PAXIL

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

Composition:

Active substance: paroxetine;

1 tablet contains paroxetine (in the form of hemihydrate hydrochloride) 20 mg;

Excipients: calcium hydrogen phosphate (dihydrate), sodium starch glycolate (type A), magnesium stearate, Opadry White YS-1R-7003 (hypromellose, titanium dioxide (E 171), polyethylene glycol 400, polysorbate 80).

**Pharmaceutical form.** Coated tablets.

Main physicochemical properties: white, coated, oval-shaped, biconvex tablets, marked "20" on one side and a dividing line on the other.

**Pharmacotherapeutic group.** Antidepressants. ATC code: N06AB05.

Pharmacological Properties.

Pharmacodynamics.

Paxil 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 reuptake by brain neurons. Chemically, Paxil differs from tricyclic, tetracyclic, and other known antidepressants.

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

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

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

Pharmacokinetics.

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

The main metabolites of the active substance of Paxil (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 the urine, with less than 2% of excreted paroxetine being unchanged. Approximately 36% of the administered dose of paroxetine is excreted in feces as metabolites.

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

The elimination half-life averages approximately 1 day.

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

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

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

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

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

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

Clinical characteristics.

Indications.

Adults

Major depressive disorder. Treatment of major depressive disorder.

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

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

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

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

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

Contraindications.

Hypersensitivity to paroxetine or to any other component of the drug.

Paxil should not be prescribed concomitantly 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 treatment. Similarly, MAOIs should not be used earlier than 2 weeks after discontinuation of Paxil (see section "Interaction with other medicinal products and other types of interactions").

The drug must not be used in combination with thioridazine, since, like other drugs that inhibit the hepatic enzyme CYP450 2D6, Paxil may increase thioridazine levels (see section "Interaction with other medicinal products and other types of interactions"). Use of thioridazine may cause QT interval prolongation associated with severe ventricular arrhythmia (e.g., torsades de pointes) and sudden death. Paxil must not be prescribed in combination with pimozide (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Serotonergic drugs

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

Paxil should be used with caution and with careful monitoring of the patient's clinical status when administered together with serotonergic drugs such as L-tryptophan, triptans, tramadol, other serotonin reuptake inhibitors, lithium, fentanyl, buprenorphine, and St. John’s wort (Hypericum perforatum). Concomitant use of paroxetine and MAO inhibitors (including linezolid—a reversible non-selective MAOI antibiotic—and methylene blue (methylthioninium chloride)) is contraindicated (see section "Contraindications").

Pimozide

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

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

Neuromuscular blockers

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 continued treatment should be made according to clinical response (tolerability and efficacy).

Procyclidine

Daily use of paroxetine significantly increases serum procyclidine levels. 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 epileptic patients when used concomitantly with these drugs.

Ability of paroxetine to inhibit the CYP2D6 enzyme

Paxil, 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 concurrently 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 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 vivo studies showed that concomitant administration of Paxil and terfenadine—a substrate of the CYP3A4 enzyme—at steady-state plasma concentrations was not accompanied by any effect of Paxil on the pharmacokinetics of terfenadine. Similarly, in vivo studies on interaction did not reveal any effect of the drug on the pharmacokinetics of alprazolam, or vice versa. Concurrent administration of Paxil with terfenadine, alprazolam, and other drugs that are substrates of CYP3A4 is unlikely to be hazardous.

Clinical studies have shown that factors such as food, antacids, digoxin, propranolol, and alcohol have no or minimal effect (i.e., do not require dosage adjustment) on the absorption or pharmacokinetics of Paxil.

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

Oral anticoagulants.

Concomitant use of oral anticoagulants and paroxetine may result in a pharmacodynamic interaction that could increase anticoagulant activity and risk of bleeding. Therefore, paroxetine should be prescribed with caution to patients receiving oral anticoagulants.

Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and antiplatelet agents.

Concomitant use of nonsteroidal anti-inflammatory drugs/acetylsalicylic acid and paroxetine may result in a pharmacodynamic interaction that could increase the risk of bleeding. Paroxetine should be prescribed with caution together with drugs that affect platelet function or increase the risk of bleeding.

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 ideation in children and adolescents with major depressive and other psychiatric disorders. Clinical trial data show that adverse events related to suicidality (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behaviour, and irritability) occurred more frequently in children and adolescents treated with Paxil compared to placebo group (see section "Adverse reactions"). There is a lack of data on the safety of the drug in children and adolescents with regard to growth, development, cognitive and behavioural characteristics.

Worsening of clinical condition and suicide risk in adults.

Young adults, especially those with major depressive disorders, may have an increased risk of suicidal behaviour during treatment with Paxil. According to the analysis of placebo-controlled clinical trials involving adult patients with psychiatric disorders, young adults (approximately 18–24 years of age) had a higher risk of developing suicidal behaviour compared to patients in the placebo group (17 out of 776 (2.19%) versus 5 out of 542 (0.92%)), although this difference was not statistically significant. No such increase in risk was observed in older patient groups (25–64 years and ≥65 years). In patients with major depressive disorders (of any age) treated with Paxil, a statistically significant increase in the frequency of suicidal behaviour was observed compared to the placebo group (11 out of 3455 (0.32%) versus 1 out of 1978 (0.05%)); all these cases were suicide attempts. However, most of these attempts (8 out of 11) during Paxil treatment occurred in young adult patients aged 18–30 years. These data on the treatment of major depressive disorders suggest that the higher risk of such complications observed in younger patients with psychiatric disorders may extend to patients up to 24 years of age.

