Rexetin^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter, Plc. (Hungary)

Packaging and Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Contact Information

GEDEON RICHTER, Plc. (Hungary)

ATC Code

N06AB05 (Paroxetine)

Active Substance

Paroxetine (Rec.INN registered by WHO)

Dosage Form

Rexetin®

Film-coated tablets, 20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; with a score on one side and an engraving ” on the other.

Excipients: magnesium stearate, sodium carboxymethyl starch (type A), hypromellose 2910, calcium hydrogen phosphate dihydrate.

Film coating composition polysorbate 80, macrogol 400, macrogol 6000, titanium dioxide (E171), hypromellose.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Psychoanaleptics, antidepressants; selective serotonin reuptake inhibitors

Pharmacological Action

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) reuptake. It is generally accepted that its antidepressant activity and efficacy in the treatment of obsessive-compulsive disorder and panic disorder are due to specific inhibition of serotonin reuptake in brain neurons.

Paroxetine differs in chemical structure from tricyclic, tetracyclic, and other known antidepressants.

Paroxetine has a weak affinity for muscarinic cholinergic receptors, and animal studies have shown that it possesses only weak anticholinergic properties.

Consistent with the selective action of paroxetine, in vitro studies have shown that it, unlike tricyclic antidepressants, has a weak affinity for α₁-, α₂-, β-adrenergic receptors, as well as for dopamine (D₂), 5-HT₁-like, 5HT₂, and histamine (H₁) receptors. The lack of interaction with postsynaptic receptors in vitro is confirmed by the results of in vivo studies, which demonstrated that paroxetine does not have the ability to depress the CNS and cause arterial hypotension.

Pharmacodynamic effects

Paroxetine does not impair psychomotor functions and does not enhance the depressant effect of ethanol on the CNS.

Like other selective serotonin reuptake inhibitors (SSRIs), Paroxetine causes symptoms of excessive stimulation of 5-HT receptors when administered to animals that have previously received MAO inhibitors or tryptophan. Behavioral and EEG assessment studies have demonstrated that Paroxetine causes weak activating effects at doses exceeding those required for serotonin reuptake inhibition. Its activating properties are not “amphetamine-like” in nature.

Animal studies have shown that Paroxetine does not affect the cardiovascular system.

In healthy individuals, Paroxetine does not cause clinically significant changes in blood pressure, heart rate, or ECG changes.

Studies have shown that, unlike antidepressants that inhibit norepinephrine reuptake, Paroxetine has a much lesser ability to inhibit the antihypertensive effects of guanethidine.

Pharmacokinetics

Absorption

After oral administration, Paroxetine is well absorbed and undergoes first-pass metabolism in the liver. Due to first-pass metabolism, a smaller amount of paroxetine enters the systemic circulation than is absorbed from the gastrointestinal tract. As the single dose of paroxetine increases or with repeated administration, partial saturation of the first-pass metabolic pathway occurs and the plasma clearance of paroxetine decreases. This leads to a disproportionate increase in paroxetine plasma concentrations, so its pharmacokinetic parameters are unstable, resulting in nonlinear kinetics. However, the nonlinearity is usually slight and is observed only in those patients in whom low plasma levels of paroxetine are achieved with low doses of the drug.

Steady-state plasma concentration is achieved within 7-14 days after starting treatment with paroxetine; its pharmacokinetic parameters are unlikely to change during long-term therapy.

Distribution

Paroxetine is widely distributed in tissues, and pharmacokinetic calculations show that only 1% of the total amount of paroxetine present in the body remains in the plasma.

At therapeutic concentrations, plasma protein binding is approximately 95%.

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

Metabolism

The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are easily eliminated from the body. Since these metabolites have virtually no pharmacological activity, it can be stated that they do not affect the therapeutic effects of paroxetine.

Metabolism does not impair paroxetine’s ability to selectively act on serotonin reuptake in neurons.

Elimination

The elimination half-life of paroxetine varies but is usually about 1 day. Less than 2% of the administered dose of paroxetine is excreted unchanged by the kidneys, while excretion as metabolites reaches 64% of the dose. About 36% of the dose is excreted through the intestines, probably entering it with bile; excretion of unchanged paroxetine through the intestines is less than 1% of the dose. Thus, Paroxetine is almost completely excreted as metabolites. The elimination of metabolites is biphasic: initially it is the result of first-pass metabolism, then it is controlled by the systemic elimination of paroxetine.

Pharmacokinetics in special patient groups

Elderly patients, patients with renal or hepatic impairment. In elderly patients, patients with severe renal impairment or hepatic impairment, the plasma concentration of paroxetine may increase, but the range of its plasma concentrations coincides with that in healthy adults.

Indications

The drug is indicated for use in adult patients aged 18 years and older for the treatment of the following conditions.

• Moderate and severe depressive episodes
• Recurrent depressive disorder

Results from studies in which patients took Paroxetine for up to 1 year indicate that it is effective in preventing relapse and return of depressive symptoms.

