INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT REXETIN® (REXETIN®)

Composition:

Active ingredient: paroxetine;

1 tablet contains 20 mg of paroxetine (as 22.76 mg of paroxetine hydrochloride hemihydrate);

Excipients:

Tablet core composition: magnesium stearate, sodium starch glycolate (type A), hypromellose, calcium hydrogen phosphate dihydrate;

Coating composition: polysorbate 80, macrogol 400, macrogol 6000, titanium dioxide (E 171), hypromellose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex, film-coated tablets with a score line on one side and engraving on the other. The tablet can be divided into equal doses.

Pharmacotherapeutic group. Antidepressants. Selective serotonin reuptake inhibitors. ATC code N06AB05.

Pharmacological properties

Pharmacodynamics

Paroxetine is a potent selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) reuptake. Its antidepressant effect and efficacy in the treatment of obsessive-compulsive and panic disorders are due to specific inhibition of neuronal 5-HT reuptake in the brain. Chemically, paroxetine differs from tricyclic, tetracyclic, and other known antidepressants.

The drug has low affinity for muscarinic cholinergic receptors. Unlike tricyclic antidepressants, it has minimal affinity for alpha1-, alpha2-, and beta-adrenergic receptors, dopaminergic (D2), 5-HT1-like, 5-HT2-, and histaminergic (H1) receptors; it does not affect psychomotor function and does not potentiate the depressant effect of ethanol.

Rexetin® does not affect cardiovascular system activity and does not cause clinically significant changes in arterial pressure, heart rate, or ECG parameters.

Rexetin®, unlike antidepressants that inhibit norepinephrine reuptake, has significantly less influence on the antihypertensive effect of guanethidine.

Pharmacokinetics

After oral administration, paroxetine is rapidly absorbed and undergoes hepatic transformation.

The main metabolites of the active substance of Rexetin (paroxetine) are polar and conjugated products of oxidation and methylation, which are rapidly eliminated from the body.

Approximately 64% of the administered dose of paroxetine is excreted in urine, with less than 2% excreted unchanged. Approximately 36% of the administered dose of paroxetine is excreted in feces as metabolites.

Paroxetine metabolites are eliminated in two phases: first, via first-pass metabolism in the liver, and then via systemic elimination of paroxetine.

The elimination half-life averages approximately 1 day.

Steady-state plasma concentration is achieved within 7–14 days after initiation of treatment, and during prolonged therapy, the pharmacokinetics of the drug remain virtually unchanged.

No correlation has been established between plasma paroxetine concentration and clinical effect (efficacy and adverse reactions).

Due to the breakdown of the drug in the liver, the amount of paroxetine circulating in the blood is lower than the amount absorbed in the gastrointestinal tract. With increasing single doses or repeated dosing, partial saturation of the first-pass hepatic metabolic pathway occurs, resulting in decreased plasma clearance. This leads to a disproportionate increase in plasma paroxetine concentration and changes in pharmacokinetic parameters, resulting in nonlinear kinetics. However, this nonlinearity is generally minor and is observed only in patients who achieve low plasma concentrations of the drug when low doses are administered.

Paroxetine is widely distributed in body tissues. Calculated pharmacokinetic parameters indicate that only 1% of the administered dose remains in plasma.

At therapeutic concentrations, approximately 95% of paroxetine is protein-bound in plasma.

Increased plasma paroxetine concentrations are observed in elderly patients and in patients with renal or hepatic impairment, but these remain within the range of fluctuations observed in healthy adult volunteers.

Clinical characteristics.

Indications.

Adults

Major depressive disorder. Treatment of major depressive disorder.

Obsessive-compulsive disorder. Treatment of symptoms and prevention of relapses in obsessive-compulsive disorder.

Panic disorder. Treatment of symptoms and prevention of relapses in panic disorder with or without agoraphobia.

Social phobias/social anxiety disorders. Treatment of social phobias/social anxiety states.

Generalized anxiety disorder. Treatment of symptoms and prevention of relapses in generalized anxiety disorder.

Post-traumatic stress disorder. Treatment of post-traumatic stress disorder.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

The medicinal product is contraindicated in combination with monoamine oxidase inhibitors (MAOIs).

In exceptional cases, linezolid (an antibiotic that is a reversible non-selective MAO inhibitor) may be used in combination with paroxetine if equipment for careful monitoring of symptoms of serotonin syndrome and blood pressure monitoring is available (see section "Interaction with other medicinal products and other forms of interaction").

Paroxetine may be administered:

no earlier than 2 weeks after discontinuation of treatment with irreversible MAOIs;
no less than 24 hours after discontinuation of treatment with reversible MAOIs (e.g., moclobemide, linezolid, methylene blue chloride [methylthioninium chloride]).