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

Other psychiatric disorders for which Paxil is prescribed may also be associated with an increased risk of suicidal behaviour, and such disorders may coexist with major depressive disorders. Additionally, patients with a history of suicidal behaviour and corresponding intentions, younger patients, and those with persistent suicidal ideation prior to the start of treatment are at higher risk for suicide attempts and suicidal thoughts. All patients should be closely monitored for worsening clinical condition (including the development of new symptoms) and suicidality during treatment, especially at the beginning of therapy or during dosage adjustments (both increases and decreases).

Patients (and caregivers) should be warned about the need for continuous monitoring for any worsening of condition (including the development of new symptoms) and/or emergence of suicidal ideation/behaviour or thoughts of self-harm, and to seek immediate medical help if such symptoms appear. It should be understood that the appearance of certain symptoms such as agitation, akathisia, or mania may be related either to the progression of the disease or to the course of treatment (see "Akathisia", "Mania and bipolar disorder" below, section "Adverse reactions").

Consideration should be given to changing the therapeutic regimen, including discontinuation of the drug, in patients whose clinical condition worsens (including the development of new symptoms) and/or who develop suicidal ideation/behaviour, especially if these symptoms are severe, occur suddenly, or were not part of the patient's previous symptom complex.

Akathisia.

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

Serotonin syndrome/neuroleptic malignant syndrome.

In isolated cases, treatment with Paxil may be associated with the development of serotonin syndrome or symptoms typical of 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 Paxil should be discontinued if such events occur (characterized by a combination of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations in vital signs, changes in mental status including confusion, agitation, extreme agitation progressing to delirium and coma), and supportive symptomatic therapy should be initiated. Paxil 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 and bipolar disorders.

A major depressive episode may be the initial manifestation of bipolar disorder. It is generally accepted (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 history of suicide attempts, bipolar disorders, and depression in family members. It should be noted that Paxil is not approved for the treatment of depression in bipolar disorder. As with other antidepressants, Paxil should be used with caution in patients with a history of mania.

Tamoxifen.

According to some studies, the efficacy of tamoxifen, measured by the risk of breast cancer recurrence/death, may be reduced when used concomitantly with Paxil, since paroxetine is an irreversible inhibitor of CYP2D6 (see section "Interaction with other medicinal products and other forms of interaction"). This risk increases with longer duration of concomitant use. When treating breast cancer with tamoxifen, an alternative antidepressant with minimal or no CYP2D6 inhibition should be prescribed.

Bone fractures.

Epidemiological studies on the risk of bone fractures have reported an association with the use of certain antidepressants, including selective serotonin reuptake inhibitors. 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 Paxil.

Monoamine oxidase inhibitors (MAOIs).

Treatment with Paxil should be initiated cautiously, no sooner than 2 weeks after discontinuation of MAOIs; 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 with concomitant treatment of paroxetine and pravastatin.

Epilepsy.

Paxil, like other antidepressants, should be used with caution in patients with epilepsy.

Seizures.

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

Electroconvulsive therapy.

There is limited clinical experience with the use of Paxil in combination with electroconvulsive therapy.

Glaucoma.

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

Hyponatremia.

Cases of hyponatremia have occasionally been reported, mostly in elderly patients. Symptoms of hyponatremia usually resolve after discontinuation of Paxil.

Haemorrhage.

Skin and mucous membrane bleeding (including gastrointestinal and gynaecological bleeding) have been observed after treatment with Paxil. Therefore, Paxil should be used with caution in patients who are concurrently receiving drugs that increase the risk of bleeding, as well as in patients with frequent bleeding or a tendency to bleeding. Elderly patients may have an increased risk of non-menstrual bleeding. SSRIs/SNRIs (selective serotonin reuptake inhibitors/norepinephrine reuptake inhibitors) may increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions").

Cardiac disorders.

Standard precautions should be observed when treating patients with concomitant cardiac disorders.

Symptoms observed in adults upon discontinuation of Paxil.

Clinical trial data show that adverse reactions upon discontinuation of Paxil occurred in 30% of adult patients compared to 20% of patients receiving placebo. The emergence of discontinuation symptoms does not indicate drug dependence or addiction due to abuse.

Reported symptoms include dizziness, sensory disturbances (including paraesthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, 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, but there have been isolated cases of such symptoms 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 Paxil be gradually reduced over several weeks or months, depending on individual patient characteristics, when discontinuing treatment (see section "Dosage and administration").

Symptoms observed in children and adolescents upon discontinuation of Paxil.

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

Sexual dysfunction.

Selective serotonin reuptake inhibitors may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Cases of persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors have been reported.

Warning about excipients.

Sodium-containing compounds

One tablet contains less than 1 mmol (23 mg) of sodium, i.e. the preparation can be considered essentially "sodium-free".

