 times daily, with or after food.

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 when discontinuing treatment.

Maintenance Therapy. It may take 3–4 weeks to observe the full effect of fluoxetine.

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

Elderly Patients: dosage should be increased cautiously. The usual daily dose should 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 when concomitant therapy includes drugs that may potentially interact with Prodep.

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

Children.

Not recommended for use in children due to insufficient clinical experience with the use of Prodep in pediatric patients.

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: induction of 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 cases of Prodep overdose.

Cardiac and respiratory 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

The undesirable reactions listed below are classified as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000).

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: inadequate secretion of antidiuretic hormone.

Metabolic and Nutritional 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, elevated mood, euphoric mood, thought disturbances, orgasmic disturbances, including anorgasmia, bruxism, suicidal thoughts and behavior, including suicide attempts and suicide, suicidal depression, deliberate self-harm, self-aggressive ideation and behavior (these symptoms may be consequences of the underlying disease).

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 hot flushes, including hot flashes.

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 bleeding gums, hematemesis, bloody stools, rectal bleeding, hemorrhagic diarrhea, melena, and ulcer-related gastric bleeding.

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, scarlatiniform 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 polyuria.

Uncommon: dysuria.

Rare: urinary retention, urinary disorders.

Reproductive System and Breast Disorders

Common: gynecological bleeding, including cervical bleeding, uterine dysfunction, uterine bleeding, genital bleeding, menometrorrhagia, polymenorrhea, postmenopausal bleeding, vaginal bleeding; erectile dysfunction, ejaculation disorders, including ejaculatory insufficiency, dysfunctional ejaculation, premature ejaculation, delayed ejaculation, retrograde ejaculation.

Uncommon: sexual dysfunction.

Rare: galactorrhea, hyperprolactinemia, priapism.

General Disorders and Administration Site Conditions

Very common: weakness, including asthenia.

Common: sensation of trembling, chills.

Uncommon: fatigue, malaise, feeling cold or hot.

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 thoughts and behavior have been reported during fluoxetine use or immediately after discontinuation of fluoxetine (see section "Special Precautions").

Bone Fractures: Epidemiological studies, conducted primarily in patients aged 50 years and older, show an increased risk of bone fractures in patients receiving serotonin reuptake inhibitors and antidepressants. The mechanism underlying this risk is unknown.

Withdrawal Syndrome: Discontinuation of fluoxetine predominantly leads to withdrawal symptoms.

The most common withdrawal symptoms are: dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and headache. Withdrawal symptoms are generally of moderate or mild severity but may be severe and prolonged (see section "Special Precautions"). Symptoms usually occur within the first few days after stopping fluoxetine. Therefore, it is recommended to gradually reduce the dose of fluoxetine over at least 1–2 weeks according to the patient's needs (see sections "Dosage and Administration" and "Special Precautions").

Shelf Life: 4 years.

Storage Conditions

Store at temperatures not exceeding 25 °C in the original packaging. Keep out of reach of children.

Packaging

10 capsules per strip, 6 strips per cardboard box.

Prescription Category: Prescription only.

Manufacturer:

1. Sun Pharmaceutical Industries Ltd.
2. Sun Pharma Laboratories Limited

Manufacturer's Address and Place of Business:

1. Survey No. 214, Plot No. 20, Gavt. Ind. Area, Phase II, Piparia, Silvassa – 396230, U.T. Dadra and Nagar Haveli, India.
2. 6-9, EPZ, Katra, Bari Brahmana, Jammu - 181133, Jammu and Kashmir, India.