Pharmacological properties of the drug Rexetine
Paroxetine is a selective 5-hydroxytryptamine (serotonin) reuptake inhibitor. The mechanism of therapeutic action of paroxetine for depression, obsessive compulsive disorders, and panic disorders is based on inhibition of neuronal reuptake of serotonin. The chemical structure of paroxetine differs from tricyclic, tetracyclic and other antidepressants. After oral administration, paroxetine is well absorbed and undergoes first-pass metabolism. Absolute bioavailability due to saturation of primary metabolic pathways varies. Simultaneous administration with food does not affect the pharmacokinetics of the drug. When taken regularly at a dose of 20 mg/day, the concentration in the blood plasma is 12–90 ng/ml (average 41 ng/ml), and the time to reach maximum concentration is 3–7 hours (average 5 hours). Paroxetine is extensively distributed in body tissues, including central nervous system tissues (average volume of distribution is 10–20 l/kg body weight, only 1% of the drug remains in the blood plasma). At blood concentrations ranging from 100 to 400 ng/ml, about 93–95% of paroxetine is bound to plasma proteins. Metabolized mainly in the liver. The main metabolites are polarized and associated products of oxidation and methylation. The predominant forms are those associated with glucuronic acid or the sulfate group. The pharmacological activity of the main metabolite is about 1/50 of the activity of the parent compound. The metabolism of paroxetine is associated with the cytochrome P450 IID6 system. In some individuals, due to a genetic defect, the activity of this isoenzyme may be reduced. The nonlinearity of the pharmacokinetics of paroxetine is due to the saturation of the cytochrome P450 IID6 enzyme system. The half-life of paroxetine ranges from 6 to 71 hours, with an average of 1 day. Equilibrium concentration in the blood plasma is achieved 7–14 days after the start of therapy; subsequently, the pharmacokinetics do not change with prolonged therapy. About 64% of paroxetine is excreted in the urine (2% unchanged, 62% as metabolites); approximately 36% - with feces (bile), mainly in the form of metabolites, ≤1% - with feces unchanged.
Clinical effectiveness of the drug Rexetine (paroxetine) for anxiety spectrum disorders
Rumyantseva G.M., Stepanov A.L., Levina T.M., State Scientific Center for Social and Forensic Psychiatry named after. V.P. Serbsky, Moscow
Introduction
Anxiety-phobic disorders are among the most common mental disorders encountered in general medical practice (A.B. Smulevich, 1999).
The higher prevalence of anxiety spectrum disorders among the population compared to depressive disorders was also revealed in large epidemiological studies conducted in the last decades of the last century (D. Regier et al., 1998).
Anxiety and depression, according to a number of scientists, are not independent diseases, but only stages in the development of a single affective pathology, in which anxiety is a more adaptive manifesting syndrome (H. van Praag, 2000).
In the structure of anxiety spectrum disorders, phobic, obsessive, hypochondriacal, compulsive and other symptoms that are part of the anxiety syndrome or comorbid disorders often occupy a significant place.
In the process of studying the contingent of people turning to private medical centers specializing in the treatment of borderline mental disorders, it was revealed that anxiety-phobic disorders occupy one of the first places among the reasons for seeking help (F40-F48 ICD-10).
At the same time, a certain specificity of the content of phobic manifestations was noted. Patients experience difficulties in expressing/verbalizing their fears, since their content could be morally condemned, incomprehensible to others, regarded as a sign of a serious and dangerous mental illness, for example, fear of harming a child or another loved one, fear of possible pregnancy and childbirth, fear of infection venereal disease, fear of homosexual attraction and/or the possibility of such contacts, fear of not being able to resist urination or defecation in a public place, etc.
As a rule, patients, suffering for a long time from their painful experiences, were afraid to go to medical institutions and hid their fears from others, often resorting to the help of psychics, removing the evil eye and damage, or religious rituals. In cases where anxiety became severe or comorbid disorders (somatoform and depressive) were added, they sought help in private medical centers, where, in their opinion, medical confidentiality is better maintained, anonymity is guaranteed and greater attention, support and care from the doctor are possible.
Such conditions are most often regarded as specific (isolated) phobias. However, at the time of contacting a specialist, the phobia, as a rule, is accompanied by a pronounced affect of anxiety and often comorbid depressive, somatoform manifestations, and panic disorder. This study is devoted to a clinical study of the effectiveness of treatment of these disorders with an antidepressant from the group of selective serotonin reuptake inhibitors (SSRIs) Rexetine.
Materials and methods
Under our supervision were 20 sick women aged 25-37 years, whose condition could be assessed within the framework of the ICD-10 rubric F40.2 - isolated phobias.
All patients had higher or incomplete higher education; 3 had two higher educations. 18 patients were married or living together; 13 of them had children.
At the time of treatment, patients complained of obsessive experiences of contrasting content: in 11 people it was the fear of harming a child or husband, which was usually accompanied by a fear of sharp, piercing objects.