Treatment with any MAOI may be initiated no earlier than 1 week after discontinuation of paroxetine.

Rexetine® is contraindicated in combination with thioridazine or pimozide (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Serotonergic medicinal products

The use of paroxetine, as with other selective serotonin reuptake inhibitors (SSRIs), in combination with serotonergic medicinal products may increase the frequency of effects associated with 5-HT and may cause serotonin syndrome, a potentially life-threatening condition (see sections "Special precautions for use" and "Side effects").

Paroxetine should be used with caution together with serotonergic medicinal products such as L-tryptophan, triptans, linezolid, methylene blue chloride (methylthioninium chloride), other SSRIs, lithium, opioids (e.g., tramadol, fentanyl, meperidine, buprenorphine [or its combination with naloxone]), and St. John's wort (Hypericum perforatum), with mandatory close monitoring of the patient's clinical status. Concomitant use of paroxetine and MAOIs is contraindicated due to the risk of serotonin syndrome (see section "Contraindications").

It is recommended to use fentanyl with caution during general anesthesia or for treatment of chronic pain.

Pimozide

Data from a study on the concomitant use of a single low dose of pimozide (2 mg) and 60 mg of paroxetine showed an increase in pimozide levels. This may be explained by the known CYP2D6-inhibiting properties of paroxetine; due to the narrow therapeutic index of pimozide and its ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see section "Contraindications").

Medicinal products that prolong the QT interval

The risk of QTc prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) increases when other medicinal products that prolong the QTc interval (e.g., certain antipsychotics) are used concomitantly (see section "Special precautions for use"). Concomitant use of thioridazine and paroxetine is contraindicated, as, like other drugs that inhibit the hepatic enzyme CYP450 2D6, paroxetine may cause increased plasma levels of thioridazine, potentially leading to QT interval prolongation (see section "Contraindications").

Enzymes involved in drug metabolism

The metabolism and pharmacokinetic parameters of paroxetine may be altered by induction or inhibition of enzymes involved in drug metabolism.

When paroxetine is used concomitantly with medicinal products that inhibit enzymes, the lowest effective doses should be prescribed.

No adjustment of the initial dose of paroxetine is required when used concomitantly with enzyme-inducing medicinal products (carbamazepine, rifampicin, phenobarbital, phenytoin) or fosamprenavir/ritonavir. The dose of paroxetine should be adjusted (both after initiation and discontinuation of enzyme inhibitor therapy) according to clinical response (tolerability and efficacy).

Muscle relaxants

SSRIs may reduce plasma cholinesterase activity, leading to prolonged neuromuscular blocking effects of mivacurium and succinylcholine.

Fosamprenavir/ritonavir

Concomitant use of fosamprenavir/ritonavir 700/100 mg twice daily with paroxetine 20 mg once daily for 10 days significantly reduced plasma levels of paroxetine by approximately 55%. Dose adjustment may be necessary depending on clinical response. Plasma levels of fosamprenavir/ritonavir when used concomitantly with paroxetine were similar to control values, indicating that paroxetine had no significant effect on the metabolism of fosamprenavir/ritonavir. There are no data on the consequences of prolonged concomitant use of paroxetine and fosamprenavir/ritonavir beyond 10 days.

Procyclidine

Daily administration of paroxetine significantly increases plasma concentrations of procyclidine. If anticholinergic effects occur, the dose of procyclidine should be reduced.

Anticonvulsants

Carbamazepine, phenytoin, sodium valproate: concomitant use does not affect the pharmacokinetic/pharmacodynamic profile of paroxetine in patients with epilepsy.

Inhibition of CYP2D6 isoenzyme by paroxetine

Paroxetine, like other antidepressants including other SSRIs, inhibits the activity of the CYP2D6 enzyme of the cytochrome P450 system. Inhibition of CYP2D6 may lead to increased plasma concentrations of concomitantly administered medicinal products metabolized by this enzyme. These include certain tricyclic antidepressants (e.g., clomipramine, amitriptyline, nortriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g., perphenazine and thioridazine, see section "Contraindications" and subsection "Medicinal products that prolong the QT interval" above), risperidone, atomoxetine, certain class 1c antiarrhythmics (e.g., propafenone and flecainide), and metoprolol. Concomitant use of paroxetine with metoprolol is not recommended when treating heart failure due to the narrow therapeutic index of metoprolol for this indication.

