Paroxetine

Pharmacological properties

Paxil is a potent selective 5-hydroxytryptamine reuptake inhibitor (5-nt, serotonin). its antidepressant effect and effectiveness in the treatment of obsessive-compulsive and panic disorders are due to the specific inhibition of the capture of 5-hydroxytryptamine by brain neurons. in its chemical structure, paxil differs from tricyclic, tetracyclic and other known antidepressants.

The drug has a low affinity for M-cholinergic receptors. The drug has a slight affinity for α₁-, α₂- and β-adrenergic receptors, dopamine (D₂), 5-NT₁-, 5-NT₂- and histamine (N₁-) receptors. It does not affect the psychomotor function and does not enhance the inhibitory effect of ethanol.

It does not negatively affect the function of the cardiovascular system: it does not cause a decrease in blood pressure, changes in heart rate and ECG parameters.

Paxil, in contrast to antidepressants, which inhibit the neuronal uptake of norepinephrine, has a much lesser effect on the hypotensive effect of guanethidine.

Pharmacokinetics After oral administration, it is rapidly absorbed and metabolized in the liver. The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are rapidly excreted from the body. About 64% of paroxetine is excreted in the urine, while in unchanged form - 2%. About 36% of the dose taken is excreted in the feces. Thus, the drug is almost completely excreted in the form of metabolites.

Paroxetine metabolites are excreted in 2 stages - first by metabolism of the first passage through the liver, and then by systemic excretion of paroxetine. T_½ averages about 1 day.

The equilibrium concentration in the blood is reached 7-14 days after the start of treatment and in the future, with continued therapy, remains practically unchanged.

No correlation was found between the concentration of the drug in plasma and clinical effects (therapeutic efficacy and incidence of side effects).

Due to the presystemic metabolism of the drug, the amount of active substance entering the systemic circulation is less than the amount of the drug that is absorbed into the digestive tract. With an increase in a single dose or repeated use, the effect of partial saturation of the metabolic pathway of the primary passage through the liver occurs and a decrease in plasma clearance is observed. This leads to a disproportionate increase in the concentration of the drug in blood plasma and a change in pharmacokinetic parameters with the appearance of a nonlinear dependence. Nevertheless, this non-linearity is mostly insignificant and is observed only in those who, when the drug is administered in low doses, achieves a low concentration of the active substance in the blood plasma.

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

When administered in therapeutic doses, approximately 95% of paroxetine binds to plasma proteins. In elderly people and patients with renal or hepatic insufficiency, an increase in the concentration of the drug in blood plasma occurs, but it does not go beyond the concentration in healthy adults.

Indications

Adults

Depression. Treatment of depression of any type, including reactive and severe depression, as well as depression, accompanied by anxiety. In the case of a satisfactory response to treatment, its continuation is effective for the prevention of relapse of depression.

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

Panic disorder. Treatment of symptoms and prevention of recurrence of panic disorder with or without concomitant agoraphobia.

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

Generalized Anxiety Disorder. Treatment of symptoms and prevention of recurrence of generalized anxiety disorder.

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

Application

General recommendations. the drug is intended for oral use, it is recommended to take it once a day - in the morning with meals. the tablet should be swallowed without chewing.

As with all other antidepressant drugs, the dose must be carefully selected individually during the first 2-3 weeks of treatment, and then adjusted depending on the clinical manifestations.

The course of treatment should be long, sufficient to ensure that the symptoms are eliminated. This period can last several months in the treatment of depression, and with obsessive-compulsive and panic disorders - even longer. As with other medications for treating mental disorders, sudden withdrawal of the drug should be avoided.

Depression. The recommended dose is 20 mg / day. Some patients may require an increase in dose. This should be done gradually, increasing the dose by 10 mg (up to a maximum of 50 mg / day), depending on the clinical effectiveness of the treatment.

Obsessive-compulsive disorder. The recommended dose is 40 mg / day. Treatment begins with a dose of 20 mg / day, then every week it is increased by 10 mg. In some patients, improvement is observed only when used in a maximum daily dose of 60 mg.

