Paroxetine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PAROXETINE (PAROXETINE)

Composition:

Active substance: paroxetine;

1 tablet contains 22.22 mg of paroxetine hydrochloride equivalent to 20 mg of paroxetine;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Medicinal form. Tablets.

Main physical and chemical properties: flat, nearly white tablets with bevelled edges, a score line on one side and the marking "20" on the other. Diameter 9.0–9.2 mm, height 3.1–3.4 mm.

Pharmacotherapeutic group. Antidepressants. 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 5-hydroxytryptamine uptake by brain neurons. Chemically, paroxetine differs from tricyclic, tetracyclic, and other known antidepressants.

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

Paroxetine does not affect cardiovascular system activity; it does not cause clinically significant changes in blood pressure, heart rate, or ECG parameters.

Unlike antidepressants that inhibit norepinephrine reuptake, paroxetine has a much lesser effect on the antihypertensive action of guanethidine.

Pharmacokinetics.

Paroxetine is rapidly absorbed after oral administration and undergoes hepatic metabolism.

The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are rapidly excreted 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 is excreted in feces as metabolites.

Paroxetine metabolites are eliminated in two stages: 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 reached within 7–14 days after initiation of treatment, and during prolonged therapy, the pharmacokinetics of the drug remain almost unchanged.

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

Due to hepatic breakdown, the amount of paroxetine circulating in the blood is lower than the amount absorbed in 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 concentration and changes in pharmacokinetic parameters, exhibiting nonlinear kinetics. However, this nonlinearity is mostly insignificant and observed only in patients who achieve low plasma concentrations of the drug when using low doses.

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 levels remain within the range of fluctuations observed in healthy adults.

Clinical characteristics.

Indications.

Treatment of major depressive disorder.

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

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

Treatment of social phobias/social anxiety disorders.

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

Treatment of post-traumatic stress disorder.

Contraindications.

Hypersensitivity to paroxetine or any other component of the medicinal product.

Paroxetine must not be prescribed concurrently with monoamine oxidase inhibitors (MAOIs), including linezolid—an antibiotic that is a reversible non-selective inhibitor of monoamine oxidase—and methylene blue (methylthioninium chloride), or earlier than 2 weeks after discontinuation of MAOI therapy (see section "Interaction with other medicinal products and other forms of interaction"). MAOIs must not be used earlier than 2 weeks after discontinuation of paroxetine treatment.

The drug must not be used in combination with thioridazine, since, like other drugs that inhibit the hepatic enzyme CYP450 2D6, paroxetine may increase thioridazine levels (see section "Interaction with other medicinal products and other forms of interaction"). The use of thioridazine may lead to QT interval prolongation with associated severe ventricular arrhythmias (e.g., torsades de pointes) and sudden death.

Paroxetine must not be prescribed in combination with pimozide (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Serotonergic drugs

As with the use of other selective serotonin reuptake inhibitors, concomitant use with serotonergic drugs may lead to a 5-HT-related effect (serotonin syndrome).

Paroxetine should be used with caution together with such serotonergic drugs as L-tryptophan, triptans, buprenorphine, tramadol and pethidine, linezolid, methylene blue (methylthioninium chloride), other serotonin reuptake inhibitors, lithium, and Hypericum perforatum (St. John's wort) herbal preparations, with careful monitoring of the patient's clinical condition. Caution is recommended when using fentanyl during general anesthesia or for treatment of chronic pain. Concomitant use of paroxetine and MAOIs is contraindicated (see section "Contraindications").

Pimozide

In a study on the concomitant use of a single low dose of pimozide (2 mg) and paroxetine, an increase in pimozide levels was observed. 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").

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, the lowest effective doses are recommended. When used concomitantly with enzyme-inducing drugs (carbamazepine, rifampicin, phenobarbital, phenytoin), no change in the initial dose of paroxetine is required. Dose adjustments during further treatment should be made according to clinical response (tolerability and efficacy).

Myorelaxants

Selective serotonin reuptake inhibitors may reduce plasma cholinesterase activity, leading to prolonged neuromuscular blocking effects of mivacurium and succinylcholine.

Fosamprenavir/ritonavir

Concomitant use of fosamprenavir/ritonavir with paroxetine significantly reduces plasma levels of paroxetine. Dose adjustments during further treatment should be based on clinical response (tolerability and efficacy).

