Semprevil®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEMPRAVYL® (SEMPRAVYL®)

Composition:

Active substance: paroxetine;

One film-coated tablet contains 20 mg of paroxetine hydrochloride hemihydrate, calculated as paroxetine;

Excipients: calcium hydrogen phosphate dihydrate, sodium starch glycolate, magnesium stearate, coating for film coating "Opadry13B58802 white"*.

* "Opadry13B58802 white": hypromellose, titanium dioxide (E 171), polyethylene glycol, polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, white or almost white film-coated tablets, with a break line on one side and smooth on the other side.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) reuptake, and its antidepressant effect and efficacy in the treatment of obsessive-compulsive disorder, social anxiety disorders/social phobias, generalized anxiety disorders, post-traumatic stress disorders, and panic disorders are believed to result from specific inhibition of 5-HT reuptake by brain neurons.

Chemically, paroxetine differs from tricyclic, tetracyclic, and other known antidepressants.

Paroxetine has low affinity for muscarinic cholinergic receptors and exhibits weak anticholinergic properties.

In contrast to tricyclic antidepressants, it has negligible affinity for alpha1-, alpha2-, and beta-adrenergic receptors, dopaminergic (D2) receptors, 5-HT1-like, 5-HT2, and histamine (H1) receptors. Paroxetine is known not to produce central nervous system depressant or hypotensive effects, does not affect psychomotor function, and does not potentiate the depressant effect of ethanol.

Like other selective serotonin reuptake inhibitors, paroxetine induces symptoms of excessive 5-HT receptor stimulation in animals previously administered monoamine oxidase inhibitors (MAOIs) or tryptophan.

Behavioral and electroencephalographic (EEG) studies show that paroxetine has only weak activating properties at doses usually exceeding those required for inhibition of 5-HT reuptake. The activating properties are not "amphetamine-like" in nature.

In healthy volunteers, paroxetine does not affect cardiovascular system activity and does not cause clinically significant changes in blood pressure, heart rate, or other electrocardiographic (ECG) parameters.

Unlike antidepressants that inhibit norepinephrine reuptake, paroxetine has markedly reduced ability to interfere with the antihypertensive effects of guanethidine.

In the treatment of depressive disorders, paroxetine demonstrates efficacy comparable to that of standard antidepressants.

There is also some evidence that paroxetine may have therapeutic value in patients who do not respond clinically to standard therapy.

Morning administration of paroxetine does not affect either the quality or duration of sleep. Moreover, patients are likely to experience improved sleep as they respond to paroxetine therapy.

Pharmacokinetics.

Absorption.

After oral administration, paroxetine is rapidly absorbed and undergoes hepatic transformation. Due to hepatic breakdown, the amount of paroxetine circulating in the blood is less than the amount absorbed from the gastrointestinal tract. With increasing single doses or repeated administration, partial saturation of the first-pass hepatic metabolic pathway occurs, resulting in decreased plasma clearance. This leads to a disproportionate increase in plasma paroxetine concentrations and changes in pharmacokinetic parameters, exhibiting nonlinear kinetics. However, this nonlinearity is generally minor and observed primarily in patients who achieve low plasma concentrations of the drug when administered low doses.

Steady-state plasma concentrations are reached within 7–14 days after initiation of treatment, and pharmacokinetics remain virtually unchanged during prolonged therapy.

Distribution.

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

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

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

Metabolism.

The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are rapidly eliminated from the body. Due to their relatively low pharmacological activity, they are unlikely to contribute to the therapeutic effect of paroxetine.

Metabolism does not interfere with the selective action of paroxetine on 5-HT reuptake by neurons.

Elimination.

Approximately 64% of the administered dose of paroxetine is excreted in urine, with less than 2% excreted unchanged. About 36% of the dose is excreted in feces, likely via bile, with unchanged paroxetine accounting for less than 1% of the dose. Thus, paroxetine is almost entirely eliminated through metabolism.

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

The mean elimination half-life is approximately 1 day.

Special patient populations.

Elderly patients and patients with renal or hepatic impairment.

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

Clinical characteristics.

Indications.

For the treatment of:

• major depressive disorder;
• obsessive-compulsive disorder;
• panic disorder with or without agoraphobia;
• social anxiety disorders / social phobias;
• generalized anxiety disorder;
• post-traumatic stress disorder.

Contraindications.

• Hypersensitivity to paroxetine or to any other component of the medicinal product.
• Combination of paroxetine with monoamine oxidase inhibitors (MAOIs). In exceptional cases, linezolid (an antibiotic which is a reversible non-selective MAO inhibitor) may be administered in combination with paroxetine provided that measures are in place for careful monitoring of symptoms of serotonin syndrome and blood pressure (see section "Interaction with other medicinal products and other forms of interaction").

Paroxetine treatment may be initiated:

• two weeks after discontinuation of irreversible MAOIs, or
• at least 24 hours after discontinuation of reversible MAOIs, such as moclobemide, linezolid, methylene blue (methylthioninium chloride).

The interval between discontinuation of paroxetine and initiation of therapy with any MAOI should be at least one week.

• Paroxetine 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.

As with other selective serotonin reuptake inhibitors (SSRIs), concomitant use with serotonergic medicinal products may lead to a 5-HT-related effect (serotonin syndrome — see section "Special precautions for use"). Paroxetine should be used with caution and under close clinical monitoring when administered concomitantly with serotonergic medicinal products such as L-tryptophan, triptans, tramadol, linezolid, methylene blue (methylthioninium chloride), SSRIs, lithium, pethidine, buprenorphine, and St. John's wort (Hypericum perforatum). Caution is also advised with fentanyl, which is used during general anesthesia or for treatment of chronic pain. Concomitant use of paroxetine and MAOIs is contraindicated due to the risk of serotonin syndrome (see section "Contraindications").

Pimozide.

An increase in pimozide levels (on average by 2.5-fold) has been demonstrated during studies of concomitant administration of a single low dose of pimozide (2 mg) and paroxetine (60 mg). This was attributed to the known inhibitory properties of paroxetine on CYP2D6. 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) may be increased when paroxetine is used concomitantly with other medicinal products that prolong the QTc interval (e.g., certain antipsychotics) (see section "Special precautions for use"). Concomitant use of thioridazine and paroxetine is contraindicated, as paroxetine, like other drugs that inhibit the hepatic enzyme CYP450 2D6, may increase 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 drugs that inhibit these enzymes, paroxetine should be prescribed at the lowest effective dose.