Panic disorder. The recommended dose is 40 mg / day. Treatment begins with an initial dose of 10 mg / day, then every week it is increased by 10 mg, depending on the clinical effect. The condition of some patients improves only when used in a maximum daily dose of 50 mg. To reduce the risk of increasing the severity of symptoms of panic disorder, which are often observed at the beginning of treatment for this disease, it is recommended to start treatment with a low dose of the drug.

Social phobias / social anxiety disorders. Generalized Anxiety Disorder. Post-traumatic stress disorder. The recommended dose is 20 mg / day. For some patients, the dose can be gradually increased by 10 mg / day, depending on the clinical effect of the treatment, to 50 mg / day. The interval between increasing doses should be at least 1 week.

Drug withdrawal. As with other psychotropic drugs, sudden withdrawal of the drug should be avoided. In clinical trials, a gradual withdrawal regimen was used, which included a 10 mg / day daily dose reduction with an interval of 1 week. After reaching a dose of 20 mg / day, patients took the drug in this dose for another 1 week before its complete cancellation. In case of withdrawal symptoms during the period of dose reduction or after withdrawal of therapy, it is necessary to resolve the issue of resuming treatment in the previous dose. Later, you can continue to reduce the dose, but more gradually.

Elderly patients. Start treatment with the usual initial dose for adults, which can then be gradually increased to 40 mg / day.

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

Renal and liver failure. In patients with severe renal failure (creatinine clearance - 30 ml / min) or liver failure, an increase in the concentration of paroxetine in the blood plasma is noted. Therefore, for such patients, the dose should be reduced to the lower limit of the dosage range.

Contraindications

Hypersensitivity to paroxetine or any other component of the drug.

Paxil should not be prescribed simultaneously with MAO inhibitors, including linezolid, an antibiotic that is a reversible non-selective MAO inhibitor and methylthionine (methylene blue), and not earlier than 2 weeks after discontinuation of treatment with MAO inhibitors (see INTERACTIONS).

Similarly, MAO inhibitors can be used no earlier than 2 weeks after stopping treatment with Paxil.

The drug cannot be used in combination with thioridazine, since, like other drugs that suppress the hepatic enzyme CYP 2D6, Paxil can increase thioridazine levels (seeINTERACTIONS). Thioridazine can cause a prolonged Q – T interval with associated severe ventricular arrhythmias (eg, torsades de pointes) and sudden death. Paxil cannot be prescribed in combination with pimozide (see INTERACTIONS).

Side effects

The side effects listed below are classified by organ and system and by frequency of occurrence. frequency is determined: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1/1000), very rarely (1/10 000), including isolated cases.

Blood and lymphatic system: rarely - increased bleeding mainly of the skin and mucous membranes (mainly ecchymosis); very rarely - thrombocytopenia.

Immune system: very rarely - allergic reactions (including urticaria and angioedema).

Endocrine system: very rarely - a syndrome caused by insufficient secretion of antidiuretic hormone.

Metabolism and digestive disorders: often - increased cholesterol, decreased appetite; rarely - hyponatremia. Hyponatremia is mainly observed in elderly patients and is sometimes associated with a syndrome caused by insufficient secretion of antidiuretic hormone.

Mental disorders: often - drowsiness, insomnia, agitation, abnormal dreams (including nightmares); infrequently - confusion, hallucinations; rarely - manic reactions, anxiety, depersonalization, panic attacks, akathisia; frequency unknown - suicidal ideation and suicidal behavior.

Symptoms that may be due to the underlying disease

Nervous system: often - dizziness, tremor, headache; infrequently - extrapyramidal disorders; rarely - convulsions, akathisia, restless legs syndrome; very rarely - serotonin syndrome (may include agitation, confusion, hyperhidrosis, hallucinations, hyperreflexia, myoclonus, tachycardia and tremor).

Extrapyramidal disorders, including orofacial dystonia, are noted in patients with motor disorders or in patients receiving treatment with antipsychotics.

Organ of vision: often - blurred vision; rarely - mydriasis (see SPECIAL INSTRUCTIONS); very rarely - acute glaucoma.

Hearing organ: frequency unknown - ringing in the ears.

