Zeldox® [Ziprasidone]

Pharmacological properties

ziprasidone has a high affinity for type 2 dopamine receptors (d2) and a significantly greater affinity for type 2a serotonin receptors (5ht2a). According to positron emission tomography (PET), 12 hours after a single dose of 40 mg, blockade of more than 80% of serotonin receptors of type 2a and more than 50% of dopamine receptors of type d2 is observed. ziprasidone also interacts with serotonin 5ht2c, 5ht1d and 5ht1a receptors, and its affinity for these receptors is the same or greater than the affinity for dopamine d2 receptors. ziprasidone has a moderate affinity for neuronal serotonin or norepinephrine transport systems, and also has a moderate affinity for histamine H1 receptors and α1 adrenoreceptors. ziprasidone showed a slight affinity for muscarinic m1 cholinergic receptors.

Ziprasidone exhibits serotonin 2 antagonist properties_A(5HT_2A) - and dopamine 2 (D₂) receptors. This suggests that the antipsychotic activity of the drug is partially mediated by a combination of these antagonistic effects. Ziprasidone is also a potent 5HT antagonist._2C5HT_1Dreceptors, potent 5HT agonist_1A-receptors and inhibitor of neuronal reuptake of norepinephrine and serotonin.

Clinical researches

Schizophrenia. In a 52-week study, ziprasidone was shown to be effective in maintaining clinical improvement during therapy in patients who showed a response to treatment at the beginning of the course. There was no clear relationship between dose and severity of response in different groups of ziprasidone. This study involved patients with both positive and negative symptoms. The effectiveness of ziprasidone has been demonstrated in both variants.

The incidence of weight gain, which was reported as an adverse reaction in short-term (4–6-week) studies of schizophrenia treatment, was low and did not differ in the ziprasidone and placebo groups (in each group the frequency was 0.4%). In a 1-year placebo-controlled study, the median weight loss was 1-3 kg in patients taking ziprasidone and 3 kg in patients receiving placebo.

In a double-blind comparative study of the treatment of schizophrenia, metabolic parameters such as body weight, fasting insulin levels, total cholesterol and TG levels, as well as the insulin resistance index were determined. In patients receiving ziprasidone, there were no significant deviations from the initial level for one of these metabolic parameters.

Results of a large post-marketing safety study. A randomized post-registration study involving 18,239 patients with schizophrenia, which included a follow-up period of 1 year, was performed to establish a relationship between the effects of ziprasidone on the Q-Tc interval and an increased risk of non-suicide-related death. This study was carried out under normal clinical practice; the results of the study showed that there was no difference in the incidence of non-suicide-related deaths between the treatment groups of ziprasidone and olanzapine (primary endpoint). This study also demonstrated the absence of differences between the groups by secondary endpoints (total mortality, mortality due to suicide, and mortality due to sudden death). At the same time, a slightly larger number of deaths as a result of cardiovascular disorders were recorded in the ziprasidone treatment group.Also, in the ziprasidone treatment group, a statistically significantly higher hospitalization rate was observed for all reasons, mainly due to an increase in the frequency of hospitalization for psychiatric reasons.

Bipolar Mania. The efficacy of ziprasidone in adult patients with mania was established in two 3-week, double-blind, placebo-controlled trials comparing ziprasidone and placebo, and in a 12-week, double-blind, triple comparing ziprasidone with haloperidol and placebo. About 850 patients who met the DSM-IV criteria for type I bipolar disorder with acute manic or mixed episodes and the presence or absence of psychotic manifestations took part in these studies. In these studies, psychotic manifestations at baseline were noted at 49.7; 34.7 or 34.9% of cases. The effectiveness of the drug was evaluated using the Mania Rating Scale; MRS. The Clinical Global Impression-Severity Scale (CGI-S) in these studies was used as a combined primary or primary secondary efficacy variable. Treatment with ziprasidone (40–80 mg 2 times a day, the average daily dose of 120 mg) led to a statistically significant significantly greater (compared with placebo) improvement in the MRS and CGI-S indices when evaluated at the final visit (3 weeks). In a 12-week study, treatment with haloperidol (average daily dose of 16 mg) resulted in a significantly greater decrease in MRS indices compared to that with ziprasidone (average daily dose of 121 mg). It has been demonstrated that the efficacy of ziprasidone and haloperidol is comparable for patients in whom the response to treatment persisted from the 3rd to the 12th week of treatment.