Procyclidine

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

Anticonvulsants

Carbamazepine, phenytoin, sodium valproate. When used concomitantly with these drugs, no effect on the pharmacokinetics/pharmacodynamics of the drug was observed in patients with epilepsy.

Paroxetine's ability to inhibit the CYP2D6 enzyme

Paroxetine, like other antidepressants that are selective 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., amitriptyline, nortriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g., perphenazine and thioridazine), risperidone, atomoxetine, certain class 1c antiarrhythmics (e.g., propafenone and flecainide), and metoprolol.

Tamoxifen

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").

CYP3A4

In in vivo experiments, concomitant use of paroxetine and terfenadine—a substrate of the CYP3A4 enzyme—at steady-state plasma concentrations was not associated with any effect of paroxetine on terfenadine pharmacokinetics. Similarly, an in vivo study of interaction did not reveal any effect of the drug on alprazolam pharmacokinetics, or vice versa. Concurrent administration of paroxetine with terfenadine, alprazolam, and other drugs that are substrates of CYP3A4 is unlikely to be hazardous.

Clinical studies have shown that absorption or pharmacokinetics of paroxetine are not affected or are minimally affected (i.e., do not require dosage adjustment) by the following factors: food, antacids, digoxin, propranolol, alcohol.

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

Oral anticoagulants

When oral anticoagulants are used concomitantly with paroxetine, a pharmacodynamic interaction may occur, potentially increasing anticoagulant activity and the risk of bleeding. Therefore, paroxetine should be prescribed with caution to patients taking oral anticoagulants.

Non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and antiplatelet agents

When non-steroidal anti-inflammatory drugs/acetylsalicylic acid are used concomitantly with paroxetine, a pharmacodynamic interaction may occur, potentially increasing the risk of bleeding.

Caution is recommended when selective serotonin reuptake inhibitors are used concomitantly with oral anticoagulants, drugs affecting platelet function, or increasing the risk of bleeding (e.g., atypical neuroleptics such as clozapine, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors), as well as in patients with a history of bleeding or coagulation disorders, which may lead to hemorrhage.

Pravastatin

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

Special precautions for use.

Children and adolescents.

Treatment with antidepressants is associated with an increased risk of suicidal behaviour and thoughts in children and adolescents with major depressive and other psychiatric disorders. Clinical studies have shown that adverse events related to suicidality (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behaviour and irritability) occur more frequently in children and adolescents treated with Paroxetine compared to placebo. There are no data on the effect of the drug on growth, development, cognitive and behavioural characteristics in children and adolescents.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide. This risk persists until significant remission occurs. Since improvement may not occur during the first weeks of treatment or even longer, careful monitoring should continue until the condition improves. Based on available clinical experience, the risk of suicide may increase during the initial recovery phase.

Other psychiatric disorders for which paroxetine is prescribed may also be associated with an increased risk of suicidal events. Moreover, these conditions may coexist with major depressive disorder. Therefore, the same precautions should be taken when treating these disorders as when treating major depressive disorder.

It is known that the risk of suicidal thoughts or suicide attempts is increased in patients with such manifestations in their history or with suicidal ideation prior to the start of treatment; therefore, they 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 with antidepressant treatment compared to placebo in patients under 25 years of age (see section "Pharmacodynamics").

Close monitoring of patients is necessary at the beginning of treatment and when changing the dose of the drug, especially in patients at increased risk. Patients (and caregivers) should be warned to monitor symptom progression in order to detect clinical worsening, suicidal behaviour or suicidal thoughts, unusual changes in behaviour, and to seek medical help immediately if such symptoms occur.

Akathisia.

Rarely, the use of Paroxetine or other selective serotonin reuptake inhibitors (SSRIs) may be associated with the development of akathisia — a condition characterised by a sense of inner restlessness and psychomotor agitation, such as inability to sit or stand still, combined with subjective feelings of discomfort. The likelihood of this condition is highest during the first weeks of treatment.

Serotonin syndrome/Neuroleptic malignant syndrome.

In isolated cases, treatment with Paroxetine may be associated with the development of serotonin syndrome or neuroleptic malignant syndrome, especially when used concomitantly with other serotonergic and/or neuroleptic drugs. Since these syndromes can lead to life-threatening conditions, treatment with Paroxetine should be discontinued if such symptoms occur (characterised by a combination of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations in vital signs, changes in mental status including confusion, irritability, 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 interaction").