• Obsessive-compulsive disorder

Paroxetine is effective in the treatment of obsessive-compulsive disorder (OCD), including as maintenance and preventive therapy.

According to placebo-controlled studies, the effectiveness of paroxetine in the treatment of OCD was maintained for at least 1 year. In addition, Paroxetine is effective in preventing relapse of OCD.

• Panic disorder

Paroxetine is effective in the treatment of panic disorder with and without agoraphobia, including as maintenance and preventive therapy.

It has been found that in the treatment of panic disorder, the combination of paroxetine and cognitive behavioral therapy is significantly more effective than cognitive behavioral therapy alone.

According to placebo-controlled studies, the effectiveness of paroxetine in the treatment of panic disorder was maintained for more than 1 year. In addition, Paroxetine is effective in preventing relapse of panic disorder.

• Social phobia

Paroxetine is effective in the treatment of social phobia, including as long-term maintenance and preventive therapy.

Sustained efficacy of paroxetine in the long-term treatment of social phobia was demonstrated in a relapse prevention study.

• Generalized anxiety disorder

Paroxetine is effective in the treatment of generalized anxiety disorder, including as long-term maintenance and preventive therapy.

Sustained efficacy of paroxetine in the long-term treatment of generalized anxiety disorder was demonstrated in a relapse prevention study.

• Post-traumatic stress disorder

Paroxetine is effective in the treatment of post-traumatic stress disorder.

ICD codes

Dosage Regimen

The drug Rexetin^® is recommended to be taken once a day in the morning with food. The tablet should be swallowed whole, without chewing.

Moderate and severe depressive episodes and recurrent depressive disorder

The recommended dose is 20 mg/day. If necessary, the dose can be increased in 10 mg/day increments to a maximum dose of 50 mg/day depending on the clinical response. As with the treatment of any antidepressants, the effectiveness of therapy should be assessed and the dose adjusted if necessary after 2-3 weeks from the start of treatment and thereafter based on clinical indications.

Patients with depression should be treated for a sufficient period of time (at least 6 months) to achieve an asymptomatic state.

Obsessive-compulsive disorder (OCD)

The recommended dose is 40 mg/day. Treatment of patients should be started with a dose of 20 mg/day, which can be increased weekly by 10 mg/day. If the response is insufficient after several weeks at the recommended dose, some patients may benefit from a gradual increase in dose to a maximum dose of 60 mg/day.

Patients with OCD should be treated for a sufficient period of time to achieve an asymptomatic state. This period may be several months.

Panic disorder

The recommended dose is 40 mg/day. Treatment of patients should be started with a dose of 10 mg/day, which can be increased weekly by 10 mg/day depending on the clinical response. If the response is insufficient after several weeks at the recommended dose, some patients may benefit from a gradual increase in dose to a maximum dose of 60 mg/day.

A low starting dose is recommended to minimize the possible increase in panic disorder symptoms that may occur at the beginning of treatment for this disorder.

Patients with panic disorder should be treated for a sufficient period of time to achieve an asymptomatic state. This period may be several months or more.

Social phobia

The recommended dose is 20 mg/day. If necessary, for patients who do not respond at 20 mg/day, the dose may be increased in 10 mg/day increments to a maximum dose of 50 mg/day depending on the clinical response. Long-term use of the drug should be regularly evaluated.

Generalized anxiety disorder

The recommended dose is 20 mg/day. If the response is insufficient after several weeks at the recommended dose, some patients may benefit from a gradual increase in dose in 10 mg/day increments to a maximum dose of 50 mg/day. Long-term use of the drug should be regularly evaluated.

Post-traumatic stress disorder

The recommended dose is 20 mg/day. If the response is insufficient after several weeks at the recommended dose, some patients may benefit from a gradual increase in dose in 10 mg/day increments to a maximum dose of 50 mg/day. Long-term use of the drug should be regularly evaluated.

Discontinuation of paroxetine

As with treatment with other psychotropic drugs, abrupt discontinuation of paroxetine should be avoided. The regimen for gradual dose reduction used in recent clinical studies involved reducing the daily dose by 10 mg per week. After reaching a dose of 20 mg/day, patients continued to take this dose for 1 week, and only after that the drug was completely discontinued. If withdrawal symptoms develop during dose reduction or after discontinuation of the drug, it is advisable to resume the previously prescribed dose. Subsequently, the physician may continue to reduce the dose, but more slowly.

Special patient groups

Elderly patients. In elderly patients, plasma concentrations of paroxetine may be increased, but the range of its plasma concentrations coincides with that in younger patients. In this category of patients, therapy should be started at the dose recommended for adults. Dose increase may have a positive effect on some patients, but the maximum dose should not exceed 40 mg/day.