The efficacy of ziprasidone for the treatment of type I bipolar disorder in children aged 10-17 years was evaluated in one placebo-controlled study lasting 4 weeks (n = 237) with inpatient or outpatient patients who met the DSM-IV criteria for manic or mixed episodes type I bipolar disorder with or without psychotic manifestations, and at baseline received a Y-MRS index of ≥17 points. During this double-blind, placebo-controlled study, a course of treatment with oral doses of ziprasidone was administered orally (80–160 mg / day in 2 doses of 40–80 mg 2 times a day for patients weighing ≥45 kg and 40–80 mg / day 2 doses of 20-40 mg 2 times a day for patients weighing 45 kg) were compared with placebo treatment. On the 1st day, a single dose of 20 mg of ziprasidone was used, then the dose was increased for 1-2 weeks, dividing it into 2 doses and focusing on the range of 120-160 mg / day (for patients weighing ≥45 kg) or 60 –80 mg / day (for patients weighing 45 mg). It was allowed to use an asymmetric dosing regimen: morning doses were 20 or 40 mg lower than evening ones. Ziprasidone was more effective than placebo in terms of changes in the overall Y-MRS index from baseline to week 4. During this clinical study, the average daily dose was 119 mg for patients weighing ≥45 kg and 69 mg for patients weighing 45 kg.

The safety of ziprasidone was evaluated in 267 children aged 10-17 years who took part in clinical trials of bipolar mania with repeated use of the drug. A total of 82 children with type I bipolar disorder used ziprasidone orally for at least 180 days.

In a 4-week study involving children aged 10-17 with bipolar mania between patients from the ziprasidone and placebo treatment groups, there were no differences in terms of the average change in baseline from indicators such as body weight, fasting glucose, and total Cholesterol, cholesterol, LDL or TG.

Long-term double-blind clinical studies of the efficacy and tolerability of ziprasidone in children have not been conducted.

Long-term clinical studies of the effectiveness of ziprasidone for the prevention of relapse of symptoms of mania / depression have not been conducted.

Pharmacokinetics Suction. C_max plasma ziprasidone is usually achieved 6–8 hours after ingestion of multiple doses of ziprasidone with food. The absolute bioavailability of a single dose of 20 mg after a meal is 60%. The bioavailability of ziprasidone with i / m use is 100%. C_max drug in blood plasma is usually achieved after 30-60 minutes after a / m single dose. Pharmacokinetic studies have shown that in the presence of food, the bioavailability of ziprasidone can increase even up to 100%. Thus, the drug is recommended to be taken simultaneously with food.

Distribution. The volume of distribution is about 1.1 l / kg. Ziprasidone binds to plasma proteins by more than 99%.

Biotransformation and excretion. T_½ ziprasidone after oral administration is 6.6 hours. The equilibrium state is reached within 1-3 days from the start of treatment. The average clearance of ziprasidone for iv use is 5 ml / min / kg. About 20% of the dose is excreted in the urine, and about 66% of the drug is excreted in the feces.

The pharmacokinetics of ziprasidone is linear in the dose range of 40–80 mg 2 times a day after meals.

Following oral administration, ziprasidone is extensively metabolized. An unchanged drug is excreted in very small amounts with urine (1%) and feces (4%). The removal of ziprasidone is carried out mainly due to three putative metabolic pathways, with 4 main circulating metabolites being formed: benzisothiazole piperazine sulfoxide, benzisothiazole piperazine sulfone, ziprasidone sulfoxide and S-methyl-dihydroziprasidone. Unchanged ziprasidone accounts for about 44% of the total number of drug derivatives in blood plasma.

Ziprasidone is primarily metabolized in two ways: due to reduction and methylation with the formation of S-methyl-dihydroziprasidone, which corresponds to about ⅔ metabolism, as well as due to oxidation, provides the remaining ¹/₃. In vitro studies using subcellular fractions of the human liver indicate that S-methyl-dihydroziprasidone is formed in 2 stages. In these studies, it was shown that the first stage is ensured primarily by chemical reduction with glutathione, as well as by enzymatic reduction with aldehyde oxidase. In the second step, methylation using thiolmethyl transferase occurs. In vitro studies have shown that CYP 3A4 is the main cytochrome P450, which catalyzes the oxidation of ziprasidone with a potentially lower participation of CYP 1A2.