Mania and bipolar disorders.

A major depressive episode may be the initial manifestation of bipolar disorder. It is believed (although not confirmed by data from controlled clinical trials) that treating such episodes with antidepressants alone may increase the likelihood of triggering mixed/mania episodes in patients at risk of developing bipolar disorder. Before initiating antidepressant treatment, patients should be carefully evaluated for any risk of developing bipolar disorder. This evaluation should include a detailed review of the patient's medical history, including 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.

Sexual dysfunction.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Cases of persistent sexual dysfunction have been reported, where symptoms persisted despite discontinuation of SSRIs/SNRIs.

Tamoxifen.

According to some studies, the efficacy of tamoxifen, measured by the risk of breast cancer recurrence or fatal events, may be reduced when used concomitantly with Paroxetine, since paroxetine is a potent 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. In patients receiving tamoxifen for breast cancer treatment, an alternative antidepressant with minimal or no CYP2D6 inhibition should be prescribed.

Drugs affecting gastric pH.

In patients taking oral suspension, gastric pH may affect paroxetine plasma concentration. In vitro data demonstrate that an acidic environment is necessary for the release of the active substance from the suspension; therefore, absorption may be reduced in patients with high gastric pH or achlorhydria, as well as after taking certain medications (antacids, H2-receptor antagonists, proton pump inhibitors), in concomitant conditions (e.g. atrophic gastritis, pernicious anaemia, chronic Helicobacter pylori infection), or after surgical procedures (vagotomy, gastrectomy). The pH dependency should be considered when changing the dosage form of paroxetine (e.g. plasma paroxetine concentration may decrease after switching from tablets to oral suspension in patients with high gastric pH). Therefore, caution is recommended when starting or discontinuing treatment with drugs that increase gastric pH, and dosage adjustment may be required.

Bone fractures.

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

Monoamine oxidase inhibitors (MAOIs).

Treatment with Paroxetine should be initiated with caution, not earlier than 2 weeks after discontinuation of MAO inhibitors; the dose should be gradually increased until optimal response is achieved.

Renal/hepatic impairment.

Use with caution in patients with severe renal or hepatic impairment.

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. Additionally, clinical studies indicate that increased blood glucose levels may occur when paroxetine is used concomitantly with pravastatin.

Epilepsy.

Paroxetine, like other antidepressants, should be used with caution in the treatment of patients with epilepsy.

Seizures.

In patients treated with Paroxetine, the overall incidence of seizures is less than 0.1%. If seizures occur, Paroxetine should be discontinued.

Electroconvulsive therapy.

Only limited clinical experience is available regarding the use of Paroxetine in combination with electroconvulsive therapy.

Glaucoma.

Paroxetine, like other serotonin reuptake inhibitors, may cause mydriasis and therefore should be used with caution in patients with closed-angle glaucoma.

Hyponatraemia.

Cases of hyponatraemia have been reported, mostly in elderly patients. Caution should also be exercised in patients at risk of hyponatraemia, for example, when taking concomitant medications or in patients with cirrhosis. Signs of hyponatraemia usually resolve after discontinuation of Paroxetine.

Haemorrhage.

Bleeding events such as ecchymoses and purpura (including gastrointestinal bleeding and gynaecological bleeding) have been observed during treatment with SSRIs. Elderly patients may have an increased risk of non-menstrual bleeding. Therefore, Paroxetine should be used with caution in patients receiving concomitant oral anticoagulants, drugs affecting platelet function, or other drugs that may increase the risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, COX-2 inhibitors), as well as in patients with frequent bleeding or predisposition to bleeding.

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

Cardiac disorders.

Standard precautions should be taken when treating patients with concomitant heart disease.

Symptoms observed in adults upon discontinuation of Paroxetine.

Clinical studies have shown that adverse reactions upon discontinuation of Paroxetine occurred in 30% of adult patients compared to 20% of patients receiving placebo. Discontinuation symptoms differ from those associated with drug dependence or abuse. The risk of discontinuation symptoms may depend on several factors, including duration of treatment, dosage, and speed of dose reduction.

Reported symptoms include confusion, palpitations, emotional instability, irritability, visual disturbances, dizziness, sensory disturbances (including paraesthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, seizures, increased sweating, headache, and diarrhoea. Generally, these symptoms are mild or moderate in severity, although they may be more intense in some patients. They usually occur within the first few days after discontinuation, 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 (see section "Dosage and administration").