When used concomitantly with enzyme-inducing drugs (carbamazepine, rifampicin, phenobarbital, phenytoin), there is no need to change the initial dose of paroxetine. The dose of paroxetine should be adjusted (after starting or stopping the enzyme inducer) according to clinical response (tolerability and efficacy).

Neuromuscular blocking agents.

SSRIs may reduce plasma cholinesterase activity, leading to prolonged neuromuscular blockade with mivacurium and succinylcholine.

Fosamprenavir/ritonavir.

Concomitant administration of fosamprenavir/ritonavir (700/100 mg twice daily) with paroxetine (20 mg daily) in healthy volunteers for 10 days significantly (approximately by 55%) reduced plasma levels of paroxetine. Plasma levels of fosamprenavir/ritonavir during concomitant administration of paroxetine were similar to control values from other studies, indicating that paroxetine had no significant effect on the metabolism of fosamprenavir/ritonavir. Data on the effect of prolonged (more than 10 days) concomitant use of paroxetine and fosamprenavir/ritonavir are lacking.

Procyclidine.

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

Anticonvulsants: carbamazepine, phenytoin, sodium valproate.

No effect on pharmacokinetics/pharmacodynamics of the drug has been observed in epileptic patients when these agents are used concomitantly.

Ability of paroxetine to inhibit the CYP2D6 enzyme.

Paroxetine, like other serotonin reuptake inhibitor antidepressants, inhibits the activity of the CYP2D6 enzyme of the cytochrome P450 system. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered drugs metabolized by this enzyme. Such drugs include certain tricyclic antidepressants (e.g., clomipramine, nortriptyline, desipramine), phenothiazine antipsychotics (e.g., perphenazine and thioridazine, see information above and in section "Contraindications"), risperidone, atomoxetine, certain class 1c antiarrhythmics (e.g., propafenone and flecainide), and metoprolol. Concomitant use of paroxetine with metoprolol is not recommended in heart failure due to the narrow therapeutic index of metoprolol for this indication.

Scientific publications have reported a pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65–75% reduction in plasma levels of one of the most active metabolites of tamoxifen, endoxifen. Some studies have demonstrated reduced efficacy of tamoxifen when certain SSRI antidepressants are used concomitantly. Since a reduction in tamoxifen efficacy cannot be excluded, concomitant use with potent CYP2D6 inhibitors (including paroxetine) should be avoided if possible (see section "Special precautions for use").

Alcohol.

As with other psychotropic agents, patients should be advised to avoid alcohol consumption during paroxetine treatment.

Oral anticoagulants.

A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. Concomitant use of paroxetine and oral anticoagulants may lead to increased anticoagulant activity and risk of bleeding. Therefore, paroxetine should be prescribed with caution in patients receiving oral anticoagulants (see section "Special precautions for use").

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

Pharmacodynamic interaction may occur when NSAIDs/acetylsalicylic acid are used concomitantly with paroxetine, increasing the risk of bleeding. Paroxetine should be used with caution when administered together with agents affecting platelet function or increasing the risk of bleeding (see section "Special precautions for use").

Caution is recommended when SSRIs are used concomitantly with oral anticoagulants, agents affecting platelet function, or agents increasing the risk of bleeding (e.g., atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, NSAIDs, cyclooxygenase-2 [COX-2] inhibitors) in patients with blood disorders or conditions that may lead to bleeding.

Pravastatin.

Observed interactions between paroxetine and pravastatin in studies suggest 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 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 therapy with an irreversible monoamine oxidase inhibitor (MAOI), or 24 hours after discontinuation of a reversible MAOI. The dose of paroxetine should be increased gradually until optimal response is achieved (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Children

Paroxetine should not be used for the treatment of children and adolescents (under 18 years of age). Behaviour related to suicide (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were observed more frequently in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If, based on clinical need, treatment is initiated, patients should be closely monitored for the emergence of suicidal symptoms.

Additionally, there are no long-term safety data in children and adolescents regarding growth, sexual maturation, cognitive and behavioural development.

Suicide / suicidal thoughts or worsening of condition.

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicidality). This 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 available clinical experience, the risk of suicide increases during the early stages of recovery.

Other psychiatric disorders for which paroxetine is prescribed may also be associated with an increased risk of suicide. Moreover, these conditions may accompany major depressive disorder. Therefore, the same precautionary measures should be taken during treatment of major depressive disorder as for other psychiatric disorders.

Since the risk of suicidal thoughts or suicide attempts is higher in patients with a history of suicidality or with pronounced suicidal ideation prior to treatment initiation, such patients should be under close supervision during therapy. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour in patients under 25 years of age treated with antidepressants compared to placebo (see section "Pharmacological properties").

Close monitoring of patients, especially those at increased risk, is necessary at the beginning of paroxetine treatment or when changing its dosage. Patients (and caregivers) should be warned to monitor for any signs of clinical worsening, suicidal behaviour/thoughts, or unusual changes in behaviour. If such symptoms occur, immediate medical advice should be sought.

Akathisia / psychomotor agitation.

Use of paroxetine has been associated with the development of akathisia — a condition characterised by a feeling of inner restlessness and psychomotor agitation, such as inability to sit or stand still, combined with subjective discomfort. The likelihood of developing this condition is greatest during the first weeks of treatment. Increasing the dose may be harmful in patients experiencing such symptoms.

Serotonin syndrome / neuroleptic malignant syndrome.

In isolated cases, treatment with paroxetine may be associated with the development of serotonin syndrome or symptoms characteristic of neuroleptic malignant syndrome, particularly when used concomitantly with other serotonergic and/or neuroleptic agents. Since these syndromes may lead to life-threatening conditions, paroxetine treatment should be discontinued if such events occur (characterised by a combination of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations in vital signs, altered mental status including confusion, agitation, extreme agitation progressing to delirium and coma), and supportive symptomatic therapy should be initiated. Paroxetine should not be used in combination with serotonergic precursors (such as L-tryptophan, 5-hydroxytryptophan) due to the risk of developing serotonin syndrome (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Mania.

As with other antidepressants, paroxetine should be used cautiously in patients with a history of mania. Paroxetine treatment should be discontinued if a manic phase develops.

Renal/hepatic impairment.

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

Diabetes mellitus.

In patients with diabetes mellitus, treatment with serotonin reuptake inhibitors may alter glycaemic control; therefore, the dose of insulin and/or oral hypoglycaemic agents should be adjusted. Clinical studies indicate that increased blood glucose levels may occur during concomitant treatment with paroxetine and pravastatin (see section "Interaction with other medicinal products and other forms of interaction").

Epilepsy.

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

Seizures.

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

Electroconvulsive therapy (ECT).

Experience with concomitant use of paroxetine and ECT is limited.