Tamoxifen has an important active metabolite, endoxifen, produced by CYP2D6, which is a key component of tamoxifen's efficacy. Irreversible inhibition of CYP2D6 by paroxetine leads to reduced plasma concentrations of endoxifen (see section "Special precautions for use"). Literature reports describe a pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, resulting in a 65–75% reduction in plasma levels of one of tamoxifen's active metabolites—endoxifen. Reduced efficacy of tamoxifen has been observed with concomitant use of certain SSRIs. Since a reduction in tamoxifen's effect cannot be excluded, concomitant use with potent CYP2D6 inhibitors (including paroxetine) should be avoided when possible (see section "Special precautions for use").

CYP3A4

In vivo studies showed that concomitant use of Rexetine and terfenadine—a substrate of the CYP3A4 enzyme—at steady-state plasma concentrations was not accompanied by any influence of paroxetine on the pharmacokinetics of terfenadine. Similarly, an in vivo study on interaction revealed no effect of the drug on the pharmacokinetics of alprazolam, and vice versa. Concomitant administration of Rexetine with terfenadine, alprazolam, and other drugs that are substrates of CYP3A4 is not expected to be hazardous.

Clinical studies have shown that the following factors do not affect or have minimal effect on the absorption or pharmacokinetics of paroxetine (i.e., dose adjustment is not required): food, antacids, digoxin, propranolol, alcohol.

Paroxetine does not potentiate the cognitive and motor impairments caused by alcohol; however, consumption of alcoholic beverages during treatment with the drug is not recommended.

Alcohol

As with other psychotropic medicinal products, patients should be advised not to consume alcoholic beverages during treatment with paroxetine.

Oral anticoagulants

Concomitant use of oral anticoagulants and paroxetine may result in a pharmacodynamic interaction, potentially increasing anticoagulant activity and the risk of bleeding; therefore, paroxetine should be prescribed with caution to patients receiving oral anticoagulants (see section "Special precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, and other antiplatelet agents

Concomitant use of NSAIDs/acetylsalicylic acid and paroxetine may result in a pharmacodynamic interaction, potentially increasing the risk of bleeding (see section "Special precautions for use"). Therefore, paroxetine should be prescribed with caution to patients receiving medications that affect platelet function or who have an increased risk of bleeding.

SSRIs should be used with caution together with oral anticoagulants, drugs affecting platelet function, or drugs increasing the risk of bleeding (e.g., atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, NSAIDs, COX-2 inhibitors), as well as in patients with a history of coagulopathy or conditions that may lead to bleeding.

Pravastatin

The interaction observed between paroxetine and pravastatin in studies suggests that concomitant use of paroxetine and pravastatin may lead to increased blood glucose levels. Diabetic patients receiving both paroxetine and pravastatin may require adjustment of the dosage of oral hypoglycemic agents and/or insulin (see section "Special precautions for use").

Special precautions for use.

Treatment with paroxetine is recommended to be initiated cautiously two weeks after discontinuation of irreversible monoamine oxidase inhibitors (MAOIs) or 24 hours after discontinuation of reversible MAOIs. The dosage of paroxetine should be gradually increased until optimal response is achieved (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Children and adolescents

Paroxetine is not recommended for use in children and adolescents (under 18 years of age).

Antidepressant treatment is associated with an increased risk of suicidal behavior and thoughts in children and adolescents with major depressive disorder and other psychiatric disorders. Clinical trial data show that suicidal behavior (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, irritability, and anger) occur more frequently in children and adolescents treated with antidepressants compared to placebo. If, based on clinical need, a decision to treat is made, careful monitoring for emergence of suicidal symptoms is required. In addition, long-term safety data regarding growth, sexual maturation, cognitive and behavioral development in children and adolescents are lacking.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). The risk persists until significant remission occurs. Since improvement may not occur during the first few weeks of treatment or even later, careful monitoring should continue until the patient's condition improves. Based on clinical experience, the risk of suicide may increase during the initial phase of recovery.

Other psychiatric disorders for which paroxetine is prescribed may also be associated with an increased risk of suicide-related events. Moreover, these conditions may coexist with major depressive disorder. Therefore, the same precautions applied during treatment of major depressive disorder should be followed when treating other psychiatric disorders.

It is known that the risk of suicidal thoughts or suicide attempts is higher in patients with a history of suicide-related events or with marked suicidal ideation prior to treatment initiation; therefore, such patients require close monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressant treatment compared to placebo in patients under 25 years of age.

Close monitoring of patients, especially at the beginning of treatment and during dosage adjustments, is essential, particularly for patients at increased risk. Patients (and caregivers) should be warned to monitor for any signs of clinical worsening, suicidal behavior or thoughts, or unusual changes in behavior and to seek immediate medical attention if such symptoms occur.