In 7 of these patients, the primary phobia was supplemented by the fear of going crazy and/or, having lost control of oneself, committing a ridiculous action: screaming, hitting, losing consciousness and being left without help, not being able to hold back urination.
3 patients had an obsessive fear of sexual attraction to members of the same sex.
In 6 patients, it was the fear of pregnancy and the possibility of carrying it to term due to the “state of their health” and the consequences for the “mental usefulness” of the unborn child.
The onset of phobic disorders in all patients is between the ages of 20-27 years.
In a clinical study, it was determined that half of the premorbid patients were close to accentuated personalities with anxious and anancastic character traits, prone to increased anxiety, responsibility, hypernormativity, doubts and fears, mainly of hypochondriacal content. Typically, these patients showed a tendency to obsessive fears regarding their health already in childhood. As a rule, these features became sharper after emotional shocks (serious illness and death of a close relative or peer, alcoholism of one of the parents, situations where children witnessed an accident or were exposed to the threat of violence).
The remaining patients did not have pronounced character accentuations and were distinguished by activity, purposefulness and were socially successful.
Their fears arose against the background of a long-term psychologically traumatic situation (disharmony in family or partner relationships, conflict at work) or shortly after acute stressful experiences (attack and violence, death of the first child, forced abortion, miscarriage, breakup).
The aggravation of painful manifestations occurred gradually either due to the addition of obsessions of other (hypochondriacal) content (fear of madness, stroke/heart attack, cancer), or due to increased anxiety and the appearance of depressive syndromes.
Despite the complexity of the clinical picture, the diagnosis of a specific phobia always came first, since for a long time the disease was limited only to these symptoms. Were comorbid in
In 9 cases there was panic disorder (F41.0), in 11 cases there was mixed anxiety-depressive disorder (F41.2).
Panic disorder occurred at the height of obsessive fears (for example, harming a child, losing consciousness on the street, on the eve of medical examinations). The structure of panic disorder included pronounced fear, bodily tension, vegetative-vascular and somatic components. The frequency and severity of panic attacks were insignificant, the conditions did not require emergency medical care, and patients coped with panic symptoms on their own or with the help of loved ones. In all patients, sleep was disturbed, dreams acquired a painful, anxious, depressing character. Avoidance behavior developed: patients stopped visiting places where there were sharp and piercing objects, subways, elevators, closed spaces, and avoided air travel.
In cases of the development of mixed anxiety-depressive disorder, the patients' condition was characterized by increased generalized anxiety. At the same time, there were equally somatic and mental components of anxiety. Then a depressed mood followed with irritability, insomnia, anhedonia, decreased appetite, and progressive loss of body weight.
The Hamilton Anxiety and Depression Scale and the Sheehan Phobia Scale were used to examine the patients.
All patients were prescribed rexetine (paroxetine) at an initial dose of 20 mg. The dose was increased to 40 mg as indicated after 1 week. 3 patients and at the 4-5th week of treatment in another 5 patients. During treatment, the patients did not change their usual life schedule and did not lose their ability to work.
In the 1st week of treatment, all patients received benzodiazepines (alprazolam, clonazepam) to correct acute feelings of anxiety, restlessness and characteristic insomnia. The dose was reduced and benzodiazepines were discontinued gradually by the end of the 2nd week.
The total duration of treatment was 5 weeks.
Results and discussion
The most sensitive to the effects of rexetine was the anxiety symptom complex.
Thus, already in the 1st week of treatment, some patients began to notice a decrease in bodily tension and feelings of internal trembling, sweating, the intensity of the feeling of incomplete inspiration decreased, and there was a tendency to improve sleep.
During the 2nd week, the regression of anxiety was more significant: influxes of painful thoughts and images of the main phobic experience (fear of going crazy/losing control, causing harm, etc.) were less intense and more rare; daily mood swings became less severe; manifestations of dissatisfaction, hostility and irritation towards the immediate environment softened.
It should be noted that the therapeutic effect occurs quite quickly. The most pronounced decrease in the intensity of anxious experiences and improvement in the well-being of patients was observed during the first 4 weeks. therapy with rexetine. Subsequently, the positive dynamics slowed down somewhat and became more gradual.
A decrease in the intensity and burden of the “mental chewing gum” followed after 2-3 weeks. along with a decrease in overall affective tension (sensual charge of experiences). Normalization of well-being to the initial, pre-painful state was observed starting from the 3-4th week of treatment.
Depressive symptoms began to reverse most significantly after 3 weeks. treatment: at first, patients reported a decrease in the constant feeling of weakness and fatigue, an increase in strength and the emergence of desires and interest in life. At this time, emotional revival and a decrease in motor and mental retardation were observed. There was also a reduction in anhedonic complaints (lack of pleasure from communication, sex, food, reading, creative hobbies, work; a feeling of apathy). By this time, the vegetative stabilizing effect of the drug appeared.