Cardiovascular system: rarely - sinus tachycardia, postural hypotension, transient increase or decrease in blood pressure; rarely - bradycardia.

Respiratory system: often - yawning.

Digestive system: very often - nausea; often - constipation, diarrhea, vomiting, dry mouth; very rarely - gastrointestinal bleeding.

Hepatobiliary system: rarely - increased levels of liver enzymes; very rarely - liver disorders (such as hepatitis, sometimes with jaundice and / or liver failure).

Skin and subcutaneous tissue: often - increased sweating; rarely - skin rashes, itching; very rarely - severe skin adverse reactions (including polymorphic erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis), photosensitivity.

Urinary system: rarely - urinary retention, urinary incontinence.

Reproductive system: very often - sexual dysfunction; rarely - hyperprolactinemia / galactorrhea; very rarely - priapism.

Musculoskeletal system: rarely - arthralgia, myalgia.

General disorders: often - asthenia, weight gain; very rarely - peripheral edema.

Symptoms due to discontinuation of the drug: often - dizziness, sensitivity disorders, sleep disorders, anxiety, headache; rarely - agitation, nausea, tremor, confusion, increased sweating, diarrhea, emotional instability, visual impairment, tachycardia, agitation.

As with other medications used to treat mental disorders, withdrawal of Paxil (especially sudden) can lead to symptoms such as dizziness, sensory disturbances (including paresthesia, electroshock and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, headache, tremor, confusion, diarrhea, sweating, tachycardia, agitation, emotional lability, visual disturbances. In most patients, these symptoms are mild or moderate and disappear without treatment. There is no special risk group for the occurrence of these symptoms, therefore, if it is necessary to discontinue treatment with Paxil, the dose should be reduced gradually (see APPLICATION and SPECIAL INSTRUCTIONS).

Side effects obtained during clinical trials on the use of the drug in children. When conducting clinical studies on the use of the drug in children, the following side effects were noted (with a frequency of at least 2% of patients, and with a frequency of occurrence 2 times higher compared with the placebo group): emotional lability (including self-harm, suicidal thoughts, crying with threats of suicide and mood changes), hostility, loss of appetite, tremors, increased sweating, hyperkinesia and agitation. Suicidal thoughts and suicide attempts were identified mainly in clinical trials in the treatment of adolescents with depressive disorders. Hostility was noted mainly in children with obsessive-compulsive disorder, especially under the age of 12 years.

When conducting studies using the regime of gradual dose reduction (reduction of the daily dose by 10 mg / day with an interval of 1 week to a dose of 10 mg / day for a week) or after discontinuation of the drug, such symptoms were detected (with a frequency of not less than 2% of patients and with a frequency of occurrence 2 times higher compared with the placebo group): emotional lability, nervousness, dizziness, nausea and abdominal pain (see SPECIAL INSTRUCTIONS).

special instructions

Children and teens. antidepressant treatment is associated with an increased risk of suicidal behavior and thoughts in children and adolescents with severe depressive and other mental disorders. according to clinical studies, side effects associated with suicidal ideation (suicide attempts and suicidal thoughts) and hostility (mainly aggressiveness, counteracting behavior and irritability) were noted more often in children and adolescents treated with paxil compared with the placebo group (see side effects). there are no results on the safety of the drug in children and adolescents in relation to growth, development, cognitive and behavioral characteristics.

Deterioration of the clinical condition and risk of suicide in adults. Young adults, especially patients with severe depressive disorder, may have an increased risk of suicidal behavior during treatment with Paxil. According to an analysis of placebo-controlled clinical trials involving adult patients with mental disorders, it was shown that young adults (18-24 years old) showed a greater risk of developing suicidal behavior than patients in the placebo group (17/776 - 2.19 % compared with 5/542 - 0.92%), although this difference is not statistically significant. In the group of older patients (25–64 years and older than 65 years), such an increase in risk was not recorded. In patients with severe depressive disorders (of any age) who used Paxil, there was a statistically significant increase in the frequency of suicidal behavior compared with the placebo group (11/3455 - 0.32% compared with 1/1978 - 0.05%, all of these cases were suicide attempts).However, most of these attempts (8 out of 11) in the treatment with Paxil have been observed in adult young patients aged 18-30 years. These data on the treatment of major depressive disorders suggest that the high risk of these complications, which was identified in the group of young patients with mental disorders, may extend to patients over the age of 24 years.