Patients with renal or hepatic impairment. Plasma concentrations of paroxetine are increased in patients with severe renal impairment (creatinine clearance less than 30 ml/min) and in patients with hepatic impairment. Such patients should be prescribed doses of the drug at the lower end of the therapeutic dose range.

Children and adolescents under 18 years of age. The use of paroxetine in children and adolescents under 18 years of age is contraindicated.

Rexetin^® should not be used in children and adolescents aged 7 to 17 years due to safety concerns related to an increased risk of suicidal behavior and hostility described in the “Adverse Reactions” and “Special Instructions” sections. The effectiveness of the drug Rexetin^® in children and adolescents from 7 to 17 years has not been established to date.

The use of paroxetine in children under 7 years of age has not been studied. The safety and efficacy of the drug Rexetin^® in children under 7 years of age have not been established to date.

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Adverse Reactions

The frequency and severity of some of the adverse reactions listed below may decrease with continued treatment, and such reactions usually do not require discontinuation of the drug.

Adverse reactions are classified by system-organ class and frequency using the following categories: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000), frequency not known (cannot be estimated from available data).

The incidence of common and uncommon adverse reactions was determined based on pooled safety data from more than 8000 patients who participated in clinical trials; the rate was calculated as the difference between the frequency of adverse reactions in the paroxetine group and the placebo group. The incidence of rare and very rare adverse reactions was determined based on post-marketing data, and this indicator reflects more the frequency of reports of such reactions than the true frequency of reactions.

Blood and lymphatic system disorders uncommon – abnormal bleeding, predominantly skin and mucosal hemorrhage (including ecchymosis and gynecological bleeding), leukopenia; very rare – thrombocytopenia.

Immune system disorders very rare – severe and potentially life-threatening allergic reactions (including anaphylactoid reactions and angioedema).

Endocrine disorders very rare – syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders common – increased cholesterol concentration, decreased appetite; uncommon – impaired glycemic control in patients with diabetes mellitus; rare – hyponatremia. Hyponatremia occurs predominantly in elderly patients and in some cases is due to the syndrome of inappropriate antidiuretic hormone secretion.

Psychiatric disorders common – drowsiness, insomnia, agitation, abnormal dreams (including nightmares); uncommon – confusion, hallucinations; rare – manic reactions, anxiety, depersonalization, panic attacks, akathisia; frequency not known – suicidal thoughts, suicidal behavior; frequency not known – aggression*, bruxism.

* cases of aggression were observed in the post-marketing period.

Cases of suicidal thoughts and suicidal behavior have been reported during treatment with paroxetine or early after discontinuation of treatment. These symptoms may also be due to the disease itself.

Nervous system disorders common – dizziness, tremor, headache, impaired concentration; uncommon – extrapyramidal disorders; rare – seizures, restless legs syndrome; very rare – serotonin syndrome (symptoms may include agitation, confusion, increased sweating, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia, and tremor). In patients with movement disorders or those who have used antipsychotics, the development of extrapyramidal symptoms, including orofacial dystonia, has been reported.

From the organ of vision common – blurred vision; uncommon – mydriasis; very rare – acute glaucoma.

From the ear and labyrinth disorders frequency unknown – tinnitus.

From the heart: uncommon – sinus tachycardia; rare – bradycardia.

From the vascular system: uncommon – transient increase and decrease in BP, postural hypotension. Transient increase and decrease in BP have been recorded after treatment with paroxetine, usually in patients with pre-existing arterial hypertension or anxiety.

From the respiratory system common – yawning.

From the GI tract very common – nausea; common – constipation, diarrhea, vomiting, dry mouth; very rare – gastrointestinal bleeding; frequency unknown – microscopic colitis.

From the liver and biliary tract rare – increased activity of liver enzymes; very rare – adverse reactions from the liver (such as hepatitis, sometimes accompanied by jaundice and/or liver failure).

Increased activity of liver enzymes has been reported. Post-registration reports of adverse reactions from the liver (such as hepatitis, sometimes accompanied by jaundice and/or liver failure) have been recorded very rarely. The question of the advisability of discontinuing treatment with paroxetine should be decided in cases where there is a prolonged increase in liver function test parameters.

From the skin and subcutaneous tissues common – increased sweating; uncommon – skin rashes, pruritus; very rare – photosensitivity reactions, severe skin reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), urticaria, .

From the kidneys and urinary tract uncommon – urinary retention, urinary incontinence.

From the reproductive system and breast very common – sexual dysfunction; rare – hyperprolactinemia/galactorrhea, menstrual cycle disorders (including menorrhagia, metrorrhagia, amenorrhea, delayed menstruation and irregular menstruation); very rare – priapism; frequency unknown – postpartum hemorrhage**

** This adverse event is registered as a class-effect for drugs of the SSRI/SNRI group (see section “Pregnancy and lactation”).

From the musculoskeletal system and connective tissue rare – arthralgia, myalgia.