Young adults, particularly those with major depressive disorders, may have an increased risk of developing suicidal behavior during treatment with paroxetine. Data from analyses of placebo-controlled clinical trials involving adult patients with psychiatric disorders showed that young adults (approximately 18–24 years) had a higher risk of developing suicidal behavior compared to placebo-treated patients, although this difference was not statistically significant. No such increase in risk was observed in older patient groups (25–64 years and over 65 years). In patients with major depressive disorders (of any age) treated with paroxetine, a statistically significant increase in the frequency of suicidal behavior was observed compared to placebo. However, most of these suicide attempts occurred in young adult patients aged 18–30 years. These data on treatment of major depressive disorders suggest that the higher risk of these complications observed in younger patients with psychiatric disorders may extend to patients up to 24 years of age.

In patients with depressive disorders, symptoms of depression may worsen and/or suicidal thoughts and behavior (suicidality) may emerge, regardless of whether they are taking antidepressants. This risk persists until significant remission occurs. Clinical experience with antidepressant treatment consistently shows that the risk of suicide may increase during the early stages of recovery.

Other psychiatric disorders for which paroxetine is prescribed may also be associated with an increased risk of suicidal behavior, and such disorders may also coexist with major depressive disorders. Additionally, patients with a history of suicidal behavior or intent, younger patients, and patients with persistent suicidal ideation prior to treatment initiation are at increased risk for suicide attempts and suicidal thoughts. All patients should be closely monitored for clinical worsening (including emergence of new symptoms) and suicidality during treatment, particularly at the beginning of treatment or during dosage adjustments (both increases and decreases).

Patients (and caregivers) should be advised to monitor continuously for any worsening of the patient's condition (including emergence of new symptoms) and/or appearance of suicidal ideation/behavior or thoughts of self-harm and to seek immediate medical help if such symptoms occur. It should be understood that the emergence of certain symptoms, such as agitation or akathisia or mania, may be related either to the underlying disease or to the course of treatment (see section "Adverse reactions" – "Akathisia/psychomotor restlessness", "Mania").

Consideration should be given to modifying the therapeutic regimen, including discontinuation of the drug, in patients experiencing clinical worsening (including emergence of new symptoms) and/or suicidal ideation/behavior, especially if these symptoms are severe, sudden in onset, or not part of the patient's prior symptom complex.

Akathisia/psychomotor restlessness

Paroxetine use has been associated with the development of akathisia – a condition characterized by inner restlessness and psychomotor agitation, such as inability to sit or stand still, combined with subjective discomfort. The likelihood of occurrence is highest during the first weeks of treatment. Increasing the dose may be harmful in patients who develop these symptoms.

Serotonin syndrome/malignant neuroleptic syndrome

In isolated cases, when paroxetine is taken, especially in combination with other serotonergic agents and/or neuroleptics or opioids (e.g., buprenorphine (as monotherapy or in combination with naloxone), meperidine, tramadol), serotonin syndrome or symptoms resembling malignant neuroleptic syndrome may develop (see sections "Interaction with other medicinal products and other forms of interaction", "Overdose", and "Adverse reactions"). Since these syndromes may lead to potentially life-threatening conditions, paroxetine treatment should be discontinued if symptoms such as hyperthermia, gastrointestinal symptoms, neuromuscular disturbances, muscle rigidity, myoclonus, autonomic instability with possible rapid changes in vital signs, mental status changes (including confusion, irritability, extreme agitation progressing to delirium and coma) occur, and supportive symptomatic therapy should be initiated.

Paroxetine should not be used in combination with serotonin precursors (e.g., L-tryptophan, 5-hydroxytryptophan) due to the risk of serotonin syndrome (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic agents is clinically justified, careful monitoring of the patient, especially at the beginning of treatment and during dose escalation, is required. Discontinuation of serotonergic agents usually leads to rapid improvement.

Mania

A major depressive episode may be the initial manifestation of bipolar disorder. It has been established (although not confirmed by data from controlled clinical trials) that treatment of such episodes with antidepressants alone may increase the likelihood of precipitating mixed/mania episodes in patients at risk for bipolar disorder. Before initiating antidepressant treatment, patients should be carefully evaluated for any risk of developing bipolar disorder. This evaluation should include a detailed patient history, including history of suicide attempts, bipolar disorders, and depression in family members. It should be noted that paroxetine is not approved for the treatment of depression in bipolar disorder. As with other antidepressants, paroxetine should be used with caution in patients with a history of mania. Paroxetine should be discontinued if a patient develops a manic episode.