Patients (4 people) noted a decrease in the frequency of gastrointestinal discomfort: senestalgia in the intestinal area, belching with air, gas formation, morning diarrhea and the urge to urinate before leaving the house.
The dynamics of essential phobic manifestations should be especially emphasized.
If the first 2 weeks. the improvement was mainly due to the reduction of the anxiety symptom complex, then in the 3rd week of therapy a decrease in the frequency of occurrence of phobic experiences was noted. Patients could not remember their fears for most of the day; they appeared sporadically in the morning and evening hours. The strength of obsessive fears also decreased; they arose “on the periphery of consciousness,” without completely absorbing the patients’ attention. The most intense reduction was observed in the fear of madness, which was most closely associated with anxious affect. The lowest dynamics were noted for pregnancy phobia. The fear of causing harm to loved ones occupies an intermediate position in terms of therapeutic lability.
An almost complete reduction of phobias was achieved in 5 patients in whom the structure of the syndrome was complicated by a mixed anxiety-depressive disorder. In 12 patients, it was noted that the remaining phobic experiences were not emotionally saturated and were a “pale shadow” of those that existed before treatment. In 3 patients, despite the positive dynamics of painful symptoms, phobias remained unchanged, only their affective intensity decreased.
By the 4-5th week of treatment, 5 patients began to experience a “freezing” of the clinical picture - the absence of further positive dynamics, which required increasing the dose of the drug to 40 mg per day.
The most resistant to therapy remained the personal characteristics of patients: uncertainty, resentment, experience of one’s own imperfection, high personal anxiety. These experiences in most patients were long-term, latent, associated with the personality structure, and the patients adapted to them.
It should be noted that the majority of the patients we treated did not note the effect of excessive activation, “excitement,” restlessness and increased anxiety in the 1st week of treatment, characteristic of some SSRIs (fluoxetine, Paxil).
In the 1st week of treatment, 8 patients still reported increased difficulty falling asleep, frequent awakenings and greater irritability, which required the prescription of tranquilizers.
In 5 patients during the 1st and 2nd weeks. treatment, an increase in the phenomenon of sweating and a feeling of heat was noted, especially with excitement and when staying in stuffy rooms.
In no case did we observe neuroleptic symptoms (hypertonicity and hyperkinesis of the facial muscles and tongue, tremor, etc.) and significant phenomena of behavioral toxicity, as well as dysuria (given the fact that the sample of patients was female). However, 1 patient with a significant decrease in body weight (46 kg) and dysmenorrhea required a reduction in the dose of rexetine to 10 mg per day for 2 weeks. at the beginning of treatment.
Conclusion
The use of rexetine in dosages of 20-40 mg for isolated phobias with comorbid panic disorder (F41.0) and mixed anxiety-depressive disorder (F41.2) revealed the high effectiveness of the drug in relieving symptoms of anxiety and depression, as well as a pronounced antiphobic effect of paroxetine, which was shown in earlier works (S.N. Mosolov et al.).
The drug significantly alleviates the condition of patients, reduces the intensity and frequency of obsessive and phobic manifestations and improves the quality of life of patients. The distinct anxiolytic properties of rexetine with good tolerability make it possible to recommend it for use in outpatient practice for the treatment of isolated phobias with comorbid manifestations of panic disorder and mixed anxiety-depressive states.
References 1. Smulevich A.B., Ivanov S.V., Dubnitskaya E.B., Drobizhev M.Yu. // Smulevich A.B. Depression in general medical practice. - M.: Bereg, 2000. - P. 65-72. 2. Mosolov S.N., Smulevich A.B., Nuller Yu.L. and others. Use of the drug Paxil (Paroxetine) in the treatment of panic disorder (results of a Russian multicenter study). - M., 2003. 3. Praag HM van. Nosologomania: a disorder of psychiatry // World J. Biol. Psychiatry. - 2000. - 1. - 151-8. 4. Regier DA et al. Prevalence of anxiety disorders and their comorbidity with mood and addictive disorders // Br. J. Psychiatry. - 173 (Suppl. 34). - 24-8.