Glaucoma.

Paroxetine, like other serotonin reuptake inhibitors, may cause mydriasis and should therefore be used cautiously in patients with known closed-angle glaucoma or a history of glaucoma.

Cardiac disorders.

Standard precautions should be taken when treating patients with concomitant cardiac diseases.

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 family history of QT prolongation, concomitant use of antiarrhythmic drugs or other agents that may potentially prolong the QT interval, presence of heart failure, ischemic heart disease, heart block or ventricular arrhythmia, bradycardia, hypokalaemia or hypomagnesaemia (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Hyponatraemia.

Cases of hyponatraemia have occasionally been reported, mostly in elderly patients. The drug should be prescribed with caution to patients at risk of developing hyponatraemia, for example due to concomitant medication use or presence of cirrhosis. Hyponatraemia usually resolves after discontinuation of paroxetine.

Bleeding.

Skin haemorrhages such as ecchymoses and purpura have been observed after treatment with SSRIs/SNRIs. Other bleeding manifestations have been reported, including gastrointestinal and gynaecological bleeding. Elderly patients may have an increased risk of non-menstrual bleeding.

SSRIs/SNRIs increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or lactation" and "Adverse reactions").

Therefore, paroxetine should be used with caution in patients receiving concomitant oral anticoagulants, drugs affecting platelet function, or other drugs that increase 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 coagulopathies or disorders that may lead to bleeding (see section "Adverse reactions").

Interaction with tamoxifen.

Paroxetine, a potent CYP2D6 inhibitor, may reduce the concentration of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, the use of paroxetine should be avoided during tamoxifen therapy (see section "Interaction with other medicinal products and other forms of interaction").

Bone fractures.

Epidemiological studies on the risk of bone fractures associated with the use of certain antidepressants, including selective serotonin reuptake inhibitors, have shown an associative link with fractures. The risk occurs during treatment and is greatest in the early stages of therapy. The possibility of bone fractures should be considered when treating patients with paroxetine.

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 indicate that discontinuation-related adverse reactions occurred in 30% of adult patients treated with paroxetine compared to 20% of patients receiving placebo. 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 speed of dose reduction.

Reported symptoms include dizziness, sensory disturbances (including paraesthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, excessive sweating, headache, diarrhoea, 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 paroxetine dosage be gradually reduced over several weeks or months, depending on individual patient characteristics, when discontinuing treatment (see section "Dosage and administration").

Sexual dysfunction.

SSRIs may cause symptoms of sexual dysfunction (see section "Adverse reactions"). In some cases, these symptoms persist after discontinuation of SSRIs.

Sodium.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Some epidemiological studies suggest an increased risk of congenital malformations, particularly cardiovascular malformations (e.g., atrial or ventricular septal defects), associated with paroxetine use during the first trimester of pregnancy. The mechanism is unknown. Data indicate that the risk of giving birth to a child with a cardiovascular defect after paroxetine use during pregnancy is less than 2/100, compared to an expected frequency of approximately 1/100 in the general population.

Paroxetine should be used during pregnancy only if clearly indicated. The prescribing physician should consider alternative treatment options for pregnant women or women planning pregnancy. Abrupt discontinuation of the drug during pregnancy should be avoided (see sections "Special precautions for use" and "Dosage and administration").

Data indicate an increased risk of postpartum haemorrhage (less than two-fold) in women who used SSRIs/SNRIs within one month before delivery (see sections "Special precautions for use" and "Adverse reactions").

Newborns should be examined if the mother continued taking paroxetine during late pregnancy, particularly in the third trimester.

Symptoms that may occur in newborns after maternal use of paroxetine in late pregnancy include: respiratory distress, cyanosis, apnoea, seizures, temperature fluctuations, feeding difficulties, vomiting, hypoglycaemia, hypertension, hypotension, hyperreflexia, tremor, shivering, irritability, lethargy, persistent crying, somnolence, and sleep disturbances. These symptoms may be due to serotonergic effects or withdrawal symptoms. In some reports, symptoms were described as neonatal withdrawal syndrome. In most cases, they occur immediately or shortly (<24 hours) after delivery.

Epidemiological data suggest that use of SSRIs during pregnancy, particularly in late pregnancy, is associated with an increased risk of persistent pulmonary hypertension in the newborn. The observed risk is approximately 5 cases per 1,000 pregnancies. In the general population, persistent pulmonary hypertension of the newborn occurs in 1 to 2 cases per 1,000 pregnancies.

Animal studies have shown reproductive toxicity but did not indicate a direct harmful effect on pregnancy, embryonic/foetal development, delivery, or postnatal development.

Lactation period.

A small amount of paroxetine is excreted in breast milk. Published study data show that paroxetine concentrations in the serum of breastfed infants were below the limit of detection (<2 ng/mL) or very low (<4 ng/mL), and no signs of drug effects were observed in these infants. Since adverse effects are not expected, breastfeeding may be considered.

Fertility.

Preclinical and in vitro studies indicate that paroxetine may affect sperm quality. However, reports on the effect of certain SSRIs (including paroxetine) on sperm quality in men taking these drugs suggest that the effect is reversible. No effect on human fertility has been observed to date.

Ability to affect reaction speed when driving or operating machinery.

Clinical experience indicates that this medicinal product does not affect cognitive functions or psychomotor reactions. However, as with other psychoactive drugs, patients should be warned of the possible impairment of ability to drive or operate machinery during treatment.

Paroxetine does not potentiate the impairment of mental and motor reactions caused by alcohol; however, concomitant use of paroxetine and alcohol is not recommended.

Method of Administration and Dosage.

Major Depressive Disorder.

The recommended dose is 20 mg once daily. Overall improvement in patients usually begins within one week, but may become evident only in the second week of treatment.

As with all other antidepressants, the dose of paroxetine should be carefully individualized and adjusted accordingly during the first 3–4 weeks of therapy, and thereafter based on clinical necessity.

If the clinical response to 20 mg is inadequate, the dose may be gradually increased (in 10 mg increments) up to the maximum dose of 50 mg daily, according to the patient's response.

Patients with depressive disorder should continue treatment for a prolonged period (at least 6 months) to ensure symptom remission.

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 until the recommended dose is reached. If the clinical response after several weeks at the recommended dose is inadequate, some patients may require gradual dose escalation up to the maximum of 60 mg daily.

The treatment duration for patients with obsessive-compulsive disorder should be sufficient to ensure symptom remission. This period may last several months or even longer (see section "Pharmacodynamics").

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 response, until the recommended dose is achieved. If the clinical response after several weeks at the recommended dose is inadequate, some patients may require gradual dose escalation up to the maximum of 60 mg daily.