In patients with depressive disorders, symptoms of depression may worsen and / or suicidal thinking and behavior (suicidality) may form, regardless of whether they take antidepressants or not. This risk persists until significant remission occurs. A common clinical experience with treatment for all courses of antidepressants is that the risk of suicide may increase in the early stages of recovery.

Other mental disorders for which Paxil is prescribed may be associated with an increased risk of suicidal behavior, and such disorders may also be associated with major depressive disorders. In addition, patients with suicidal behavior and intentions in the past, young patients and patients with a constant suicidal mood before starting treatment are a high-risk group for suicide attempts and suicidal thoughts. All patients should be closely monitored to detect deterioration in clinical condition (including the development of new symptoms) and suicidality during treatment, especially at the beginning of treatment or when a dose is changed (both increase and decrease).

Patients (and those who care for them) should be warned about the need for constant monitoring of any aggravation of the patients condition (including the development of new symptoms) and / or the appearance of suicidal intentions / behavior or thoughts of harming themselves and immediately seek medical help if they appearances. It should be understood that the onset of certain symptoms, such as agitation, akathisia, or mania, can be associated with both the course of the disease and the course of treatment (see Akatisia, Mania and Bipolar Disorder, ADVERSE EFFECTS).

Consideration should be given to changing the treatment regimen, including discontinuing the drug in patients with a clinical deterioration (including the development of new symptoms) and / or the appearance of suicidal intentions / behavior, especially if these symptoms are severe, occur suddenly, or are not part of the previous symptom complex of this patient .

Akathisia. Rarely, the use of Paxil or other selective serotonin reuptake inhibitors can be associated with the development of akathisia, a condition characterized by a feeling of internal anxiety and psychomotor agitation, such as the inability to sit quietly or stand in combination with a subjective feeling of discomfort. The likelihood of this is highest during the first weeks of treatment.

Serotonin / antipsychotic malignant syndrome. In rare cases, treatment with Paxil may be associated with the development of serotonin syndrome or symptoms characteristic of a neuroleptic malignant syndrome, especially when combined with other serotonergic and / or antipsychotic drugs. Since these syndromes can cause life-threatening conditions, treatment with Paxil should be discontinued when such phenomena occur (characterized by a combination of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid changes in the main indicators of the functional state of the body, changes in mental status, including confusion consciousness, irritability, extreme agitation with progressive delirium and coma) and prescribe a supportive symptomatic therapy.Paxil should not be used in combination with serotonin precursors (such as L-trypophan, oxytriptan) because of the risk of developing serotonergic syndrome (see CONTRAINDICATIONS and INTERACTIONS).

Mania and bipolar disorder. A major depressive episode may be the initial manifestation of bipolar disorder. It is generally accepted (although not supported by controlled clinical trials) that treating such episodes with antidepressants alone may increase the likelihood of accelerated occurrence of mixed / manic episodes in patients with an increased risk of developing bipolar disorder. Before starting treatment with antidepressants, patients should be carefully examined to identify any risk of developing bipolar disorder. Such an examination should include a detailed examination of the patient’s medical history, including the presence of suicidal attempts, bipolar disorders and depression in family members. Please note that Paxil is not approved for the treatment of depression in bipolar disorder. Like other antidepressants, Paxil should be used with caution in patients with a history of mania.

Tamoxifen. According to some studies, it was found that the effectiveness of tamoxifen, as measured by the risk of breast cancer recurrence / death, can be reduced while using Paxil because paroxetine is an irreversible inhibitor of CYP 2D6 (see INTERACTIONS). This risk increases with the duration of the combined use. In the treatment of breast cancer with tamoxifen, an alternative antidepressant is prescribed to the patient without significant or lack of CYP 2D6 inhibition.