Bone fractures

Epidemiological data on the risk of bone fractures indicate an association between the use of certain antidepressants, including SSRIs, and fractures. The risk occurs during treatment and is greatest during the initial stages of therapy. The possibility of bone fractures should be considered when treating patients with paroxetine.

Renal/hepatic impairment

Caution is recommended when administering the drug to patients with severe renal or hepatic impairment (see section "Dosage and administration").

Diabetes

Glycemic control may change in patients with diabetes during treatment with SSRIs. Dose adjustments of insulin and/or oral hypoglycemic agents may be required. In addition, data suggest a possible increase in glucose concentration when paroxetine is used concomitantly with pravastatin.

Epilepsy

As with other antidepressants, paroxetine should be used with caution in patients with epilepsy.

Seizures

Seizures occur in less than 0.1% of patients taking paroxetine. If seizures occur, paroxetine treatment should be discontinued.

Electroconvulsive therapy (ECT)

Experience with concomitant use of paroxetine and ECT is limited.

Glaucoma

Paroxetine, like other SSRIs, may cause mydriasis; therefore, the drug should be used with caution in patients with current narrow-angle glaucoma or a history of glaucoma.

Cardiovascular disorders

Standard precautions are required when treating patients with cardiovascular disorders.

QT interval prolongation

Cases of QT interval prolongation have been reported in the post-marketing period.

Paroxetine should be used with caution in patients with a history (including family history) of QT interval prolongation, in patients receiving concomitant antiarrhythmic drugs or other medicinal products that may cause QT prolongation, and in patients with conditions such as heart failure, ischemic heart disease, heart block, ventricular arrhythmias, bradycardia, hypokalemia, or hypomagnesemia (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Hyponatremia

Hyponatremia rarely occurs during paroxetine treatment, primarily in elderly patients. The drug should be prescribed with caution to patients at risk of hyponatremia, for example, due to concomitant medications or presence of cirrhosis. Hyponatremia usually resolves after discontinuation of paroxetine.

Bleeding

After paroxetine treatment, hemorrhages in the skin (ecchymoses and purpura) and mucous membranes (including gastrointestinal and gynecological bleeding) have been observed. SSRIs/SNRIs may increase the risk of postpartum hemorrhage (see sections "Use during pregnancy and lactation", "Adverse reactions"). Patients should use SSRIs with caution when used concomitantly with oral anticoagulants, drugs affecting platelet function, or other drugs that may increase the risk of bleeding (e.g., atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants [TCAs], acetylsalicylic acid, NSAIDs, COX-2 inhibitors), and in patients with a history of frequent coagulopathies or conditions that may lead to bleeding (see section "Adverse reactions"). Elderly patients may have an increased risk of non-menstrual bleeding.

Interaction with tamoxifen

Paroxetine, a potent CYP2D6 inhibitor, may reduce endoxifen concentration, one of the most important active metabolites of tamoxifen. Therefore, concomitant use of paroxetine should be avoided during tamoxifen treatment (see section "Interaction with other medicinal products and other forms of interaction"). Some studies have shown that the efficacy of tamoxifen, measured by the risk of breast cancer recurrence or death, may be reduced when used concomitantly with paroxetine, since paroxetine is an irreversible inhibitor of CYP2D6 (see section "Interaction with other medicinal products and other forms of interaction"). This risk increases with longer duration of concomitant use. An alternative antidepressant with minimal or no CYP2D6 inhibition should be prescribed to patients undergoing breast cancer treatment with tamoxifen.

Withdrawal symptoms observed upon discontinuation of paroxetine

Withdrawal symptoms upon discontinuation of treatment are common, especially if the drug is stopped abruptly (see section "Adverse reactions"). Clinical trial data show that in adults, adverse reactions upon discontinuation of paroxetine occurred in 30% of patients compared to 20% in the placebo group. The emergence of withdrawal symptoms does not indicate addiction or dependence due to drug abuse.

The risk of developing withdrawal symptoms may depend on several factors, including duration of therapy, dose, and rate of dose reduction.

Reported symptoms include dizziness, sensory disturbances (including paresthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, increased sweating, headache, diarrhea, palpitations, emotional instability, irritability, and visual disturbances. Generally, these symptoms are mild or moderate in severity, although in some patients they may be very intense. They usually occur within the first few days after discontinuation of the drug, although isolated cases have been reported in patients who accidentally missed a single dose. These symptoms usually resolve spontaneously within 2 weeks, although in some patients the process may be prolonged (2–3 months or longer). Therefore, it is recommended that the dose of paroxetine be gradually reduced over several weeks or months, depending on individual patient characteristics, when discontinuing treatment (see "Discontinuation of paroxetine" in section "Dosage and administration").