The treatment duration for patients with panic disorder should be sufficient to ensure symptom remission. This period may last several months or even longer (see section "Pharmacodynamics").

Social Anxiety Disorder / Social Phobia.

The recommended dose is 20 mg once daily. If the clinical response after several weeks at the recommended dose is inadequate, some patients may require gradual dose escalation by 10 mg increments up to the maximum of 50 mg/day. Long-term use should be regularly evaluated (see section "Pharmacodynamics").

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 effect, up to 50 mg daily. Long-term use should be regularly evaluated (see section "Pharmacodynamics").

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 50 mg daily. Long-term use should be regularly evaluated (see section "Pharmacodynamics").

Withdrawal symptoms observed after discontinuation of paroxetine.

Abrupt discontinuation should be avoided (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). In clinical trials, a tapering regimen was used, involving a reduction of the daily dose by 10 mg weekly. If pronounced symptoms occur during dose reduction or after discontinuation, consideration should be given to resuming treatment at the previous dose.

Subsequently, gradual dose reduction may be continued.

Special Patient Groups.

Elderly Patients.

Elevated plasma concentrations of paroxetine are observed in elderly patients, although the concentration range partially overlaps with that observed in younger patients. Treatment should be initiated at the standard adult starting dose. Some patients may require dose escalation, but the maximum dose should not exceed 40 mg daily.

Renal/Hepatic Impairment.

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

Method of Administration.

Paroxetine is recommended to be taken once daily in the morning with food.

The tablet should be swallowed whole without chewing.

Children.

Paroxetine should not be used for the treatment of children (under 18 years of age), as controlled clinical trials have demonstrated an association between paroxetine use and increased risk of suicidal behavior and hostility. Furthermore, efficacy was not adequately demonstrated in these studies. The safety and efficacy of paroxetine in children under 7 years of age have not been studied.

Overdose.

Symptoms.

In cases of paroxetine overdose, in addition to the symptoms listed in the section "Adverse Reactions", elevated body temperature and involuntary muscle contractions have been observed.

These effects resolve without serious consequences in most patients, even after ingestion of 2000 mg. Occasionally, coma or ECG changes have been observed; fatalities are very rare and have mostly occurred when paroxetine was taken concomitantly with other psychotropic agents or alcohol.

Treatment.

There is no specific antidote.

Management of overdose should include general supportive and symptomatic measures, as with overdose of other antidepressants. Administration of 20–30 g of activated charcoal may be beneficial within several hours of ingestion to reduce paroxetine absorption. Supportive therapy with monitoring of vital functions and close observation of the patient in a hospital setting is indicated. Treatment should be tailored according to the patient's clinical condition.

Adverse Reactions.

Some of the adverse reactions listed below may decrease in intensity and frequency with continued treatment and usually do not require discontinuation of therapy.

Adverse reactions are listed by system organ class and frequency. Frequency is defined as: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1 000); very rare (<1/10 000); not known (cannot be estimated from available data).

Blood and lymphatic system disorders.

Uncommon: increased bleeding tendency, predominantly of the skin and mucous membranes (including ecchymoses and gynecological bleeding), leukopenia.

Very rare: thrombocytopenia.

Immune system disorders.

Very rare: severe and potentially fatal allergic reactions (including anaphylactoid reactions and angioedema).

Endocrine disorders.

Very rare: syndrome caused by inadequate secretion of antidiuretic hormone.

Metabolism and nutrition disorders.

Common: increased cholesterol levels, decreased appetite.

Uncommon: altered glycaemic control has been reported in patients with diabetes mellitus (see section "Special precautions and warnings for use");

Rare: hyponatraemia, mainly observed in elderly patients and sometimes associated with syndrome caused by inadequate secretion of antidiuretic hormone.

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 and warnings for use").

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

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

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

These symptoms may also be related to the underlying disease.

Nervous system disorders.

Common: dizziness, tremor, headache, difficulty concentrating.

Uncommon: extrapyramidal disorders.

Rare: seizures, restless legs syndrome.

Very rare: serotonin syndrome (may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia, and tremor).

Extrapyramidal disorders, including orofacial dystonia, are observed in patients with movement disorders or in patients treated with neuroleptics.

Eye disorders.

Common: blurred vision.

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

Very rare: acute glaucoma.

Ear and labyrinth disorders.

Frequency not known: tinnitus.

Cardiac disorders.

Uncommon: sinus tachycardia, transient increase or decrease in blood pressure, postural hypotension.

Rare: bradycardia.

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.

Very rare: gastrointestinal haemorrhage.

Frequency not known: microscopic colitis.

Hepatobiliary disorders.

Rare: increased liver enzymes.

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

There have been reports of increased liver enzymes. Very rarely, hepatic adverse reactions (such as hepatitis, sometimes associated with jaundice and/or hepatic failure) have also been reported. Discontinuation of paroxetine should be considered if elevated liver tests persist.

Skin and subcutaneous tissue disorders.

Common: increased sweating;

Uncommon: skin rashes, pruritus;

Very rare: severe skin 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.

An increased risk of postpartum haemorrhage has been reported during treatment with SSRIs/SNRIs (see sections "Special precautions and warnings for use" and "Use during pregnancy or breastfeeding").

Musculoskeletal and connective tissue disorders.

Rare: arthralgia, myalgia.

Epidemiological studies, mainly conducted in patients aged 50 years and older, suggest an increased risk of bone fractures in patients treated with SSRIs and tricyclic antidepressants. The mechanism underlying this risk is unknown.

General disorders and administration site conditions.

Common: asthenia, weight gain.

Very rare: peripheral oedema.

Symptoms associated with discontinuation of paroxetine.

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

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

Discontinuation of paroxetine (especially abrupt) usually leads to withdrawal symptoms. Reported symptoms include dizziness, sensory disturbances (including paraesthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional lability, irritability, and visual disturbances.

These phenomena are usually mild or moderate in severity and resolve spontaneously; however, in some patients they may be severe and/or prolonged. Therefore, if paroxetine treatment is no longer required, it should be discontinued gradually by tapering the dose (see sections "Special precautions and warnings for use", "Dosage and administration", and "Use during pregnancy or breastfeeding").

Adverse reactions observed in clinical trials of paroxetine in children.

In clinical trials of paroxetine in children, increased frequency of the following adverse effects was observed: suicidal behaviour (including suicide attempts and suicidal thoughts), deliberate self-harm, hostility, decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood swings), bleeding (predominantly of the skin and mucous membranes).