Bone fractures. According to epidemiological studies examining the risk of bone fractures, some antidepressants, including selective serotonin reuptake inhibitors, have been reported to be associated with fractures. The risk arises during treatment and is significant in the initial stages of therapy. In the treatment of patients with Paxil, the possibility of bone fractures should be considered.

MAO inhibitors. Treatment with Paxil should be started with caution, not earlier than 2 weeks after the withdrawal of MAO inhibitors; the dose should be increased gradually - until the optimal response.

Renal / liver failure. It is recommended to use with caution in patients with severe renal or hepatic insufficiency.

Diabetes. In patients with diabetes mellitus, treatment with serotonin reuptake inhibitors can change the glycemic profile, so the dose of insulin and / or oral hypoglycemic drugs should be adjusted.

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

Bouts. In patients taking Paxil, the overall frequency of seizures is 0.1%.

In the event of a patient having seizures, the use of the drug Paxil should be discontinued.

Electroconvulsive therapy. Only insignificant clinical experience has been gained with the use of Paxil in combination with electroconvulsive therapy.

Glaucoma. Paxil, like other serotonin reuptake inhibitors, can cause mydriasis, so it should be used with caution in patients with angle-closure glaucoma.

Hyponatremia. Sometimes there have been cases of hyponatremia, mainly in the elderly. After discontinuation of the drug Paxil, the signs of hyponatremia basically disappeared.

Hemorrhages. After treatment with Paxil, hemorrhages in the skin and mucous membranes (including gastrointestinal bleeding) were detected.Therefore, Paxil should be used with caution in the treatment of patients simultaneously taking drugs that increase the risk of bleeding, as well as patients with frequent bleeding or predisposition to them.

Heart disease. When treating patients with concomitant heart disease, the usual measures should be followed.

Symptoms that are observed in adults with the withdrawal of the drug Paxil. According to clinical trials, in adults, adverse reactions during the withdrawal of treatment with Paxil occurred in 30% of patients compared with 20% who took placebo. The appearance of symptoms during drug withdrawal is not similar to the situation when addiction or dependence on the drug occurs in case of abuse.

Symptoms such as dizziness, sensory disturbances (including paresthesia, electroshock, and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremors, cramps, sweating, headache, and diarrhea have been reported. In general, these symptoms are mild or mild, although in some patients they may be more intense. They usually occur within the first few days after discontinuation of the drug, but isolated cases of the occurrence of these symptoms in patients who accidentally missed a single dose were reported. Typically, these symptoms disappear on their own within 2 weeks, although in some patients this process can be lengthy (2-3 months or longer). Therefore, it is recommended that when you cancel the drug Paxil, the dose should be reduced gradually, over several weeks or months, depending on the individual characteristics of the patient (see APPLICATION).

Symptoms detected in children and adolescents with the withdrawal of Paxil. According to clinical trials, in children and adolescents, side effects when discontinuing treatment with Paxil occurred in 32% of patients compared with 24% of patients taking placebo. After discontinuation of the drug Paxil, such side effects occurred (with a frequency of at least 2% of patients and with a frequency of occurrence 2 times higher compared with the placebo group): emotional lability (including suicidal intentions, suicide attempts, mood changes and tearfulness), nervousness dizziness, nausea, and abdominal pain (see ADVERSE EFFECTS).

Use during pregnancy and lactation

Fertility. Some clinical studies have shown that selective serotonin reuptake inhibitors, including Paxil, can affect sperm quality. It is believed that these phenomena disappear after discontinuation of treatment. Changes in sperm quality may affect the fertility of some men.

Pregnancy. According to animal studies, no teratogenic or embryotoxic effect was detected.

According to recent epidemiological studies on monitoring pregnancy results in women taking antidepressants in the first trimester of pregnancy, an increase in the risk of congenital developmental disorders, mainly from the cardiovascular system (for example, an atrial or interventricular septal defect) associated with paroxetine, has been reported. According to these data, it can be assumed that the risk of having a baby with a cardiovascular defect in a woman who took paroxetine during pregnancy is about 1:50 compared with the expected risk of such a defect in the general population, which is about 1: 100.