In children and adolescents, adverse effects upon discontinuation of paroxetine occurred in 32% of patients compared to 24% in the placebo group. The following adverse effects occurred after discontinuation of the drug (with an incidence of at least 2% and at least twice as high as in the placebo group): emotional lability (including suicidal ideation, suicide attempts, mood swings, and tearfulness), restlessness, dizziness, nausea, and abdominal pain (see section "Adverse reactions").

Sexual dysfunction

SSRIs/SNRIs may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Cases of persistent sexual dysfunction, where symptoms persist despite discontinuation of SSRIs/SNRIs, have been reported.

Excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Fertility

Clinical studies have shown that SSRIs, including paroxetine, may affect sperm quality. These effects are considered reversible after discontinuation of treatment. Changes in sperm quality may affect fertility in some men.

Pregnancy

Animal studies have not shown teratogenic or embryotoxic effects.

Epidemiological data on pregnancy outcomes in women treated with antidepressants during the first trimester of pregnancy have reported an increased risk of congenital malformations, primarily cardiovascular (e.g., atrial or ventricular septal defects), associated with paroxetine use. According to these data, the risk of giving birth to an infant with a cardiovascular defect in a woman treated with paroxetine during pregnancy is approximately 1 in 50, compared to an expected risk of approximately 1 in 100 in the general population.

The physician should consider the possibility of alternative treatments for pregnant women or women planning pregnancy and prescribe paroxetine only when the expected benefit to the mother outweighs the potential risk to the fetus. If a decision is made to discontinue treatment in a pregnant woman, additional information should be sought from the relevant sections of the Instructions for Medical Use, which describe doses and symptoms occurring upon discontinuation of paroxetine (see sections "Special precautions for use" and "Dosage and administration").

There are reports of preterm delivery in women treated with paroxetine or other SSRIs, although causal relationships with drug intake have not been established.

Newborns should be examined if the mother continued taking paroxetine during the third trimester of pregnancy, as there are reports of complications in newborns when mothers were treated with paroxetine or other SSRIs during this period, although a causal relationship with drug intake has not been established. Reported effects include respiratory distress, cyanosis, apnea, seizures, temperature fluctuations, feeding difficulties, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, shakiness, excitability, lethargy, persistent crying, and somnolence. In some reports, symptoms were described as neonatal withdrawal syndrome. In most cases, symptoms occurred immediately or shortly (<24 hours) after delivery.

Epidemiological data indicate that the use of SSRIs (including paroxetine) in pregnant women, particularly in late pregnancy, is associated with an increased risk of persistent pulmonary hypertension in the newborn. In women who used serotonin reuptake inhibitors during late pregnancy, this risk was increased 4–5 times compared to the general patient population (1–2 cases per 1000 pregnancies in the general patient group).

Observational data indicate an increased risk (less than 2-fold) of postpartum hemorrhage after use of SSRIs/SNRIs within one month before delivery (see sections "Special precautions for use", "Adverse reactions").

Lactation period

A small amount of paroxetine is excreted in breast milk. No signs of drug effects on newborns have been observed; however, paroxetine should not be used during breastfeeding except when the expected benefit to the mother outweighs the potential risk to the infant.

Ability to influence reaction rate while driving or operating machinery.

Clinical experience with paroxetine suggests that this drug does not affect cognitive or psychomotor functions. However, as with other psychoactive drugs, patients should be warned about the potential impact on their ability to drive or operate machinery.

Concomitant use of paroxetine and alcohol is not recommended, although paroxetine does not enhance the negative effects of alcohol on psychomotor functions.

Dosage and Administration

General Recommendations

The medication is intended for oral administration and should be taken once daily in the morning with food. The tablet should be swallowed whole, without chewing. The tablet has a score line, allowing a 10 mg dose to be obtained if necessary.

As with all other antidepressants, the dose should be carefully individualized during the first 2–3 weeks of treatment, and then adjusted according to clinical response.

The treatment course should be sufficiently long to ensure symptom remission. This period may last several months when treating major depressive disorder, and even longer for obsessive-compulsive disorder and panic disorder. As with other medications used to treat psychiatric disorders, abrupt discontinuation of the drug should be avoided.

Major Depressive Disorder. The recommended dose is 20 mg once daily. Some patients may require dose increases. This should be done gradually, increasing the dose by 10 mg (up to a maximum of 50 mg daily), depending on clinical response.

Obsessive-Compulsive Disorder. The recommended dose is 40 mg once daily. Treatment should be initiated at a dose of 20 mg daily, with weekly increments of 10 mg. In some patients, improvement may only be observed with the maximum dose of 60 mg daily.