Use of the drug Rexetine
1 time per day, preferably in the morning during meals without chewing. As with therapy with other antidepressants, depending on the clinical condition of the patient, the dose of the drug can be changed after 2-3 weeks. The recommended daily dose for depression is 20 mg. As with other antidepressants, the effect in most cases develops gradually. Some patients may need to increase the dose of the drug. If necessary, the daily dose is increased weekly by 10 mg (until the effect is achieved); the maximum daily dose is 50 mg. The initial daily dose for OCD is 20 mg. If necessary, the dose is increased weekly by 10 mg until the required therapeutic effect is achieved. The usual dose is usually 40 mg/day and should not exceed 60 mg/day. The recommended therapeutic dose for panic disorder is 40 mg/day. Therapy should begin with a low dose (10 mg/day) with a weekly increase of 10 mg until the desired effect is achieved. The maximum daily dose is 60 mg. For social phobia, therapy begins with a dose of 20 mg/day. If after a 2-week course of treatment there is no significant improvement in the patient’s condition, the dose of the drug is increased weekly by 10 mg/day until the desired effect is achieved. The maximum daily dose is 50 mg. For maintenance therapy, 20 mg/day is usually sufficient. The recommended dose for PTSD is 20 mg/day; if necessary, it can be increased to a maximum of 50 mg/day. To prevent relapses, maintenance therapy is necessary. Its duration after the disappearance of symptoms of depression can be 6–8 months, and in case of obsessive and panic disorders, even more. As with the use of other psychotropic drugs, abrupt termination of the course of treatment should be avoided. Debilitated and elderly patients may experience elevated serum levels of the drug, so the recommended starting dose for them is 10 mg/day. If necessary, it is increased by 10 mg weekly. The maximum daily dose is 40 mg. In case of hepatic and renal failure (creatinine clearance ≤30 ml/min), the concentration of paroxetine in the blood plasma increases, therefore the recommended daily dose of the drug in such cases is 20 mg. This dose can be increased depending on the patient's condition, but one should limit the use of the drug to the minimum effective dose.
Rexetine, 30 pcs., 30 mg, film-coated tablets
Inside,
1 time per day, preferably in the morning, during meals, without chewing.
As with therapy with other antidepressants, depending on the clinical condition of the patient, the dosage of the drug can be changed after 2-3 weeks.
For depression:
The recommended daily dose is 20 mg. As with other antidepressants, the effect in most cases develops gradually. Some patients may require an increase in the dose of the drug. Depending on the patient’s response to therapy, the daily dose can be increased by 10 mg at intervals of 1 week until a therapeutic effect is achieved; the maximum daily dose is 50 mg.
For obsessive-compulsive disorders (obsessiveness syndrome):
the initial dose is 20 mg/day. The dose may be increased by 10 mg weekly until the desired therapeutic response is achieved. The maximum daily dose is usually 40 mg, but should not exceed 60 mg.
For panic disorders:
The recommended therapeutic dose is 40 mg/day. Therapy should begin with a small dose (10 mg/day), with a weekly increase in dosage by 10 mg/day until the desired effect is achieved. The maximum daily dose should not exceed 60 mg. The recommended low initial dose of the drug is due to the possibility of a temporary increase in the intensity of the symptoms of the disease at the beginning of therapy.
For social phobias:
Therapy can be started with a dose of 20 mg/day. If after a 2-week course of treatment there is no significant improvement in the patient's condition, the dose of the drug can be increased weekly by 10 mg until the desired effect is achieved. The maximum daily dose should not exceed 50 mg. For maintenance therapy, a daily dose of 20 mg is usually sufficient.
For generalized anxiety disorder:
The recommended therapeutic dose is 20 mg/day. Depending on the patient’s response to therapy, the daily dose can be increased gradually by 10 mg; the maximum daily dose is 50 mg.
For post-traumatic stress disorder:
The recommended therapeutic dose is 20 mg/day. Depending on the patient's response to therapy, the daily dose can be increased periodically by 10 mg, the maximum daily dose is 50 mg.
Depending on the clinical condition of the patient, maintenance therapy must be carried out to prevent possible relapses. This course, after the symptoms of depression disappear, can last 4–6 months, and for obsessive and panic disorders, even more. As with other psychotropic drugs, abrupt cessation of treatment should be avoided. In weakened and elderly patients, the level of the drug in the blood serum may increase above normal, so the recommended initial dose is 10 mg/day. This dose can be increased by 10 mg weekly, depending on the patient's condition.
The maximum dose should not exceed 40 mg/day.
The drug is not indicated for children due to lack of clinical experience.
In case of renal (Cl creatinine <30 ml/min) or liver failure, the concentration of paroxetine in the blood plasma increases, therefore the recommended daily dose of the drug in these cases is 20 mg. This dose can be increased depending on the patient's condition, but one should strive to maintain it at the lowest possible level.