Epidemiological studies, mainly conducted in patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving drugs of the SSRI group and tricyclic antidepressants. The mechanism leading to this risk is unknown.

General disorders common – asthenia, increased body weight; very rare – peripheral edema.

Symptoms occurring upon discontinuation of paroxetine treatment

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

Uncommon agitation, nausea, tremor, confusion, increased sweating, emotional lability, visual disturbances, palpitations, diarrhea, irritability.

As with the withdrawal of other psychotropic drugs, discontinuation of paroxetine treatment (especially abrupt) may cause symptoms such as dizziness, sensory disturbances (including paresthesia, electric shock sensations and tinnitus), sleep disorders (including vivid dreams), agitation or anxiety, nausea, headache, tremor, confusion, diarrhea, increased sweating, palpitations, emotional lability, irritability, visual disturbances. In most patients, these symptoms are mild or moderate and resolve spontaneously. No specific group of patients is known to be at increased risk of developing such symptoms; therefore, if treatment with paroxetine is no longer necessary, the drug dose should be reduced slowly until complete discontinuation.

Children

The following adverse reactions were observed in clinical studies involving children: emotional lability (including self-harm, suicidal thoughts, suicide attempts, crying and mood swings), bleeding, hostility, decreased appetite, tremor, increased sweating, hyperkinesia and agitation. Suicidal thoughts and suicide attempts were mainly observed in clinical studies involving adolescents with moderate to severe depressive episodes and recurrent depressive disorder. Increased hostility was noted, in particular, in children with obsessive-compulsive disorder, especially in children under 12 years of age.

In clinical studies with gradual reduction of the daily dose (the daily dose was reduced by 10 mg per day at one-week intervals to a dose of 10 mg per day for one week), symptoms such as emotional lability, nervousness, dizziness, nausea and abdominal pain were recorded in at least 2% of patients during the reduction of the paroxetine dose or after complete withdrawal of the drug and occurred at least 2 times more often than in the placebo group.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to paroxetine or to any of the excipients included in the drug;
• Combination with MAO inhibitors. In exceptional cases, linezolid (an antibiotic that is a reversible non-selective MAO inhibitor) may be combined with paroxetine provided that acceptable alternatives to linezolid treatment are not available, and the potential benefit of using linezolid outweighs the risks of serotonin syndrome or neuroleptic malignant syndrome, as a reaction in a particular patient. Equipment for careful monitoring of serotonin syndrome symptoms and BP monitoring must be available;
  • Treatment with paroxetine is allowed:
    • 2 weeks after discontinuation of treatment with irreversible MAO inhibitors;
    • At least 24 hours after discontinuation of treatment with reversible MAO inhibitors (e.g., moclobemide, linezolid, methylthioninium chloride (methylene blue));
    • At least 1 week should elapse between discontinuation of paroxetine and initiation of therapy with any MAO inhibitor.
• Patients receiving treatment with drugs that can prolong the QT interval and also inhibit the activity of the hepatic isoenzyme CYP450 2D6, such as thioridazine or pimozide (see section “Drug Interactions”);
• Children and adolescents under 18 years of age. Controlled clinical studies of paroxetine in the treatment of moderate to severe depressive episodes and recurrent depressive disorder in children and adolescents did not prove its efficacy, therefore Paroxetine is not indicated for the treatment of this age group. The safety and efficacy of paroxetine have not been studied in patients of a younger age category (under 7 years).

Use in Pregnancy and Lactation

Pregnancy

Epidemiological studies of pregnancy outcomes when taking antidepressants in the first trimester indicate an increased risk of congenital anomalies, particularly of the cardiovascular system (e.g., ventricular and atrial septal defects), associated with the use of paroxetine. The mechanism leading to this risk is unknown. According to available data, the frequency of development of cardiovascular system defects with the use of paroxetine during pregnancy is approximately less than 1/50 compared to the expected incidence of such defects in the general population, which is approximately 1/100 newborns.

When prescribing paroxetine, the physician should consider the possibility of alternative treatment for pregnant women and women planning pregnancy. Paroxetine should be prescribed only if its potential benefit outweighs the possible risk. If a decision is made to discontinue paroxetine treatment during pregnancy, the physician should follow the recommendations in the sections “Dosage Regimen” (“Discontinuation of Paroxetine”) and “Special Instructions” (“Symptoms observed upon discontinuation of paroxetine treatment in adults”).

Reports of premature birth have been registered in women who received Paroxetine or other drugs of the SSRI group during pregnancy, but a causal relationship between the use of these drugs and premature birth has not been established.

Observational data indicate an increased (less than 2-fold) risk of postpartum hemorrhage after the use of drugs of the SSRI/SNRI group within one month before delivery.