Suicidal thoughts and suicide attempts were mainly observed in children treated for major depressive disorder; hostility was mainly observed in children with obsessive-compulsive disorder, particularly those under 12 years of age.

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

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of its business activities.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.

INSTRUCTIONS

for medical use of the medicinal product

SEMPRAVYL®

(SEMPRAVYL®)

Composition:

Active substance: paroxetine;

One film-coated tablet contains 20 mg of paroxetine hydrochloride hemihydrate, calculated as paroxetine;

Excipients: calcium hydrogen phosphate dihydrate, sodium starch glycolate, magnesium stearate, coating agent "Opadry13B58802 white"*.

* "Opadry13B58802 white": hypromellose, titanium dioxide (E 171), macrogol, polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, white or almost white, film-coated tablets, with a break line on one side and smooth on the other.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Paroxetine is a potent and selective inhibitor of serotonin (5-HT) reuptake, and its antidepressant effect and efficacy in the treatment of obsessive-compulsive disorder, social anxiety disorders/social phobias, generalized anxiety disorders, post-traumatic stress disorders, and panic disorders are believed to result from specific inhibition of neuronal serotonin reuptake in the brain.

Chemically, paroxetine differs from tricyclic, tetracyclic, and other known antidepressants.

Paroxetine has low affinity for muscarinic cholinergic receptors and exhibits weak anticholinergic properties.

In contrast to tricyclic antidepressants, it has negligible affinity for alpha1-, alpha2-, and beta-adrenergic receptors, dopaminergic (D2) receptors, 5-HT1-like, 5-HT2, and histamine (H1) receptors. Paroxetine is known not to produce central nervous system depressant or hypotensive effects and does not impair psychomotor function or potentiate the depressant effects of ethanol.

Like other selective serotonin reuptake inhibitors (SSRIs), paroxetine induces symptoms of excessive 5-HT receptor stimulation in animals previously administered monoamine oxidase inhibitors (MAOIs) or tryptophan.

Behavioral and electroencephalographic (EEG) studies indicate that paroxetine has only weak activating properties at doses usually exceeding those required for inhibition of serotonin reuptake. The activating properties are not "amphetamine-like" in nature.

When administered to healthy volunteers, paroxetine does not affect cardiovascular function and does not cause clinically significant changes in blood pressure, heart rate, or other electrocardiographic (ECG) parameters.

Unlike antidepressants that inhibit norepinephrine reuptake, paroxetine has a significantly reduced ability to interfere with the antihypertensive effects of guanethidine.

In the treatment of depressive disorders, paroxetine demonstrates efficacy comparable to that of standard antidepressants.

There is also some evidence that paroxetine may have therapeutic value in patients who do not respond clinically to standard therapy.

Morning administration of paroxetine does not affect either the quality or duration of sleep. Moreover, patients often experience improved sleep as they respond to paroxetine therapy.

Pharmacokinetics.

Absorption.

After oral administration, paroxetine is rapidly absorbed and undergoes hepatic transformation. Due to first-pass metabolism in the liver, the amount of paroxetine circulating in the blood is less than the amount absorbed from the gastrointestinal tract. With increasing single doses or repeated administration, partial saturation of the first-pass metabolic pathway occurs, resulting in reduced plasma clearance. This leads to a disproportionate increase in plasma paroxetine concentrations and changes in pharmacokinetic parameters, exhibiting nonlinear kinetics. However, this nonlinearity is generally minor and observed primarily in patients who achieve low plasma concentrations at low doses.

Steady-state plasma concentrations are reached within 7–14 days after initiation of treatment, and pharmacokinetics remain nearly unchanged during continued long-term therapy.

Distribution.

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

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

No correlation has been found between plasma paroxetine concentrations and clinical effects (efficacy and adverse reactions).

Metabolism.

The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are rapidly eliminated from the body. Due to their relatively low pharmacological activity, these metabolites are unlikely to contribute to the therapeutic effect of paroxetine.

Metabolism does not interfere with paroxetine's selective action on neuronal serotonin reuptake.

Elimination.

Approximately 64% of the administered dose is excreted in urine, with less than 2% excreted unchanged. About 36% of the dose is excreted in feces, likely via bile, with unchanged paroxetine accounting for less than 1% of the dose. Thus, paroxetine is almost entirely eliminated through metabolism.

Paroxetine metabolites are eliminated in two phases: first through hepatic first-pass metabolism, followed by systemic elimination of paroxetine.

The mean elimination half-life is approximately 1 day.

Special patient populations.

Elderly patients and patients with renal/hepatic impairment.

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

Clinical characteristics.

Indications.

For the treatment of:

• Major depressive disorder;
• Obsessive-compulsive disorder;
• Panic disorder with or without agoraphobia;
• Social anxiety disorders / social phobias;
• Generalized anxiety disorder;
• Post-traumatic stress disorder.

Contraindications.

• Hypersensitivity to paroxetine or to any other component of the medicinal product.
• Combination of paroxetine with monoamine oxidase inhibitors (MAOIs). In exceptional cases, linezolid (an antibiotic that is a reversible non-selective MAO inhibitor) may be prescribed in combination with paroxetine provided that means for careful monitoring of symptoms of serotonin syndrome and blood pressure monitoring are available (see section "Interaction with other medicinal products and other types of interactions").

Paroxetine treatment may be initiated:

• Two weeks after discontinuation of irreversible MAOIs, or
• At least 24 hours after discontinuation of reversible MAOIs, e.g., moclobemide, linezolid, methylene blue (methylthioninium chloride).

The interval between discontinuation of paroxetine and initiation of therapy with any MAOI should be at least one week.

• Paroxetine is contraindicated in combination with thioridazine or pimozide (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Serotonergic medicinal products.

As with other selective serotonin reuptake inhibitors (SSRIs), concomitant use with serotonergic medicinal products may lead to 5-HT-related effects (serotonin syndrome — see section "Special precautions for use"). Paroxetine should be used with caution together with such serotonergic medicinal products as L-tryptophan, triptans, tramadol, linezolid, methylene blue (methylthioninium chloride), SSRIs, lithium, pethidine, buprenorphine, and St. John's wort (Hypericum perforatum), and close clinical monitoring is mandatory. Caution is also recommended with fentanyl, which is used during general anesthesia or for treatment of chronic pain. Concomitant use of paroxetine and MAO inhibitors is contraindicated due to the risk of serotonin syndrome (see section "Contraindications").

Pimozide.