Side effects of the drug Rexetine
The incidence and severity of side effects during therapy are reduced, so in most cases they do not require discontinuation of the drug. From the digestive tract: nausea (12%), sometimes - constipation, diarrhea, anorexia, rarely - increased liver function tests, extremely rarely - severe liver dysfunction. A cause-and-effect relationship between paroxetine and liver damage has not been proven, however, in case of liver dysfunction, it is recommended to discontinue use of paroxetine. From the side of the central nervous system : drowsiness (9%), tremor (8%), general weakness and increased fatigue (7%), insomnia (6%), in some cases - headache, increased irritability, paresthesia, confusion, somnambulism, rarely - extrapyramidal disorders and orofacial dystonia. Extrapyramidal disorders are noted mainly in cases where movement disorders are a symptom of an underlying disease, or with previous intensive use of antipsychotics. Epileptiform seizures, which are also common with other antidepressants, have been reported rarely. From the autonomic nervous system : sweating (9%), feeling of dryness in the mouth (7%). From the senses : in some cases - visual impairment, mydriasis, attacks of acute glaucoma. From the cardiovascular system: in some cases - tachycardia, ECG changes, vasodilation, blood pressure changes, fainting. From the genitourinary system: ejaculation disorders (13%), in some cases - other manifestations of sexual dysfunction, rarely - difficulty urinating. Electrolyte disturbances: hyponatremia with the development of edema, impaired consciousness or epileptiform symptoms was sometimes noted. After discontinuation of the drug, the level of sodium in the blood serum normalizes. In some cases, this condition developed due to overproduction of antidiuretic hormone. Most of these cases were observed in elderly patients who, in addition to paroxetine, received diuretics and other drugs. Dermatological reactions and hypersensitivity reactions: isolated cases of skin hyperemia, subcutaneous hemorrhages, swelling of the face and extremities, anaphylactic reactions (urticaria, bronchospasm, angioedema), itching have been described. Other: myopathy, myalgia, hyperglycemia, galactorrhea, hypoglycemia, fever and the development of influenza-like conditions were sometimes noted. Extremely rarely - thrombocytopenia; a cause-and-effect relationship with taking the drug has not been proven. Several cases of increased bleeding have been described. Taking paroxetine may be accompanied by an increase or decrease in body weight. Paroxetine is less likely to cause dry mouth, constipation, and drowsiness than tricyclic antidepressants. Sudden withdrawal of the drug can cause dizziness, sensory disturbances (paresthesia), a feeling of fear, sleep disturbances, agitation, tremor, nausea, sweating and confusion, so the drug should be discontinued gradually, and it is advisable to reduce the dose every other day.
Special instructions for the use of the drug Rexetine
In patients with a history of mania, the use of paroxetine may lead to a relapse. Paroxetine should be used with caution in patients with cardiovascular diseases; like other antidepressants, paroxetine should be used with caution if there is a history of epilepsy. In clinical observations, paroxetine caused the development of epileptiform seizures in 0.1% of cases. If such a complication develops, the drug should be discontinued. Patients with suicidal tendencies should be under medical supervision until a pronounced antidepressant effect of therapy develops. The likelihood of developing hyponatremia is increased in elderly patients with hypovolemia receiving diuretics. After discontinuation of paroxetine, serum sodium levels return to normal. In some cases, treatment with paroxetine was accompanied by increased bleeding (mainly manifested by ecchymosis and purpura). In these patients, a disorder of platelet aggregation was noted, apparently associated with the utilization of serotonin by platelets. Like other selective serotonin reuptake inhibitors, paroxetine can cause mydriasis and should be used with caution in patients with glaucoma. The use of paroxetine during pregnancy and lactation is possible only after assessing the degree of potential risk to the fetus and the expected therapeutic effect in the mother. According to some data, the use of selective serotonin reuptake inhibitors in the last trimester of pregnancy was accompanied by an increased incidence of preterm birth and other perinatal complications. Paroxetine passes into breast milk. No negative effect of paroxetine on psychomotor activity or cognitive function has been established, however, until an individual reaction to the drug is identified, especially at the beginning of the course of treatment, driving or other potentially hazardous activities should be avoided. Rarely, a hyperglycemic state may occur when taking paroxetine.
Instructions for use REXETIN®
Treatment with Rexetine® should be started with caution 2 weeks after stopping the use of irreversible MAO inhibitors, or 24 hours after stopping the reversible MAO inhibitor. The dose of paroxetine should be gradually increased until optimal effect is achieved.
Suicide/suicidal ideation or clinical worsening
Depression is associated with an increased risk of suicidal ideation, self-harm and suicide (suicidal acts and behavior). This risk persists until significant remission occurs. Since improvement may not occur for the first few weeks or more of use, patients should be under medical supervision until improvement occurs. Accumulated clinical experience suggests that the risk of suicide may increase in the early stages of recovery.
Other psychiatric disorders for which paroxetine is intended to treat may also be associated with an increased risk of suicidal behavior and behavior. In addition, these conditions may co-occur with major depressive disorder. The precautions that were observed in the treatment of patients with major depressive disorder should also be observed in the treatment of patients with other mental disorders.
Patients with a history of suicidal behavior or behavior or predominant suicidal ideation prior to treatment are known to be at significant risk for suicidal ideation or suicide attempts and should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with mental disorders demonstrated an increased risk of suicidal behavior with antidepressants compared with placebo in patients <25 years of age.
Drug treatment, especially in the early stages and after dose changes, should be accompanied by careful monitoring of patients, especially high-risk patients. Patients (and their caregivers) should be prepared to monitor for any sudden clinical deterioration, suicidal behavior or thoughts, and unusual changes in behavior. If these symptoms appear, you should consult a doctor immediately.