The doctor should consider the possibility of using alternative treatment for a pregnant woman or woman who plans to become pregnant, and prescribe paroxetine only when the expected benefit to the mother outweighs the potential risk to the fetus.In the case of a decision to discontinue treatment, a pregnant woman should consult the relevant sections of the instructions for use of medicines for additional information, which describes the doses and symptoms that occur when paroxetine is discontinued (see APPLICATION and SPECIAL INSTRUCTIONS).

Premature births in women taking Paxil or other selective serotonin reuptake inhibitors have been reported, although no causal relationship has been established with the drug.

Newborns should be examined if the pregnant woman continued to take Paxil in the third trimester of pregnancy, since there are reports of complications in newborns treated with Paxil or other selective serotonin reuptake inhibitors during this period, although a causal relationship with the drug has not been established. The following effects have been reported: respiratory distress syndrome, cyanosis, apnea, cramps, fluctuations in body temperature, feeding difficulties, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremors, trembling, agitation, lethargy, constant crying and drowsiness. In some reports, symptoms are described as neonatal manifestations of withdrawal. In most cases, they occur immediately or soon (24 hours) after childbirth.

According to epidemiological studies, the use of selective serotonin reuptake inhibitors (including paroxetine) in pregnant women, especially in late pregnancy, has been associated with an increased risk of developing persistent pulmonary hypertension in newborns. In women taking serotonin reuptake inhibitors in late pregnancy, this risk increased by 4–5 times compared with the general group of patients (1-2 cases per 1000 pregnant women in the general group of patients).

Lactation. A small amount of Paxil is excreted in breast milk. No signs of the effect of the drug on newborns have been identified, but Paxil should not be used during breastfeeding, unless the expected benefit to the mother outweighs the potential risk to the baby.

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

Based on the results of controlled clinical trials, efficacy has not been demonstrated and supporting data on the use of Paxil in children with depression have not been obtained. The safety and effectiveness of the drug in children under 7 years of age have not been investigated.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Experience in the use of Paxil in clinical practice suggests that this drug does not affect cognitive function or psychomotor reactions. However, as with other psychoactive drugs, patients should be warned of a possible impaired ability to drive vehicles or work with other mechanisms during treatment.

Interactions

Serotonergic drugs. as with other selective serotonin reuptake inhibitors, combined use with serotonergic drugs can lead to a 5-nt-associated effect (serotonin syndrome).

Paxil should be used with serotonergic drugs such as L-tryptophan, triptan, tramadol, other serotonin reuptake inhibitors, lithium, fentanyl and St. Johns wort herb (Hypericum perforatum) with caution and with careful careful monitoring of the patient’s clinical condition. The combined use of paroxetine and MAO inhibitors (including linezolid, an antibiotic that is a reversible non-selective MAO inhibitor, and methylthionine chloride (methylene blue)) is contraindicated (see CONTRAINDICATIONS).

Pimozide.According to a study on the combined use of a single low dose of pimozide (2 mg) and paroxetine, an increase in pimozide level was recorded. This was due to the well-known CYP D26-inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its ability to lengthen the Q – T interval, the simultaneous use of pimozide and paroxetine is contraindicated (see CONTRAINDICATIONS).

Enzymes involved in the metabolism of drugs. The metabolism and pharmacokinetic parameters of paroxetine may change under the influence of induction or inhibition of enzymes involved in the metabolism of drugs.

With the simultaneous use of paroxetine with drugs that inhibit enzymes, it is recommended to prescribe the minimum effective dose. With simultaneous use with drugs that induce enzymes (carbamazepine, rifampicin, phenobarbital, phenytoin), there is no need to change the initial dose of paroxetine. Changing the dose during subsequent treatment is necessary according to the clinical effect (tolerance and effectiveness).

Fosamprenavir / ritonavir. The combined use of fosamprenavir / ritonavir with paroxetine significantly reduces the plasma level of paroxetine. Changing the dose during subsequent treatment is necessary depending on the clinical effect (tolerance and effectiveness).

Procyclidine. With the daily use of paroxetine, the level of procyclidine in the blood plasma increases significantly. In case of anticholinergic effects, the dose of procyclidine should be reduced.

Anticonvulsants. Carbamazepine, phenytoin, sodium valproate. At