Symptoms observed in children and adolescents upon discontinuation of Paroxetine.

Clinical studies have shown that adverse reactions upon discontinuation of Paroxetine occurred in 32% of children and adolescents compared to 24% of patients receiving placebo. After discontinuation of Paroxetine, the following adverse effects occurred (in at least 2% of patients and at least twice as many as in the placebo group): emotional lability (including suicidal ideation, suicide attempts, mood changes, and tearfulness), restlessness, dizziness, nausea, and abdominal pain (see section "Adive reactions").

Sodium content. One tablet contains less than 1 mmol (23 mg) of sodium, i.e. the medicinal product is considered practically sodium-free.

Use during pregnancy or breastfeeding.

Fertility.

Some clinical studies suggest that selective serotonin reuptake inhibitors, 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.

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

The physician should consider the possibility of alternative treatment for pregnant women or women planning pregnancy and prescribe paroxetine only when the expected benefit to the mother outweighs the potential risk to the foetus. If a decision is made to discontinue treatment during pregnancy, additional information should be sought from the relevant sections of the product information regarding doses and symptoms associated with discontinuation of paroxetine (see sections "Dosage and administration" and "Special precautions for use").

There have been reports of preterm birth in women treated with paroxetine or other selective serotonin reuptake inhibitors, although a causal relationship with drug use has not been established.

Newborns should be monitored if the mother continued taking paroxetine during the third trimester of pregnancy, as there have been reports of complications in newborns following maternal treatment with paroxetine or other selective serotonin reuptake inhibitors during this period, although a causal relationship with drug use has not been established. Reported effects include respiratory distress, cyanosis, apnoea, seizures, temperature fluctuations, feeding difficulties, vomiting, hypoglycaemia, hypertension, hypotension, hyperreflexia, tremor, jitteriness, irritability, lethargy, persistent crying, and somnolence. In some reports, symptoms were described as neonatal withdrawal syndrome. In most cases, symptoms occur immediately or shortly (<24 hours) after delivery.

Epidemiological data suggest that the use of selective serotonin reuptake inhibitors (including paroxetine) during pregnancy, particularly in late pregnancy, is associated with an increased risk of persistent pulmonary hypertension in newborns. 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 population).

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

Breastfeeding.

A small amount of paroxetine is excreted in breast milk. No signs of adverse 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 affect reaction speed when driving vehicles or operating machinery.

Clinical experience with Paroxetine suggests 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 vehicles or operate machinery during treatment. Paroxetine does not enhance 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.

The drug is intended for oral administration and should be taken once daily – in the morning with food. The tablet should be swallowed whole, without chewing.

As with other agents used to treat psychiatric disorders, abrupt discontinuation of the drug should be avoided.

Major Depressive Disorder. The recommended daily dose is 20 mg. Improvement usually begins within one week, although in some cases improvement may only become evident during the second week of treatment.

As with all other antidepressants, the dose should be carefully individualized during the first 3–4 weeks of treatment and then adjusted according to clinical response.

For some patients who respond inadequately to a 20 mg dose, dose escalation may be required. This should be done gradually, increasing the dose by 10 mg (up to a maximum of 50 mg daily) depending on clinical efficacy. The treatment course for patients with depression should be sufficiently long, at least 6 months, to ensure symptom remission.

Obsessive-Compulsive Disorder. The recommended daily dose is 40 mg. Treatment should be initiated at a dose of 20 mg daily, then gradually increased by 10 mg daily to the recommended dose. In some patients, improvement is observed only when the maximum dose of 60 mg daily is used. The treatment duration for obsessive-compulsive disorder should be sufficiently long to ensure symptom remission. This period may last several months or longer.

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

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

Social Anxiety Disorders/Social Phobias. The recommended dose is 20 mg 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. Long-term use of the drug should be periodically reviewed.

Generalized Anxiety Disorder. The recommended dose is 20 mg daily. If insufficient efficacy is observed with 20 mg, the dose may be gradually increased by 10 mg daily, depending on clinical response, up to a maximum of 50 mg daily. Long-term use of the drug should be periodically reviewed.

Post-Traumatic Stress Disorder. The recommended dose is 20 mg daily. If insufficient efficacy is observed with 20 mg, the dose may be gradually increased by 10 mg daily, depending on clinical response, up to a maximum of 50 mg daily. Long-term use of the drug should be periodically reviewed.