Newborns whose mothers took Paroxetine in late pregnancy should be monitored, as there are reports of complications in newborns associated with the use of paroxetine or other SSRI drugs in the third trimester of pregnancy. However, a causal relationship between the mentioned complications and this drug therapy has not been confirmed. The described clinical complications included: respiratory distress syndrome, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, hypertonia, irritability, lethargy, constant crying and drowsiness. In some reports, the symptoms were described as neonatal manifestations of withdrawal syndrome. In most cases, the described complications occurred immediately after delivery or shortly after it (< 24 hours).

According to epidemiological studies, the use of SSRI drugs (including Paroxetine) during pregnancy, particularly in late stages, is associated with an increased risk of developing persistent pulmonary hypertension of the newborn. The increased risk is observed in children born to mothers who took SSRI drugs in late pregnancy and is 4-5 times higher than that observed in the general population (1-2 per 1000 pregnancies).

Results of animal studies indicate reproductive toxicity of the drug, but no direct adverse effect on pregnancy, embryonic and fetal development, childbirth or postnatal development has been established.

Breastfeeding period

Small amounts of paroxetine pass into breast milk. In published studies of breastfed infants, the concentration of paroxetine was undetectable (<2 ng/ml) or very low (<4 ng/ml). No signs of drug exposure were detected in the infants. Nevertheless, Paroxetine should not be taken during breastfeeding except in cases where its benefit to the mother outweighs the potential risks to the infant.

Fertility

According to animal studies, Paroxetine may affect sperm quality. Data from in vitro studies on human material may indicate some effect on sperm quality, however, case reports of the use of some drugs from the SSRI group (including Paroxetine) in humans have shown that the effect on sperm quality was reversible.

To date, no effect on human fertility has been observed.

Use in Hepatic Impairment

Plasma concentrations of paroxetine increase in patients with impaired liver function. Such patients should be prescribed doses of the drug in the lower part of the therapeutic dose range.

Use in Renal Impairment

Plasma concentrations of paroxetine increase in patients with severe renal impairment (creatinine clearance less than 30 ml/min). Such patients should be prescribed doses of the drug in the lower part of the therapeutic dose range.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

In elderly patients, plasma concentrations of paroxetine may be increased, but the range of its plasma concentrations coincides with those in younger patients. In this category of patients, therapy should be started with the dose recommended for adults, which can be increased to 40 mg/day.

Special Precautions

Clinical worsening and suicide risk in adults

Young patients, especially those with moderate to severe depressive episodes and recurrent depressive disorder, may be at increased risk of suicidal behavior during therapy with paroxetine.

An analysis of placebo-controlled studies in adults with mental illnesses indicates an increase in the frequency of suicidal behavior in young patients (in a prospectively defined age from 18 to 24 years) while taking paroxetine compared to the placebo group: 17/776 (2.19%) versus 5/542 (0.92%) respectively, although the observed difference was not statistically significant. In patients of older age groups (from 25 to 64 years and over 65 years), no increase in the frequency of suicidal behavior was observed. In adults of all age groups with moderate to severe depressive episodes and recurrent depressive disorder, a statistically significant increase in the frequency of suicidal behavior was observed during treatment with paroxetine compared to the placebo group (frequency of suicide attempts: 11/3455 (0.32%) versus 1/1978 (0.05%) respectively). However, the majority of these cases while taking paroxetine (8 out of 11) were reported in younger patients aged 18 to 30 years. Data obtained from a study involving patients with moderate to severe depressive episodes and recurrent depressive disorder may indicate an increased frequency of suicidal behavior in young patients, which may persist in patients over 24 years of age with various mental disorders.

In patients with depression, worsening of depressive symptoms and/or the emergence of suicidal thoughts and suicidal behavior (suicidality) may occur regardless of receiving antidepressants. This risk persists until significant remission is achieved. In general, clinical experience with all antidepressants shows that the risk of suicide may increase in the early stages of recovery. Other mental disorders for which Paroxetine is indicated may also be associated with an increased risk of suicidal behavior, and these disorders may also be comorbid with moderate to severe depressive episodes and recurrent depressive disorder.

Furthermore, patients with a history of suicidal behavior or suicidal thoughts, young patients, as well as patients with pronounced suicidal thoughts before starting treatment are at the greatest risk of suicidal thoughts or suicide attempts. It is necessary to ensure monitoring of all patients for timely detection of clinical worsening (including the development of new symptoms) and suicidality throughout the entire course of treatment, especially at the beginning of treatment or during changes in the drug dose (increase or decrease).

It is important to warn patients (and their caregivers) to monitor for worsening of their condition (including the development of new symptoms) and/or the emergence of suicidal behavior or thoughts of self-harm. If these symptoms occur, it is necessary to seek medical help immediately. It should be remembered that the appearance of symptoms such as agitation, akathisia or mania may be associated both with the underlying disease and be a consequence of the therapy used.

If symptoms of clinical worsening (including the development of new symptoms) and/or suicidal thoughts, and/or suicidal behavior occur, especially if they appear suddenly, increase in severity, or if the symptoms were not part of the previous symptom complex in this patient, it is necessary to reconsider the treatment regimen, up to drug withdrawal.