Use during pregnancy or breastfeeding.

Fertility.

Some clinical studies have shown that selective serotonin reuptake inhibitors, including Paxil, 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 shown no teratogenic or embryotoxic effects.

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 data, the risk of giving birth to an infant with a cardiovascular defect in a woman treated with paroxetine during pregnancy is approximately 1 in 50, compared to an expected risk of approximately 1 in 100 in the general population.

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

Studies have shown an increased risk (less than 2-fold) of postpartum haemorrhage in women who took SSRIs/SNRIs within one month before delivery (see sections "Special precautions for use" and "Adverse reactions").

There are reports of preterm birth in women treated with Paxil or other selective serotonin reuptake inhibitors, although causal relationships with drug intake have not been established.

Newborns should be monitored if the mother continued taking Paxil during the third trimester of pregnancy, as there are reports of complications in newborns following maternal treatment with Paxil or other selective serotonin reuptake inhibitors during this period, although a causal relationship with drug intake 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, they occur immediately or shortly (<24 hours) after delivery.

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

Breastfeeding.

A small amount of Paxil is excreted in breast milk. No signs of drug effects on newborns have been observed; however, Paxil 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 or operating machinery.

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

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

Dosage and Administration.

General recommendations.

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

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

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

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

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

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

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

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

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

Post-traumatic stress disorder. The recommended dose is 20 mg once daily. For some patients in whom 20 mg is insufficient, the dose may be gradually increased by 10 mg daily, depending on clinical response, up to a maximum of 50 mg daily.

Discontinuation of Paxil.

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

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

Children. Paxil is not indicated for use in children.

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

Children.

Paxil is not indicated for use in children.

Based on results from controlled clinical trials, efficacy has not been demonstrated, and there is no supporting evidence for the use of Paxil in children with depression. The safety and efficacy of the drug in children under 7 years of age have not been studied.

Overdose.

In cases of Paxil 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, agitation, and tachycardia.

These effects generally resolved without serious consequences, even after ingestion of doses up to 2000 mg. Coma or ECG changes have occasionally been reported; fatal outcomes are very rare and have mostly occurred when Paxil was taken concomitantly with other psychotropic drugs and sometimes with alcohol.

There is no specific antidote.

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

Adverse Reactions

The adverse effects listed below are classified by system organ class and frequency of occurrence. Frequency is defined as: 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 fatal 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: there are reports of altered glycemic profile in patients with diabetes mellitus (see section "Special precautions").

Rare: hyponatremia. Hyponatremia is mainly observed in elderly patients and is sometimes associated with the 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).

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

Eye.

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.

Respiratory system.

Common: yawning.

Gastrointestinal system.

Very common: nausea.

Common: constipation, diarrhea, vomiting, dry mouth.

Very rare: gastrointestinal hemorrhage.

Frequency not known: microscopic colitis.

Hepatobiliary system.

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 been reported. Discontinuation of paroxetine should be considered if elevated liver function tests persist.

Skin and subcutaneous tissue.

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 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.

There is a reported risk of postpartum hemorrhage during treatment with SSRIs/SNRIs (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

Musculoskeletal system.

Rare: arthralgia, myalgia.

Epidemiological studies, conducted primarily in patients aged 50 years and older, suggest an increased risk of bone fractures in patients receiving SSRIs (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 associated with discontinuation of the drug.

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

Uncommon: agitation, nausea, tremor, confusion, sweating, diarrhea, emotional lability, visual disturbances, palpitations, restlessness.

As with other drugs used to treat psychiatric disorders, discontinuation of Paxil (especially abrupt discontinuation) may lead to 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 the occurrence of these symptoms; therefore, if discontinuation of Paxil treatment is necessary, the dose should be gradually reduced (see sections "Dosage and administration" and "Special precautions").

Adverse reactions observed in clinical trials in pediatric patients.

In clinical trials involving pediatric patients, the following adverse effects were observed (with an incidence of at least 2% and occurring at twice the rate compared to the placebo group): emotional lability (including self-harm, suicidal thoughts, suicidal threats with crying, and mood changes), hostility, decreased appetite, tremor, increased sweating, hyperkinesia, and agitation. Suicidal thoughts and suicide attempts were observed primarily during clinical trials in the treatment of adolescents with depressive disorders. Hostility was observed mainly in children with obsessive-compulsive disorder, particularly in children under 12 years of age.

In studies using a tapering regimen (reducing the daily dose by 10 mg/day weekly until reaching 10 mg/day over one week) or after discontinuation of the drug, the following symptoms were observed (with an incidence of at least 2% and occurring at twice the rate compared to the placebo group): emotional lability, nervousness, dizziness, nausea, and abdominal pain (see section "Special precautions").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients can report suspected adverse reactions to GSK Ukraine LLC via the 24-hour hotline (044) 585-51-85 or by email at [email protected].

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of the reach of children.

Packaging.

14 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Delpharm Poznan S.A., Poland.

Delpharm Poznan S.A., Poland.

Manufacturer's address.

189 Grunwaldzka Str., 60-322 Poznan, Poland.