An increase in pimozide levels (on average by 2.5 times) was demonstrated during a study of concomitant administration of a single low dose of pimozide (2 mg) and paroxetine (60 mg). This was explained by the known inhibitory properties of paroxetine on CYP2D6. 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) may increase when paroxetine is used concomitantly with other medicinal products that prolong the QTc interval (e.g., certain antipsychotics) (see section "Special precautions for use"). Concomitant use of thioridazine and paroxetine is contraindicated, as paroxetine, like other drugs that inhibit the hepatic enzyme CYP450 2D6, may increase plasma levels of thioridazine, which can prolong the QT interval (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 drugs that inhibit enzymes, paroxetine should be prescribed at the lowest effective dose.

When used concomitantly with enzyme-inducing drugs (carbamazepine, rifampicin, phenobarbital, phenytoin), there is no need to change the initial dose of paroxetine. The dose of paroxetine (after initiation of treatment or after discontinuation of the enzyme inducer) should be adjusted 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 administration of fosamprenavir/ritonavir (700/100 mg twice daily) with paroxetine (20 mg daily) for 10 days in healthy volunteers significantly reduced (by approximately 55%) plasma levels of paroxetine. Plasma levels of fosamprenavir/ritonavir during concomitant use of paroxetine were similar to control values from other studies, indicating that paroxetine had no significant effect on the metabolism of fosamprenavir/ritonavir. Data on the effect of prolonged (more than 10 days) concomitant use of paroxetine and fosamprenavir/ritonavir are lacking.

Procyclidine.

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

Anticonvulsants: carbamazepine, phenytoin, sodium valproate.

No effect on the pharmacokinetics/pharmacodynamics of the drug has been observed in patients with epilepsy when these drugs are used concomitantly.

Ability of paroxetine to inhibit the CYP2D6 enzyme.

Paroxetine, like other antidepressants that are serotonin reuptake inhibitors, inhibits the activity of the CYP2D6 enzyme of the cytochrome P450 system. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered drugs metabolized by this enzyme. Such drugs include certain tricyclic antidepressants (e.g., clomipramine, nortriptyline, and desipramine), phenothiazine antipsychotics (e.g., perphenazine and thioridazine, see information above and in section "Contraindications"), risperidone, atomoxetine, certain class 1c antiarrhythmics (e.g., propafenone and flecainide), and metoprolol. Concomitant use of paroxetine with metoprolol is not recommended in heart failure due to the narrow therapeutic index of metoprolol for this indication.

Scientific publications have reported pharmacokinetic interactions between CYP2D6 inhibitors and tamoxifen, showing a 65–75% reduction in plasma levels of one of the most active metabolites of tamoxifen, endoxifen. Some studies have shown reduced efficacy of tamoxifen when used concomitantly with certain SSRI antidepressants. Since a reduction in tamoxifen efficacy cannot be excluded, concomitant use with potent CYP2D6 inhibitors (including paroxetine) should be avoided if possible (see section "Special precautions for use").

Alcohol.

As with other psychotropic agents, patients should be advised to avoid alcohol consumption during treatment with paroxetine.

Oral anticoagulants.

A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. Concomitant use of paroxetine and oral anticoagulants may lead to increased anticoagulant activity and risk of bleeding. Therefore, paroxetine should be prescribed with caution in patients receiving oral anticoagulants (see section "Special precautions for use").

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

Pharmacodynamic interaction may occur when NSAIDs/acetylsalicylic acid are used concomitantly with paroxetine, increasing the risk of bleeding. Paroxetine should be used with caution together with drugs that affect platelet function or increase the risk of bleeding (see section "Special precautions for use").

Caution is recommended when using SSRIs concomitantly 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, cyclooxygenase-2 [COX-2] inhibitors) in patients with coagulation disorders or conditions that may lead to bleeding.

Pravastatin.

The interaction between paroxetine and pravastatin observed 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 dose adjustments 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 dose of paroxetine should be increased gradually until optimal response is achieved (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Children

Paroxetine should not be used for the treatment of children and adolescents (under 18 years of age). Behaviour related to suicide (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) have been observed more frequently in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If, based on clinical need, a decision to treat is made, careful monitoring for emergence of suicidal symptoms is required.

Furthermore, there are no long-term safety data in children and adolescents regarding growth, sexual maturation, cognitive and behavioural development.

Suicide/suicidal thoughts or worsening of condition.

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicidality). This 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 available clinical experience, the risk of suicide is increased in the early stages of recovery.

Other psychiatric disorders for which paroxetine is prescribed may also be associated with an increased risk of suicide. In addition, these conditions may accompany major depressive disorder. Therefore, when treating major depressive disorder, the same precautionary measures should be followed as for other psychiatric disorders.

As the risk of suicidal thoughts or suicide attempts is higher in patients with a history of suicidality or pronounced suicidal ideation prior to treatment initiation, such patients should be under close supervision during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour in patients under 25 years of age treated with antidepressants compared to placebo (see section "Pharmacological properties").

Close monitoring of patients, especially those at increased risk, is necessary at the beginning of paroxetine treatment or when changing its dosage. Patients (and caregivers) should be warned to monitor for any signs of clinical worsening, suicidal behaviour/thoughts, or unusual changes in behaviour. If such symptoms occur, immediate medical advice should be sought.

Akathisia/psychomotor restlessness.

Paroxetine has been associated with the development of akathisia — a condition characterised by inner restlessness and psychomotor agitation, such as inability to sit or stand still, combined with a subjective feeling of discomfort. The likelihood of developing this condition is greatest during the first weeks of treatment. Increasing the dose may be harmful in patients who develop such symptoms.

Serotonin syndrome/neuroleptic malignant syndrome.

In isolated cases, treatment with paroxetine may be associated with the development of serotonin syndrome or symptoms characteristic of neuroleptic malignant syndrome, particularly when used concomitantly with other serotonergic and/or neuroleptic agents. Since these syndromes may lead to life-threatening conditions, treatment with paroxetine should be discontinued if such events occur (characterised by a combination of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations in vital signs, altered mental status including confusion, agitation, extreme agitation progressing to delirium and coma), and supportive symptomatic therapy should be initiated. Paroxetine should not be used in combination with serotonergic precursors (such as L-tryptophan, 5-hydroxytryptophan) due to the risk of serotonin syndrome (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interactions").

Mania.

As with other antidepressants, paroxetine should be used with caution in patients with a history of mania. Paroxetine treatment should be discontinued if a patient develops a manic episode.

Renal/hepatic impairment.

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

Diabetes mellitus.

In patients with diabetes mellitus, treatment with serotonin reuptake inhibitors may alter glycaemic control, and therefore the dose of insulin and/or oral hypoglycaemic agents should be adjusted. Clinical studies indicate that increased blood glucose levels may occur during concomitant treatment with paroxetine and pravastatin (see section "Interaction with other medicinal products and other forms of interaction").