Panic Disorder. The recommended dose is 40 mg once daily. Treatment should be initiated at a dose of 10 mg daily, with weekly increments of 10 mg, depending on clinical effect. In some patients, improvement may only be observed with the maximum dose of 60 mg daily.

To minimize the risk of symptom exacerbation, which is commonly observed at the beginning of treatment for panic disorder, it is recommended to initiate therapy with a low dose.

Social Anxiety Disorder/Social Phobia. The recommended dose is 20 mg once daily. For some patients, the dose may be gradually increased by 10 mg daily, depending on clinical response, up to a maximum of 50 mg daily. The interval between dose increases should be at least 1 week.

Generalized Anxiety Disorder. The recommended dose is 20 mg once daily. For some patients in whom 20 mg is insufficiently effective, the dose may be gradually increased by 10 mg daily, depending on clinical response, up to a maximum of 50 mg daily.

Post-Traumatic Stress Disorder. The recommended dose is 20 mg once daily. For some patients in whom 20 mg is insufficiently effective, the dose may be gradually increased by 10 mg daily, depending on clinical response, up to a maximum of 50 mg daily.

Discontinuation of Paroxetine

As with other medications used to treat psychiatric disorders, abrupt discontinuation should be avoided. In clinical trials, a gradual dose reduction regimen was used, involving weekly reductions of 10 mg daily. After reaching a dose of 20 mg daily, patients continued on this dose for an additional week before complete discontinuation. If pronounced symptoms occur during dose reduction or after discontinuation, consideration should be given to resuming treatment at the previous dose. Subsequently, dose reduction may be continued, but more slowly.

Elderly Patients. Treatment should be initiated at the standard starting dose for adults, which may then be gradually increased up to 40 mg daily. Increased plasma concentrations of paroxetine have been observed in elderly patients; however, the concentration range in this patient group overlaps with that observed in younger patients.

Children. Rextine® is not indicated for use in children.

Based on results from controlled clinical trials, efficacy has not been demonstrated, and there is no confirmed evidence supporting the use of paroxetine for treating depression in children. Safety and efficacy of the drug in children under 7 years of age have not been established.

Renal and Hepatic Impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min) or hepatic impairment, increased plasma concentrations of paroxetine are observed. Therefore, the dose should be reduced to the lower end of the recommended dosing range in such patients.

Children.

The medication is not indicated for use in children.

Overdose

Symptoms and Signs

In cases of paroxetine overdose, in addition to the adverse reactions listed in the section "Adverse Reactions," symptoms such as elevated body temperature, changes in blood pressure, involuntary muscle contractions, agitation, and tachycardia have been observed.

These effects generally resolved without serious consequences in most patients, even after ingestion of doses up to 2000 mg. Occasionally, coma or changes in ECG parameters have been reported. Fatal outcomes are very rare and have mostly occurred when Rextine® was taken concomitantly with other psychotropic agents and sometimes with alcohol.

Treatment

There is no specific antidote.

Management of overdose should include general supportive measures similar to those used for overdose with other antidepressants. Within several hours after ingestion, administration of 20–30 g of activated charcoal may be considered to reduce absorption, if feasible. Supportive care with frequent monitoring of vital signs and close observation of the patient's condition is indicated. Treatment should be tailored according to the patient's clinical status.

Adverse Reactions

The intensity and frequency of some of the adverse reactions listed below associated with the use of the drug may decrease during continued treatment and usually do not require discontinuation of therapy. Adverse reactions are listed by organ systems and frequency, defined as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000), including isolated cases, frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: abnormal bleeding, mainly of the skin and subcutaneous tissues (including ecchymoses and gynecological bleeding), leukopenia.

Rare: thrombocytopenia.

Immune system disorders

Rare: severe and potentially life-threatening allergic reactions (including anaphylactoid reactions and angioedema).

Endocrine system disorders

Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Common: increased cholesterol concentrations, decreased appetite.

Uncommon: impaired glycaemic control observed in patients with diabetes mellitus (see section "Special precautions for use").

Rare: hyponatraemia.

Hyponatraemia has been reported mainly in elderly patients; it is sometimes associated with SIADH.

Psychiatric disorders

Common: somnolence, insomnia, agitation, abnormal dreams (including nightmares).

Uncommon: confusion, hallucinations.

Rare: manic reactions, restlessness, depersonalization, panic attacks, akathisia (see section "Special precautions for use").

Frequency not known: suicidal ideation, suicidal behaviour, aggression*, bruxism.