During in vitro studies, ziprasidone, S-methyl-dihydroziprasidone and ziprasidone sulfoxide exhibit common properties that can cause a prolongation of the Q – Tc interval. S-methyl-dihydroziprasidone is excreted mainly with feces by biliary excretion. An insignificant role in the metabolism of this compound is played by metabolic transformations under the influence of CYP 3A4. Ziprasidone sulfoxide is excreted mainly by the kidneys, the secondary route of excretion is metabolic transformation under the influence of CYP 3A4.

Special patient groups. The pharmacokinetic screening of patients did not reveal significant differences in the pharmacokinetics of the drug in smokers and those who do not smoke.

There were no significant differences in the pharmacokinetics of ziprasidone depending on the age or gender of the patients. The pharmacokinetics of ziprasidone in children aged 10-17 years was similar to that in adults after adjusting for differences in body weight. When using ziprasidone in patients with impaired renal function of varying severity, there was no progressive increase in exposure to ziprasidone.These observations coincide with the fact that renal clearance plays a very insignificant role in the overall clearance of the drug. After ingestion of 20 mg 2 times a day for 7 days, exposure levels in patients with mild (creatinine clearance - 30–60 ml / min), moderate (10–29 ml / min) and severe (dialysis required) degrees were respectively 146; 87 and 75% exposure level in healthy volunteers (creatinine clearance 70 ml / min). It is still unknown whether plasma concentration of metabolites in such patients increased.

In patients with impaired liver function of mild or moderate severity (Child and Pugh classes A and B), due to cirrhosis, the plasma concentration after oral administration increased by 30% compared with healthy volunteers, and T_½ increased by about 2 hours. The effect of impaired liver function on the concentration of metabolites in blood plasma is unknown.

Indications

Capsules ziprasidone is indicated for the treatment of schizophrenia in adults.

Ziprasidone is indicated for the treatment of manic or mixed episodes of moderate severity in patients with bipolar disorder (prevention of episodes of bipolar disorder has not been established, see Pharmacodynamics).

Rr. Zeldox is used to quickly monitor the state of agitation in patients with schizophrenia for a maximum of 3 consecutive days in the case when oral administration of the drug is impractical.

The use of this dosage form should be discontinued as quickly as possible from a clinical point of view, and begin to use the drug in the form of capsules.

Application

Capsules for oral administration

Adults The recommended dose for the emergency treatment of schizophrenia and bipolar mania is 40 mg 2 times a day with meals. Depending on the individual characteristics of the clinical condition, the daily dose can be further increased to a maximum level of 80 mg 2 times a day. If there is evidence, the maximum recommended daily dose can be used already on the 3rd day of treatment. It is very important not to exceed the maximum daily dose, since the safety profile for doses exceeding 160 mg / day is not confirmed, and the use of ziprasidone is associated with a dose-dependent increase in the duration of the Q – T interval (see CONTRAINDICATIONS, SPECIAL INSTRUCTIONS).

For the supportive treatment of patients with schizophrenia, ziprasidone should be used in the minimum effective dose. In most cases, 20 mg 2 times a day may be sufficient.

Elderly patients. It is usually not indicated to reduce the initial dose of the drug for patients over the age of 65, but this possibility should be considered in the presence of appropriate clinical factors.

Patients with impaired renal function. Patients with impaired renal function do not require dose adjustment of the drug (see Pharmacokinetics).

Patients with impaired liver function. When using the drug in patients with liver failure, the possibility of using low doses of the drug should be considered (see SPECIAL INSTRUCTIONS and Pharmacokinetics).

Rr. This dosage form of the drug Zeldoks is intended exclusively for IM use. The use of the drug in / in should be avoided. Use this dosage form of the drug in patients should only be in the case when oral administration of the drug is impractical.

Dilution Instructions Dissolve the contents of the vial (powder) with 1.2 ml of water for injection (solvent) supplied with the vial. This will ensure the formation of a solution of ziprasidone with a concentration of 20 mg / ml. After adding the solvent, the vial should be shaken until the powder is completely dissolved. You can use only a transparent solution, free from visible impurities. Withdraw only 1 dose from each vial (0.5 ml corresponds to 10 mg of ziprasidone, 1 ml corresponds to 20 mg of ziprasidone).Residual fluid in the vial should be disposed of.

Adults The recommended dose is 10 mg and is used if necessary, while the maximum daily dose of 40 mg should not be exceeded.