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 treated with paroxetine. If seizures occur, treatment with the drug should be discontinued.

Electroconvulsive therapy (ECT).

Experience with concomitant use of paroxetine and ECT is limited.

Glaucoma.

Paroxetine, like other serotonin reuptake inhibitors, may cause mydriasis; therefore, it should be used with caution in patients with existing closed-angle glaucoma or a history of glaucoma.

Cardiac disorders.

Standard precautions should be taken when treating patients with concomitant cardiac 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 family history of QT interval prolongation, when used concomitantly with antiarrhythmic drugs or other medicinal products that may potentially prolong the QT interval, in patients with heart failure, ischemic heart disease, cardiac conduction block, ventricular arrhythmia, bradycardia, hypokalaemia or hypomagnesaemia (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Hyponatraemia.

Cases of hyponatraemia have occasionally been reported, mostly in elderly patients. The medicinal product should be prescribed with caution in patients at risk of developing hyponatraemia, for example due to concomitant use of other medicinal products or in the presence of cirrhosis. Hyponatraemia usually resolves after discontinuation of paroxetine.

Bleeding.

Skin haemorrhages such as ecchymoses and purpura have been observed after treatment with SSRIs/SNRIs. Other bleeding events have been reported, including gastrointestinal and gynaecological bleeding. Elderly patients may have an increased risk of non-menstrual bleeding.

SSRIs/SNRIs increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions").

Therefore, paroxetine should be used with caution in patients who are concurrently taking oral anticoagulants, agents affecting platelet function, or other drugs that increase 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 coagulopathies or diseases that may lead to bleeding (see section "Adverse reactions").

Interaction with tamoxifen.

Paroxetine, a potent CYP2D6 inhibitor, may cause reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, paroxetine should be avoided during treatment with tamoxifen (see section "Interaction with other medicinal products and other forms of interaction").

Bone fractures.

Epidemiological studies on the risk of bone fractures associated with the use of certain antidepressants, including selective serotonin reuptake inhibitors, have shown an association with fractures. The risk occurs during treatment and is greatest in the early stages of therapy. The possibility of bone fractures should be considered when treating patients with paroxetine.

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 indicate that discontinuation-related adverse reactions occurred in 30% of adult patients treated with paroxetine compared to 20% of patients receiving placebo. The emergence of discontinuation symptoms does not indicate drug addiction or dependence associated with drug abuse.

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

Reported symptoms include dizziness, sensory disturbances (including paraesthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, excessive sweating, headache, diarrhoea, 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, but isolated cases have been reported in patients who inadvertently 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 section "Dosage and administration").

Sexual dysfunction.

SSRIs may cause symptoms of sexual dysfunction (see section "Adverse reactions"). In some cases, these symptoms persisted after discontinuation of SSRIs.

Sodium.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Some epidemiological studies suggest an increased risk of congenital malformations, particularly cardiovascular malformations (e.g., atrial or ventricular septal defects), associated with the use of paroxetine during the first trimester of pregnancy. The mechanism is unknown. Data indicate that the risk of giving birth to a child with a cardiovascular defect after maternal paroxetine use is less than 2/100 compared to an expected frequency of approximately 1/100 in the general population.

Paroxetine should be used during pregnancy only if clearly indicated. The prescribing physician should consider alternative treatments for pregnant women or women planning pregnancy. Abrupt discontinuation of the drug during pregnancy should be avoided (see sections "Special precautions for use" and "Dosage and administration").

Data indicate an increased risk of postpartum haemorrhage (less than two-fold) in women who used SSRIs/SNRIs within one month before delivery (see sections "Special precautions for use" and "Adverse reactions").

Newborns should be monitored if the mother continued taking paroxetine late in pregnancy, particularly during the third trimester.

Symptoms that may occur in newborns after maternal use of paroxetine late in pregnancy include: respiratory distress, cyanosis, apnoea, seizures, temperature fluctuations, feeding difficulties, vomiting, hypoglycaemia, hypertension, hypotension, hyperreflexia, tremor, twitching, irritability, lethargy, persistent crying, somnolence, and sleep disturbances. These symptoms may be caused by serotonergic effects or withdrawal symptoms. In some reports, symptoms have been described as neonatal withdrawal syndrome. In most cases, they occur immediately or shortly (<24 hours) after delivery.

Epidemiological data suggest that maternal use of SSRIs during pregnancy, particularly in late pregnancy, is associated with an increased risk of persistent pulmonary hypertension in the newborn. The observed risk is approximately 5 cases per 1,000 pregnancies. In the general population, persistent pulmonary hypertension of the newborn occurs in one to two cases per 1,000 pregnancies.

Animal studies have shown reproductive toxicity but have not indicated a direct harmful effect on pregnancy, embryonic/foetal development, delivery, or postnatal development.

Breastfeeding period.

A small amount of paroxetine is excreted in breast milk. Published study data show that concentrations of paroxetine in infant serum from breastfed infants of women taking the drug were below the limit of detection (<2 ng/mL) or very low (<4 ng/mL), and no signs of drug effects were observed in these infants. Since effects are not expected, breastfeeding may be considered.

Fertility.

Preclinical and in vitro studies have shown that paroxetine may affect sperm quality. However, reports on the effect of certain SSRIs (including paroxetine) on sperm quality in men taking these drugs suggest that the effect is reversible. No effect on human fertility has been observed to date.

Ability to affect reaction speed when driving or operating machinery.

Clinical experience indicates that this medicinal product does not affect cognitive functions or psychomotor reactions. However, as with other psychoactive drugs, patients should be warned about the possible impairment of ability to drive or operate machinery during treatment.

Paroxetine does not potentiate the impairment of mental and motor reactions caused by alcohol; however, concomitant use of paroxetine and alcohol is not recommended.

Dosage and Administration

Major Depressive Disorder

The recommended dose is 20 mg once daily. Overall improvement in patients generally begins within one week, but may become clearly evident only during the second week of treatment.

As with all other antidepressants, the dose of paroxetine should be carefully individualized and adjusted accordingly during the first 3–4 weeks of therapy, and thereafter based on clinical need.

If the clinical response to 20 mg is inadequate, the dose may be gradually increased (in 10 mg increments) up to the maximum dose of 50 mg daily, according to the patient's response.

Patients with depressive disorder should continue treatment for a prolonged period (at least 6 months) to ensure sustained symptom relief.

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 until the recommended dose is reached. If the clinical response after several weeks at the recommended dose is inadequate, some patients may require gradual dose escalation up to the maximum of 60 mg daily.