*Cases of aggression have been reported during the post-marketing period.

Cases of suicidal ideation and suicidal behaviour have been reported during paroxetine therapy or shortly after discontinuation of treatment (see section "Special precautions for use").

These symptoms may also be related to the underlying disease.

Nervous system disorders

Common: dizziness, tremor, headache, difficulty concentrating.

Uncommon: extrapyramidal disorders.

Rare: serotonin syndrome (possible symptoms: agitation, confusion, sweating, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia, and tremor).

Extrapyramidal disorders, including orofacial dystonia, have been reported in patients with movement disorders or in those taking neuroleptics.

Eye disorders

Common: blurred vision.

Uncommon: mydriasis (see section "Special precautions for use").

Rare: acute glaucoma.

Ear and labyrinth disorders

Frequency not known: tinnitus.

Cardiac disorders

Uncommon: sinus tachycardia.

Rare: bradycardia.

Vascular disorders

Uncommon: transient increases or decreases in blood pressure, postural hypotension.

Transient increases or decreases in blood pressure have been reported after paroxetine treatment, usually in patients with pre-existing hypertension or anxiety.

Respiratory, thoracic and mediastinal disorders

Common: yawning.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, diarrhoea, vomiting, dry mouth.

Rare: gastrointestinal haemorrhage.

Frequency not known: microscopic colitis.

Hepatobiliary disorders

Rare: elevated liver enzymes.

Very rare: hepatic disorders (such as hepatitis, sometimes with jaundice and/or hepatic failure).

There have been reports of increased liver enzyme levels. Additionally, very rare post-marketing cases of hepatic adverse reactions (such as hepatitis, sometimes associated with jaundice and/or hepatic failure) have been reported. Discontinuation of paroxetine should be considered if elevated liver enzymes persist.

Skin and subcutaneous tissue disorders

Common: increased sweating.

Uncommon: skin rash, pruritus.

Rare: severe skin adverse reactions (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), urticaria, photosensitivity reactions.

Renal and urinary disorders

Uncommon: urinary retention, urinary incontinence.

Reproductive system and breast disorders

Very common: sexual dysfunction.

Rare: hyperprolactinaemia/galactorrhoea, menstrual disorders (including menorrhagia, metrorrhagia, amenorrhoea, delayed and irregular menstruation).

Very rare: priapism.

Frequency not known: postpartum haemorrhage. This effect has been reported for the therapeutic class of SSRIs/SNRIs (see sections "Special precautions for use", "Use during pregnancy and breastfeeding").

Musculoskeletal and connective tissue disorders

Rare: arthralgia, myalgia.

Epidemiological studies, conducted primarily in patients aged 50 years and older, suggest an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

General disorders and administration site conditions

Common: asthenia, weight gain.

Rare: peripheral oedema.

Withdrawal symptoms upon discontinuation of the medicinal product

Common: dizziness, sensory disturbances, sleep disturbances, anxiety, headache.

Uncommon: agitation, nausea, tremor, confusion, sweating, emotional lability, visual disturbances, palpitations, diarrhoea, irritability.

As with other drugs used to treat psychiatric disorders, discontinuation of paroxetine (especially abrupt discontinuation) may lead to the emergence of symptoms such as dizziness, sensory disturbances (including paraesthesia, electric shock-like sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, restlessness, visual disturbances. In most patients, these symptoms are mild or moderate in severity and resolve without treatment; however, in some patients, they may be severe and/or prolonged. There is no specific risk group for the occurrence of these symptoms; therefore, if discontinuation of paroxetine therapy is necessary, the dose should be gradually reduced (see sections "Special precautions for use" and "Dosage and administration").

Adverse effects observed in clinical trials in children

Data have been obtained on the following adverse reactions: increased suicidal behaviour (including suicide attempts and suicidal thoughts), self-harm, and increased hostility. Suicidal thoughts and suicide attempts were observed primarily in clinical trials treating adolescents with major depressive disorder. Increased hostility was observed mainly in children with obsessive-compulsive disorders, particularly in children under 12 years of age. Additional adverse reactions: decreased appetite, tremor, increased sweating, hyperkinesia, agitation, emotional lability (including crying and mood swings), bleeding, mainly of the skin and mucous membranes.

Upon dose reduction or discontinuation of the drug, the following symptoms were observed: emotional lability (including crying, mood swings, self-harm, suicidal thoughts and suicide attempts), restlessness, dizziness, nausea, and abdominal pain (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep the medication out of reach of children.

Packaging.

10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Gedeon Richter".

Manufacturer's address and location of business activity.

H-1103 Budapest, Demrédi street 19-21, Hungary.