Akathisia

In rare cases, treatment with paroxetine or other SSRI drugs is accompanied by the occurrence of akathisia, which is manifested by a feeling of inner restlessness and psychomotor agitation, when the patient cannot sit or stand still; with akathisia, the patient usually experiences subjective discomfort. The likelihood of akathisia is highest in the first few weeks of treatment.

Serotonin syndrome, neuroleptic malignant syndrome

During treatment with paroxetine, serotonin syndrome or symptoms similar to neuroleptic malignant syndrome may rarely develop, particularly if Paroxetine is used in combination with other serotonergic drugs and/or antipsychotics. These syndromes can be potentially life-threatening, and therefore treatment with paroxetine should be discontinued if they occur (they are characterized by groups of symptoms such as hyperthermia; muscle rigidity; myoclonus; autonomic disorders with possible rapid changes in vital signs; changes in mental status, including confusion, irritability, extremely severe agitation, progressing to delirium and coma) and supportive symptomatic therapy should be initiated. Paroxetine should not be used in combination with serotonin precursors (such as L-tryptophan, oxitriptan) due to the risk of developing serotonin syndrome.

Mania and bipolar disorder

A major depressive episode may be the initial manifestation of bipolar disorder. It is generally accepted (although not proven by controlled clinical studies) that treating such an episode with an antidepressant alone may increase the likelihood of accelerated development of a mixed or manic episode in patients at risk for bipolar disorder. Before starting treatment with an antidepressant, thorough screening should be performed to assess the risk of bipolar disorder in a given patient; such screening should include a detailed psychiatric history, including data on family history of suicide, bipolar disorder and depression. It should be noted that Paroxetine is not intended for the treatment of a depressive episode within bipolar disorder. Like other antidepressants, Paroxetine should be used with caution in patients with a history of mania.

Tamoxifen

Some studies have shown that the efficacy of tamoxifen, assessed by the risk of breast cancer recurrence and mortality, may decrease when used concomitantly with paroxetine due to irreversible inhibition of the CYP2D6 isoenzyme by paroxetine. The risk may increase with long-term concomitant use. When using tamoxifen for the treatment or prevention of breast cancer, the possibility of using alternative antidepressants that do not have an inhibitory effect on the CYP2D6 isoenzyme or have this effect to a lesser extent should be considered.

Bone fractures

Epidemiological studies assessing the risk of bone fractures have revealed an association between bone fractures and the use of certain antidepressants, including drugs from the SSRI group. The risk was observed during the course of treatment with antidepressants and was maximal at the beginning of the treatment course. The possibility of bone fractures should be considered when using paroxetine.

Diabetes Mellitus

In patients with diabetes mellitus, treatment with SSRIs may affect glycemic control parameters. Adjustment of the insulin dose and/or oral hypoglycemic drugs may be required. Study data also suggest that the concomitant use of paroxetine and pravastatin may lead to an increase in plasma glucose levels.

MAO Inhibitors

Treatment with paroxetine should be initiated cautiously no earlier than 2 weeks after discontinuation of an irreversible MAO inhibitor or 24 hours after discontinuation of treatment with reversible MAOIs (RIMAs). The dose of paroxetine should be increased gradually until the optimal therapeutic effect is achieved.

Impaired Renal or Hepatic Function

Caution is recommended when using paroxetine in patients with severe renal impairment or patients with impaired hepatic function.

Epilepsy

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

Seizures

The frequency of seizures in patients taking Paroxetine is less than 0.1%. If a seizure occurs, treatment with paroxetine should be discontinued.

Electroconvulsive Therapy

There is only limited experience with the concomitant use of paroxetine and electroconvulsive therapy.

Glaucoma

Like other SSRIs, Paroxetine may cause mydriasis and should be used with caution in patients with narrow-angle glaucoma and in patients with a history of glaucoma.

Hyponatremia

Hyponatremia occurs rarely during treatment with paroxetine and predominantly in elderly patients. The drug should be prescribed with caution to patients at risk of hyponatremia, for example, associated with concomitant drug therapy and liver cirrhosis. After discontinuation of paroxetine, blood sodium levels usually return to normal.

Bleeding

Cases of bleeding from the skin and mucous membranes (including gastrointestinal and gynecological bleeding) have been reported in patients taking paroxetine. Therefore, Paroxetine should be used with caution in patients who are concurrently receiving drugs that increase the risk of bleeding, in patients with a known tendency to bleed, and in patients with conditions predisposing to bleeding. The use of drugs from the SSRI and SNRI (serotonin and norepinephrine reuptake inhibitors) groups may increase the risk of postpartum hemorrhage (see sections “Adverse Reactions” and “Pregnancy and Lactation”).

Heart Disease

When treating patients with heart disease, the usual precautions should be observed.