The treatment course for patients with obsessive-compulsive disorder should be sufficiently long to ensure symptom remission. This period may last several months or even longer (see section "Pharmacodynamics").

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 response, until the recommended dose is reached. If the clinical response after several weeks at the recommended dose is inadequate, some patients may require gradual dose escalation up to the maximum of 60 mg daily.

The treatment course for patients with panic disorder should be sufficiently long to ensure symptom remission. This period may last several months or even longer (see section "Pharmacodynamics").

Social Anxiety Disorder / Social Phobia

The recommended dose is 20 mg once daily. If the clinical response after several weeks at the recommended dose is inadequate, some patients may require gradual dose escalation in 10 mg increments up to the maximum of 50 mg daily. Long-term use should be regularly evaluated (see section "Pharmacodynamics").

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 in 10 mg increments, depending on clinical response, up to 50 mg daily. Long-term use should be regularly evaluated (see section "Pharmacodynamics").

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 in 10 mg increments, depending on clinical response, up to 50 mg daily. Long-term use should be regularly evaluated (see section "Pharmacodynamics").

Withdrawal Symptoms Observed After Discontinuation of Paroxetine

Abrupt discontinuation should be avoided (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). In clinical trials, a tapering regimen was used, involving a reduction of the daily dose by 10 mg weekly. If pronounced symptoms occur during dose reduction or after discontinuation, consideration should be given to reinstating the previous dose.

Subsequently, the dose may be gradually reduced again.

Special Patient Groups

Elderly Patients

Elevated plasma concentrations of paroxetine are observed in elderly patients, although the concentration range partially overlaps with that seen in younger patients. Treatment should be initiated at the standard adult starting dose. Some patients may require dose escalation, but the maximum dose should not exceed 40 mg daily.

Renal or Hepatic Impairment

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

Administration

Paroxetine should be taken once daily in the morning with food.

The tablet should be swallowed whole, without chewing.

Children

Paroxetine should not be used in children (under 18 years of age), as controlled clinical trials have shown an association between paroxetine use and increased risk of suicidal behavior and hostility. Furthermore, efficacy was not adequately demonstrated in these studies. The safety and efficacy of paroxetine in children under 7 years of age have not been studied.

Overdose

Symptoms

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

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

Treatment

There is no specific antidote.

Management of overdose should include general supportive and symptomatic measures, similar to those used in overdose with other antidepressants. Administration of 20–30 g of activated charcoal may be beneficial within several hours of overdose to reduce absorption. Supportive therapy with monitoring of vital functions and close observation of the patient in a hospital setting is indicated. Treatment should be tailored according to the patient's clinical condition.

Adverse reactions.

Some of the adverse reactions listed below may decrease in intensity and frequency with continued treatment and usually do not require discontinuation of therapy.

Adverse reactions are listed by system organ class and frequency. Frequency is defined as: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); unknown (cannot be estimated from available data).

Blood and lymphatic system disorders.

Uncommon: increased bleeding tendency, primarily of the skin and mucous membranes (including ecchymoses and gynecological bleeding), leukopenia.

Very rare: thrombocytopenia.

Immune system disorders.

Very rare: severe and potentially fatal allergic reactions (including anaphylactoid reactions and angioedema).

Endocrine system disorders.

Very rare: syndrome due to inadequate antidiuretic hormone secretion.

Metabolism and nutrition disorders.

Common: increased cholesterol levels, decreased appetite.

Uncommon: altered glycaemic control has been reported in patients with diabetes mellitus (see section "Special precautions for use").

Rare: hyponatraemia, mainly observed in elderly patients and sometimes associated with syndrome due to inadequate antidiuretic hormone secretion.

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 unknown: suicidal ideation, suicidal behaviour, aggression, bruxism.

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

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

These symptoms may also be related to the underlying disease.

Nervous system disorders.

Common: dizziness, tremor, headache, difficulty in concentration.

Uncommon: extrapyramidal disorders.

Rare: seizures, restless legs syndrome.

Very rare: serotonin syndrome (may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia, and tremor).

Extrapyramidal disorders, including orofacial dystonia, are observed in patients with movement disorders or in patients treated with neuroleptics.

Eye disorders.

Common: blurred vision.

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

Very rare: acute glaucoma.

Ear and labyrinth disorders.

Frequency unknown: tinnitus.

Cardiac disorders.

Uncommon: sinus tachycardia, transient increase or decrease in blood pressure, postural hypotension.

Rare: bradycardia.

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.

Very rare: gastrointestinal bleeding.

Frequency unknown: microscopic colitis.

Hepatobiliary disorders.

Rare: increased levels of 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. Very rarely, hepatic adverse reactions (such as hepatitis, sometimes associated with jaundice and/or hepatic failure) have also been reported. Discontinuation of paroxetine should be considered if elevated liver function tests persist.

Skin and subcutaneous tissue disorders.

Common: increased sweating.

Uncommon: skin rash, pruritus.

Very rare: severe skin 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 unknown: postpartum haemorrhage.

An increased risk of postpartum haemorrhage has been reported during treatment with SSRIs/SNRIs (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").

Musculoskeletal and connective tissue disorders.

Rare: arthralgia, myalgia.

Epidemiological studies, mainly conducted in patients aged 50 years and older, suggest an increased risk of bone fractures in patients treated with SSRIs and tricyclic antidepressants. The mechanism underlying this risk is unknown.

General disorders and administration site conditions.

Common: asthenia, weight gain.

Very rare: peripheral oedema.

Symptoms associated with discontinuation of paroxetine.

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

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

Discontinuation of paroxetine (especially abrupt) is usually associated with withdrawal symptoms. Reported symptoms include dizziness, sensory disturbances (including paraesthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional lability, irritability, and visual disturbances.

These events are generally mild to moderate in severity and self-limiting; however, in some patients, they may be severe and/or prolonged. Therefore, if treatment with paroxetine is no longer required, it should be discontinued gradually by tapering the dose (see sections "Special precautions for use", "Dosage and administration", and "Use during pregnancy or breastfeeding").

Adverse reactions observed in clinical trials of paroxetine in children.

In clinical trials of paroxetine in children, increased frequency of the following adverse effects was observed: suicidal behaviour (including suicide attempts and suicidal thoughts), deliberate self-harm, hostility, decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood swings), bleeding (mainly of the skin and mucous membranes).

Suicidal thoughts and suicide attempts were mainly observed in children treated for major depressive disorder; hostility was observed in children with obsessive-compulsive disorder, particularly those under 12 years of age.

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and place of business.

54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.