Akathisia/psychomotor agitation
Paroxetine has been associated with the development of akathisia, which is characterized by an internal feeling of restlessness and psychomotor restlessness, such as the inability to sit or stand quietly, and which is usually associated with a subjective feeling of discomfort. The risk of developing akathisia is highest in the first few weeks of treatment. In patients with these symptoms, the condition may worsen as the dose is increased.
Serotonin syndrome/NMS
In rare cases, serotonin syndrome or NMS may occur when paroxetine is taken, especially in combination with serotonergic and/or antipsychotic drugs. Because these syndromes can be potentially life-threatening, treatment with paroxetine should be discontinued if these signs (characterized by a group of symptoms such as pyrexia, stupor, myoclonus, autonomic nervous system disturbance with possible sudden fluctuations in vital signs, mental status changes including confusion) are present , irritability, extreme agitation progressing to delirium and coma) and supportive symptomatic therapy was started. Paroxetine should not be used in combination with serotonin precursors (such as L-tryptophan, oxytriptan) due to the risk of serotonin syndrome.
Mania
As with other antidepressants, paroxetine should be used with caution in patients with a history of manic episodes. Paroxetine should be discontinued in all patients experiencing acute manic episodes.
Kidney/liver failure
Caution should be exercised when using paroxetine in patients with severe renal or hepatic impairment.
Diabetes
In patients with diabetes, treatment with selective serotonin reuptake inhibitors (SSRIs) should be accompanied by glycemic control. Doses of insulin and/or oral hypoglycemic agents may need to be revised.
Epilepsy
Like all antidepressants, paroxetine should be used with caution in patients with epilepsy.
Convulsions
The incidence of seizures is less than 0.1% in patients taking paroxetine. If seizures occur, the drug should be discontinued by all patients.
Electroconvulsive therapy
There is insufficient clinical experience with the use of paroxetine in electroconvulsive therapy.
Glaucoma
Like other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with acute-angle glaucoma or a history of glaucoma.
Cardiac disorders
Patients with cardiac disorders should take the usual precautions.
Hyponatremia
Hyponatremia is rare, mainly in elderly patients. The drug should be prescribed with caution to patients at risk of hyponatremia, for example, with concomitant drug therapy and cirrhosis. Hyponatremia usually resolves completely when paroxetine is stopped.
Bleeding
There is evidence of skin hemorrhages, such as ecchymosis and purpura, with SSRIs. Other hemorrhagic manifestations, such as gastrointestinal bleeding, have also been observed. Elderly patients are at increased risk.
SSRIs should be used with caution concomitantly with oral anticoagulants, drugs that affect platelet function, or with other drugs that may increase the risk of bleeding (for example, atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, NSAIDs , COX-2 inhibitors), as well as in patients with bleeding episodes or conditions predisposing to bleeding.
Interaction with tamoxifen
Some studies have shown that the effectiveness of tamoxifen, as measured by the risk of recurrence/mortality from breast cancer, may be reduced when used concomitantly with paroxetine as a result of paroxetine's irreversible inhibition of the CYP2D6 isoenzyme. The concomitant use of paroxetine and tamoxifen used to treat or prevent breast cancer should be avoided if possible.
Withdrawal syndrome when stopping paroxetine
Withdrawal syndrome when stopping paroxetine is common, especially if patients stop taking the drug abruptly. Clinical studies found that 30% of patients experienced side effects when stopping paroxetine, compared with 20% of patients who experienced side effects when stopping placebo. The occurrence of withdrawal symptoms does not prove that the drug is addictive or addictive. The risk of withdrawal symptoms may depend on several factors, such as the duration of treatment, dose size, and rate of dose reduction.
Dizziness, sensory disturbances (including paresthesia, electric shock sensation, ringing in the ears), sleep disturbances (including intense dreams), agitation or restlessness, nausea, tremors, confusion, sweating, headache, diarrhea, rapid heartbeat, emotional instability, irritability and visual impairment. In general, these symptoms are mild to moderate, but may be severe in some patients. Symptoms usually occur within the first few days after stopping the drug, and very rarely in patients who accidentally missed taking the drug. Most symptoms go away on their own within 2 weeks, although in some patients they may last longer (2-3 months or more). Therefore, when stopping the drug, it is recommended to gradually reduce the dose over several weeks or months, according to the individual characteristics of the patient.
Alcohol
Although paroxetine does not exacerbate alcohol-induced psychomotor depression, as with other psychotropic drugs, concomitant use of Rexetine and alcohol should be avoided.
Use in pediatrics
Paroxetine should not be prescribed to children and adolescents under 18 years of age.
Suicidal behavior (suicide attempt and suicidal ideation) and hostility (primarily aggression, resistance, anger) were most frequently observed in clinical studies in children and adolescents treated with paroxetine compared with placebo. If a decision to prescribe a drug based on clinical need is made, the patient should be carefully monitored for the presence of suicidal symptoms. In addition, there is insufficient data from long-term studies on the safety of the drug in children and adolescents with regard to their growth, puberty, behavior, and cognitive development.