QT Interval Prolongation

Cases of QT interval prolongation have been reported in the post-marketing period. Paroxetine should be used with caution in patients

• With a history of QT interval prolongation;
• Taking antiarrhythmic or other drugs that may potentially prolong the QT interval;
• With relevant pre-existing heart conditions.

Additional information is provided in the “Contraindications” and “Drug Interactions” sections.

Symptoms Observed Upon Discontinuation of Paroxetine Treatment in Adults

According to the results of clinical trials in adults, the incidence of adverse reactions upon discontinuation of paroxetine was 30%, while the incidence of adverse reactions in the placebo group was 20%. The occurrence of withdrawal symptoms does not mean that the drug is addictive or causes dependence, as is the case with substances of abuse.

Withdrawal symptoms such as dizziness, sensory disturbances (including paresthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, confusion, increased sweating, headache, diarrhea, palpitations, emotional lability, irritability, and visual disturbances have been described. These symptoms are usually mild to moderate, but in some patients they may be severe. They usually occur within the first few days after discontinuation of the drug, but in very rare cases they occur in patients who have accidentally missed just a single dose. As a rule, the symptoms resolve on their own within 2 weeks, but in some patients they may persist longer (2-3 months or more). It is recommended to reduce the dose of paroxetine gradually, over several weeks or months before its complete discontinuation, depending on the needs of the individual patient.

Symptoms Observed Upon Discontinuation of Paroxetine Treatment in Children and Adolescents

According to the results of clinical trials in children and adolescents, the incidence of adverse reactions upon treatment discontinuation in patients taking Paroxetine was 32%, while the incidence of adverse reactions in the placebo group was 24%. After discontinuation of paroxetine, the following adverse reactions were reported in at least 2% of patients and occurred at least twice as often as in the placebo group: emotional lability (including suicidal thoughts, suicide attempts, mood changes, and crying), nervousness, dizziness, nausea, and abdominal pain.

Children and Adolescents (under 18 years)

The drug Rexetin^® should not be used in children and adolescents under 18 years of age. Treatment of children and adolescents with moderate to severe depressive episodes, recurrent depressive disorder, and other mental illnesses with antidepressants is associated with an increased risk of suicidal thoughts and suicidal behavior. In clinical trials, adverse reactions related to suicidality (suicide attempts and suicidal thoughts), hostility (predominantly aggression, conduct disorder, and anger) were observed more frequently in children and adolescents receiving Paroxetine than in patients of this age group who received placebo. Currently, there are no data on the long-term safety of paroxetine for children and adolescents concerning the effect of this drug on growth, maturation, and cognitive and behavioral development.

Sexual Dysfunction

SSRIs may cause symptoms of sexual dysfunction. There have been reports of symptoms of sexual dysfunction persisting even after discontinuation of SSRIs.

Effect on Ability to Drive and Operate Machinery

Clinical experience with paroxetine indicates that it does not impair cognitive and psychomotor functions. However, as with treatment with any other psychotropic drugs, patients should be especially careful when driving vehicles and operating machinery.

Overdose

Symptoms Available information on paroxetine overdose indicates its safety over a wide dose range. In cases of paroxetine overdose, in addition to the symptoms described in the “Adverse Reactions” section, fever, changes in blood pressure, involuntary muscle contractions, anxiety, and tachycardia have been observed. The condition of patients usually normalized without serious consequences even after a single dose of up to 2000 mg. Some reports have described symptoms such as coma and ECG changes; fatal outcomes have been very rare, usually in situations where patients took Paroxetine together with other psychotropic drugs and with alcohol (or without it).

Treatment A specific antidote for paroxetine is unknown. Treatment should include general measures used for overdose of any antidepressant. Administration of 20-30 g of activated charcoal may be considered to reduce the absorption of paroxetine, preferably within a few hours after the overdose. Supportive therapy and frequent monitoring of vital physiological parameters are indicated. Patient management should be conducted according to the clinical picture or in accordance with the recommendations of the national poison control center, if available.

Drug Interactions

Serotonergic Drugs

The use of paroxetine, like other SSRIs, concomitantly with serotonergic drugs may cause effects related to 5-HT receptors (serotonin syndrome). Caution should be exercised and careful clinical monitoring should be carried out when serotonergic drugs (such as L-tryptophan, triptans, tramadol, linezolid, methylthioninium chloride (methylene blue), SSRIs, lithium preparations, and preparations containing St. John’s wort (Hypericum perforatum)) are used concomitantly with paroxetine.

Concomitant use of paroxetine with MAO inhibitors, including linezolid (an antibiotic that is a reversible non-selective MAO inhibitor) and methylthioninium chloride (methylene blue), is contraindicated. For more details on exceptional cases of using paroxetine in combination with linezolid, see the “Contraindications” section.