Discontinuation of Paroxetine.

As with other drugs used to treat psychiatric disorders, abrupt discontinuation should be avoided. In clinical trials, a gradual dose reduction regimen was used, involving a decrease of 10 mg daily every week. After reaching a dose of 20 mg daily, patients continued taking the drug at this dose for an additional week before complete discontinuation. If severe symptoms occur during dose reduction or after stopping treatment, consideration should be given to resuming treatment at the previous dose. Subsequently, the dose may be reduced again, but at a slower rate.

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, but the concentration range in this patient group is comparable to that in younger patients.

Children. Paroxetine is not indicated for the treatment of children.

Renal and Hepatic Impairment. In patients with severe renal impairment (creatinine clearance less than 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 dosage range in such patients.

Children. Paroxetine is not indicated for the treatment of children.

Overdose.

In cases of paroxetine overdose, in addition to the symptoms listed in the section "Adverse Reactions," the following have been observed: elevated body temperature, changes in blood pressure, involuntary muscle contractions, anxiety, and tachycardia.

These effects generally resolved without serious consequences in patients, even after ingestion of 2000 mg. Occasionally, coma or ECG changes were observed; fatal outcomes were very rare and mostly occurred when paroxetine was taken concomitantly with other psychotropic agents, sometimes with alcohol.

No specific antidote is known.

Management of overdose should include general supportive measures, as for overdose with other antidepressants. Supportive care with monitoring of vital signs and careful observation of the patient's condition is indicated.

Adverse Reactions

The adverse effects listed below are classified by organ systems and frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000, including isolated cases).

Blood and lymphatic system

Uncommon: increased bleeding tendency, mainly of the skin and mucous membranes (including ecchymoses and gynecological bleeding).
Very rare: thrombocytopenia.

Immune system

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

Endocrine system

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

Metabolism and nutrition disorders

Common: increased cholesterol levels, decreased appetite.
Uncommon: altered glycemic profile has been reported in diabetic patients (see section "Special precautions").
Rare: hyponatremia. Hyponatremia is mainly observed in elderly patients and is 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.
Frequency not known: suicidal ideation, suicidal behavior, and aggression.

These symptoms may also be related to the underlying disease.

Nervous system

Common: dizziness, tremor, headache.
Uncommon: extrapyramidal disorders.
Rare: seizures, akathisia, restless legs syndrome.
Very rare: serotonin syndrome (may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, tachycardia, and tremor), difficulty concentrating, shivering.

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

Eye organs

Common: blurred vision.
Uncommon: mydriasis (see section "Special precautions").
Very rare: acute glaucoma.

Ear and labyrinth disorders

Frequency not known: tinnitus.

Cardiovascular system

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

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

Respiratory system

Common: yawning.

Gastrointestinal system

Very common: nausea.
Common: constipation, diarrhea, dry mouth.
Very rare: gastrointestinal bleeding.
Frequency not known: microscopic colitis.

Hepatobiliary system

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 function tests persist.

Skin and subcutaneous tissue

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.

Urinary system

Uncommon: urinary retention, urinary incontinence.

Reproductive system

Very common: sexual dysfunction.
Rare: hyperprolactinemia/galactorrhea, menstrual disorders (including menorrhagia, metrorrhagia, amenorrhea, delayed and irregular menstruation).
Very rare: priapism.
Frequency not known: postpartum hemorrhage (pertains to the therapeutic group of SSRIs/SNRIs (see sections "Special precautions" and "Pregnancy and lactation")).

Musculoskeletal system

Rare: arthralgia, myalgia.

Epidemiological studies, conducted mainly in patients aged 50 years and older, suggest an increased risk of bone fractures in patients receiving SSRIs (selective serotonin reuptake inhibitors) and TCAs (tricyclic antidepressants). The mechanism leading to this risk is unknown.

General disorders

Common: asthenia, weight gain.
Very rare: peripheral edema.

Symptoms related to drug discontinuation

Common: dizziness, sensory disturbances, sleep disturbances, anxiety, headache.
Uncommon: agitation, nausea, tremor, confusion, sweating, diarrhea, emotional lability, visual disturbances.

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions to the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product.

In case of adverse reactions or questions regarding the safety of the medicinal product, please contact via the feedback form on the website: www.ukraine.medochemie.com

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, out of reach of children.

Packaging. 10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Limited.

Manufacturer's address.
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.