Impact on the ability to drive vehicles and operate machinery
Clinical studies have not revealed a negative effect of the drug Rexetine® on cognitive and psychomotor function. Despite this, as with other psychoactive drugs, patients should exercise caution in assessing their ability to drive or work in environments where there is an increased risk of injury.
Experimental results
Toxicological studies
were carried out on rhesus monkeys and albino rats. The metabolism of the drug in both groups of animals was similar to that in humans. Lipophilic amines, including tricyclic antidepressants, were hypothesized to induce phospholipidosis in rats. A one-year study of phospholipidosis found that the dose used was 6 times the recommended clinical dose range.
Carcinogenicity:
A two-year study of paroxetine did not show a carcinogenic effect of paroxetine.
Genetic toxicity:
no genetic toxicity was detected in in vivo and in vitro tests.
Reproductive toxicity:
Results from experiments in rats indicate that paroxetine affects the fertility of males and females. In rats, neonatal mortality was increased and ossification was delayed. Late effects were mostly related to maternal toxicity and did not have a direct effect on the fetus/newborn.
Drug interactions Rexetine
After completing a course of treatment with a MAO inhibitor, paroxetine therapy should be started cautiously, with low initial doses, gradually increasing the dose until the optimal effect is achieved. After completing the course of treatment with Rexetine, MAO inhibitors should not be prescribed for 2 weeks. Simultaneous administration of drugs or the absence of the required period of time between their use threatens the development of serotonergic reactions (nausea, vomiting, diarrhea, convulsions, tremor, hyperreflexia, impaired coordination of movements, profuse sweating, skin flushing, increased blood pressure, lethargy, drowsiness), which can sometimes be significantly expressed and lead to death. Neuroleptic malignant syndrome-like events have been reported rarely. When tryptophan and paroxetine are used simultaneously, headache, nausea, increased sweating, and dizziness are possible, so this combination should be avoided. There may be a pharmacodynamic interaction between paroxetine and warfarin (increased bleeding with unchanged prothrombin time), so paroxetine should be prescribed with caution to patients taking oral anticoagulants. In some cases of simultaneous use with sumatriptan, weakness, hyperreflexia, and coordination problems were noted. When using this combination, medical supervision is required. Undesirable interactions with tricyclic antidepressants are typical for all serotonin reuptake inhibitors. Since paroxetine can also inhibit the metabolism of tricyclic antidepressants via cytochrome P450 IID6, the dose of the latter should be reduced . Use with caution in combination with antipsychotics (extrapyramidal disorders are possible). When used simultaneously with lithium salts, regularly monitor the level of lithium in the blood serum. Inducers or inhibitors of liver microsomal enzymes may affect the pharmacokinetics of paroxetine. Like other antidepressants that are metabolized by cytochrome P450 IID6, paroxetine inhibits the activity of this enzyme. Therefore, it should be used with caution with drugs metabolized by this isoenzyme: some antidepressants (for example, nortriptyline, amitriptyline, imipramine, desipramine and fluoxetine), phenothiazines (for example, thioridazine), class Ic antiarrhythmic drugs (for example, propafenone, flecainide and encainide ), as well as quinidine, cimetidine, codeine. Cimetidine inhibits some cytochrome P450 isoenzymes. As a result, with simultaneous use, the concentration of paroxetine in the blood plasma increases. Phenobarbital increases the activity of some cytochrome P450 isoenzymes. When used in combination, the plasma concentration of paroxetine is reduced and the half-life is shortened. With simultaneous use of paroxetine and phenytoin, the concentration of paroxetine in the blood plasma decreases, and side effects may increase. When using other antiepileptic drugs, clinical side effects may also increase. Paroxetine is highly bound to plasma proteins. When used simultaneously with drugs that also bind to plasma proteins, it is possible to increase the concentration of paroxetine and increase the severity of side effects. Paroxetine increases the concentration of procyclidine in the blood plasma, therefore, if anticholinergic side effects occur, it is necessary to reduce the dose of procyclidine. An increase in the concentration of theophylline in the blood is possible, therefore it is recommended to regularly monitor the concentration of theophylline in the blood serum when used simultaneously with paroxetine. An increase in the effect of alcohol on the central nervous system when used simultaneously with paroxetine was not detected, however, due to the effect of paroxetine on liver enzyme systems, it is necessary to avoid drinking alcohol during treatment with this drug.
Reksetin® (Rexetin®)
Food, antacids: Food and antacids do not affect the absorption and pharmacokinetics of paroxetine.
MAO inhibitors: Like other serotonin reuptake inhibitors, undesirable interactions between MAO inhibitors and paroxetine have been observed in animal studies (See: Special Instructions).
Tryptophan: Headache, nausea, increased sweating and dizziness have been reported in patients treated concomitantly with tryptophan and paroxetine, so the combined use of paroxetine and tryptophan should be avoided.