Pimozide

In a study of the concomitant use of paroxetine (60 mg) and a single low dose of pimozide (2 mg), an average 2.5-fold increase in plasma pimozide concentration was recorded. This fact is explained by the known property of paroxetine to inhibit the CYP2D6 isoenzyme. Due to the narrow therapeutic range of pimozide and its known ability to prolong the QT interval, the concomitant use of pimozide and paroxetine is contraindicated.

Drug-Metabolizing Enzymes

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

When using paroxetine concomitantly with an inhibitor of drug-metabolizing enzymes, it is recommended to use paroxetine at a dose at the lower end of the therapeutic dose range. The initial dose of paroxetine is not adjusted if it is used concomitantly with a drug that is a known inducer of drug-metabolizing enzymes (e.g., carbamazepine, rifampicin, phenobarbital, phenytoin). Any subsequent adjustment of the paroxetine dose (after starting or stopping the enzyme inducer) should be determined by its clinical effect (tolerability and efficacy).

Fosamprenavir and Ritonavir

Concomitant use of fosamprenavir/ritonavir with paroxetine led to a significant decrease in plasma paroxetine concentration. Plasma concentrations of fosamprenavir/ritonavir during concomitant use with paroxetine were comparable to control values from other studies, indicating no significant effect of paroxetine on the metabolism of fosamprenavir/ritonavir. There are no data on the effect of long-term concomitant use of paroxetine with fosamprenavir/ritonavir. Any adjustment of the paroxetine dose should be determined by its clinical effect (tolerability and efficacy).

Procyclidine

Daily intake of paroxetine significantly increases plasma procyclidine concentration. If anticholinergic effects develop, the dose of procyclidine should be reduced.

Anticonvulsants

Concomitant use of paroxetine and anticonvulsants (carbamazepine, phenytoin, sodium valproate) does not affect their pharmacokinetic and pharmacodynamic profiles in patients with epilepsy.

Muscle Relaxants

SSRIs may reduce plasma cholinesterase activity, leading to an increased duration of neuromuscular blockade by mivacurium and suxamethonium.

Ability of Paroxetine to Inhibit the CYP2D6 Isoenzyme

Like other antidepressants, including other SSRIs, Paroxetine inhibits the hepatic CYP2D6 isoenzyme belonging to the cytochrome P450 system. Inhibition of the CYP2D6 isoenzyme may lead to increased plasma concentrations of concomitantly used drugs that are metabolized by this enzyme. Such drugs include some tricyclic antidepressants (e.g., amitriptyline, imipramine, clomipramine, nortriptyline, and desipramine), phenothiazine antipsychotics (perphenazine and thioridazine), risperidone, atomoxetine, some class 1C antiarrhythmics (e.g., propafenone and flecainide), and metoprolol.

The use of Paroxetine in combination with metoprolol is not recommended in heart failure due to the narrow therapeutic range of metoprolol for this indication.

The irreversible inhibition of the CYP2D6 isoenzyme system by paroxetine may lead to a decrease in plasma endoxifen concentration and a reduction in the effectiveness of tamoxifen.

CYP3A4

An in vivo interaction study evaluating the concomitant use of paroxetine and terfenadine, a substrate of the CYP3A4 isoenzyme, under steady-state conditions showed that Paroxetine does not affect the pharmacokinetics of terfenadine. In a similar in vivo interaction study, no effect of paroxetine on the pharmacokinetics of alprazolam was found, and vice versa. Concomitant use of paroxetine with terfenadine, alprazolam, and other drugs that are substrates of the CYP3A4 isoenzyme is not expected to have a negative impact on the patient.

Drugs Affecting Gastric pH

Clinical studies have shown that the absorption and pharmacokinetics of paroxetine are independent or practically independent (i.e., the existing dependence does not require dose adjustment) of

• Food intake;
• Antacids;
• Digoxin;
• Propranolol;
• Alcohol.

Alcohol

Paroxetine does not enhance the negative effects of alcohol on motor and mental functions, but as with other psychotropic drugs, alcohol consumption should be avoided during therapy with paroxetine.

Oral Anticoagulants

A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. Concomitant use of paroxetine and oral anticoagulants may increase anticoagulant activity and the risk of bleeding. Therefore, Paroxetine should be used with caution in the treatment of patients receiving oral anticoagulants.

NSAIDs, Acetylsalicylic Acid, and Other Antiplatelet Drugs

A pharmacodynamic interaction between paroxetine and NSAIDs/acetylsalicylic acid may occur. Concomitant use of paroxetine and NSAIDs/acetylsalicylic acid may increase the risk of bleeding.

Caution should be exercised when treating patients receiving SSRIs concomitantly with oral anticoagulants, with drugs that affect platelet function or 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 when treating patients with a history of bleeding disorders or conditions that may predispose to bleeding.

Pravastatin

Based on study data, it is assumed that concomitant use of paroxetine and pravastatin may lead to increased plasma glucose concentrations. Patients with diabetes mellitus taking Paroxetine and pravastatin may require adjustment of the dose of hypoglycemic drugs and/or insulin.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.