Warfarin: A pharmacodynamic interaction is expected between paroxetine and warfarin (increased bleeding was noted with unchanged prothrombin time). Therefore, paroxetine should be prescribed with extreme caution to patients taking oral anticoagulants.
Sumatriptan: In a few cases of combined use, general weakness, hyperreflexia, and coordination problems were noted. If it is necessary to use sumatriptan and a serotonin reuptake inhibitor simultaneously, the latter must be done under strict medical supervision.
Tricyclic antidepressants (TCAs): As with the concomitant use of other serotonin reuptake inhibitors with TCA drugs, caution is required since paroxetine may inhibit the metabolism of TCAs through the isoenzyme (CYP) IID6. Therefore, the TCA dose must be reduced. (See: Combined use with drugs that induce and inhibit the metabolic enzyme system) Combined use with drugs that induce and inhibit the metabolic enzyme system:
Drugs that enhance or inhibit the activity of liver enzyme systems may affect the metabolism and pharmacokinetics of paroxetine. When used concomitantly with inhibitors of metabolic liver enzymes, the lowest effective dose of paroxetine should be used. Combined use with liver enzyme inducers does not require adjustment of the initial dose of paroxetine; further changes in dosage depend on the clinical effect (efficacy and tolerability).
Drugs whose metabolism is carried out with the participation of the CYP 2D6 isoenzyme.
Paroxetine significantly inhibits the activity of this enzyme. Therefore, special caution requires its simultaneous use with drugs whose metabolism occurs with the participation of this isoenzyme, including: some antidepressants (for example, nortriptyline, amitriptyline, imipramine, desipramine and fluoxetine), phenothiazines (for example, thioridazine), antiarrhythmic drugs of group 1C ( eg propafenone, flecainide and encainide) or which block its action (eg quinidine, cimetidine, codeine).
Drugs whose metabolism is carried out with the participation of the CYP3A4 isoenzyme:
There are no reliable clinical data on the inhibition of the CYP3A4 isoenzyme by paroxetine, so drugs that inhibit this enzyme (for example, terfenadine) can probably be used without problems.
Cimetidine: Cimetidine inhibits some cytochrome P450 isoenzymes. As a result, when used together, the level of paroxetine concentration in the blood plasma increases at the stage of dynamic equilibrium.
Phenobarbital: Phenobarbital increases the activity of some cytochrome P450 isoenzymes. When used together, the concentration of paroxetine in the blood plasma decreases and the half-life is shortened.
Anticonvulsants (Phenytoin): When paroxetine and phenytoin are used together, the concentration of paroxetine in the blood plasma is reduced, but the frequency of side effects of phenytoin may increase. When using other anticonvulsants, the incidence of their side effects may also increase. In patients with epilepsy treated for a long time with carbamazepine, phenytoin or sodium valproate, additional administration of paroxetine did not cause changes in the pharmacokinetic and pharmacodynamic properties of anticonvulsants; There was no increase in paroxysmal convulsive readiness.
Drugs that bind to plasma proteins:
Paroxetine is highly bound to plasma proteins. When used simultaneously with drugs that also bind to plasma proteins, side effects may increase due to an increase in the concentration of paroxetine in the blood plasma.
Digoxin: Since there is insufficient clinical experience with concomitant use, caution is recommended during their simultaneous use.
Diazepam: Diazepam during a course of use does not affect the pharmacokinetics of paroxetine.
Procyclidine: Paroxetine significantly increases the concentration of procyclidine in the blood plasma, therefore, if anticholinergic side effects occur, it is necessary to reduce the dose of procyclidine.
Beta blockers: In clinical trials, paroxetine had no effect on propranolol blood levels.
Theophylline: In some cases, an increase in the concentration of theophylline in the blood has been noted. Although the interaction between paroxetine and theophylline has not been proven in clinical studies, regular monitoring of theophylline blood levels is recommended.
Alcohol: An increase in the effect of alcohol when used simultaneously with paroxetine was not detected. However, due to the effect of paroxetine on the liver enzyme system, it is necessary to avoid drinking alcohol during treatment with paroxetine.
Overdose of the drug Rexetine, symptoms and treatment
Paroxetine therapy is safe over a wide range of doses. Overdose symptoms have occurred with a single dose of 2000 mg or with high doses of paroxetine in combination with other drugs or alcohol. Signs of overdose - nausea, vomiting, tremor, mydriasis, feeling of dryness in the mouth, agitation, sweating, drowsiness, dizziness, flushing of the facial skin; convulsions or coma did not develop. Death occurred only with a simultaneous overdose of paroxetine and another drug as a result of an adverse interaction. There is no specific antidote. In case of overdose, it is necessary to ensure airway patency, if necessary, oxygen therapy, perform gastric lavage or induce vomiting, and prescribe 20–30 g of activated carbon orally every 4–6 hours in the first 2 days. Continuous monitoring of vital signs is recommended. Forced diuresis, hemodialysis or hemoperfusion are ineffective if most of the paroxetine has already been transferred from the blood to the tissues.