The drug in doses of 10 mg can be administered every 2 hours. Some patients may require an initial dose of 20 mg. In this case, the next dose of 10 mg can be administered after 4 hours. Subsequently, the drug at a dose of 10 mg can be administered every 2 hours until the maximum daily dose of 40 mg is reached.

The use of ziprasidone IM for more than 3 days has not been investigated. If you need long-term use, you should as soon as possible switch from the IM application of ziprasidone to the oral administration of ziprasidone in the form of capsules in a dosage of 80 mg 2 times a day.

Elderly patients. Clinical experience with the use of the drug IM in elderly patients 65 years of age is limited. It is not recommended to use the IM preparation in this category of patients (see SPECIAL INSTRUCTIONS).

Patients with impaired renal function. Patients with impaired renal function should be prescribed ziprasidone IM with caution (see Pharmacokinetics).

Patients with impaired liver function. Consideration should be given to using low doses of the drug in patients with hepatic impairment (see SPECIAL INSTRUCTIONS and Pharmacokinetics).

Contraindications

Hypersensitivity to ziprasidone or any of the excipients indicated in the "composition" section. established lengthening of the q – t interval. syndrome of congenital lengthening of the q – t interval. recent acute myocardial infarction. decompensated heart failure. arrhythmias, the use of antiarrhythmic drugs of classes ia and iii. simultaneous use of drugs that extend the q – t interval. Such drugs include, in particular, antiarrhythmic drugs of classes ia and iii, arsenic trioxide, halofantrine, levomethadil acetate, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron mesylate, mefloquine cipdindol, or ), dofetilide, sotalol, quinidine, chlorpromazine, droperidol, pentamidine, probucol or tacrolimus.

Side effects

During clinical trials, ziprasidone was orally administered to about 6,500 adults (see Pharmacological Properties). The most common adverse reactions in clinical trials of schizophrenia were sedation and akathisia. The most common adverse reactions in clinical studies of bipolar mania were sedation, akathisia, extrapyramidal disorders, and dizziness.

The following are adverse reactions (with a frequency exceeding the incidence in placebo groups) found in combined short-term (4–6 weeks) studies of schizophrenia using fixed doses and in short-term (3 weeks) studies of bipolar mania using variable doses. Additional reactions, messages received after the drug entered the market, included in the frequency category “Unknown”, are shown in italics.

Adverse reactions are given by class and frequency: very often (≥1 / 10), often (from ≥1 / 100 to 1/10), infrequently (from ≥1 / 1000 to 1/100), rarely (from ≥1 / 10 000 to 1/1000), very rarely (1/10 000), unknown (impossible to establish on the basis of the available information).

The adverse reactions listed below may also be associated with underlying diseases and / or with the use of concomitant medications.

Infections and infestations: rarely - rhinitis.

Disorders of metabolism and digestion: infrequently - increased appetite; rarely - hypocalcemia.

From the psyche: often - anxiety; infrequently - agitation, a sense of anxiety, a feeling of constriction in the throat, nightmares; rarely - panic attacks, symptoms of depression, bradyphrenia, depression of emotions, anorgasmia; unknown - insomnia, mania / hypomania.

From the nervous system: often - dystonia, akathisia, extrapyramidal disorders, parkinsonism (including stiffness like a gear wheel, bradykinesia, hypokinesia), tremor, dizziness, sedation, drowsiness, headache; infrequently - generalized tonic-clonic convulsions, tardive dyskinesia, dyskinesia, salivation, ataxia, dysarthria, spasm of the eye, impaired attention, pathological drowsiness, hypesthesia, paresthesia, lethargy; rarely - torticollis, paresis, akinesis, hypertonicity, restless legs syndrome; unknown - malignant antipsychotic syndrome, serotonin syndrome (see INTERACTIONS), paresis of facial muscles.

On the part of the blood system and lymphatic system: rarely - lymphopenia, an increased number of eosinophils.

From the side of the heart: infrequently - increased heartbeat, tachycardia; seldom - lengthening of the corrected Q – T interval on an ECG; unknown - ventricular tachycardia of the torsade de pointes type (see SPECIAL INSTRUCTIONS).

From the side of the organ of vision: often - blurred vision; infrequently - photophobia; rarely - amblyopia, visual impairment, itchy eyes, dry eyes.

From the side of the organ of hearing and balance: infrequently - vertigo, ringing in the ears; rarely - pain in the ear.

From the vessels: infrequently - hypertensive crisis, hypertension, orthostatic hypotension, arterial hypotension; rarely - systolic hypertension, diastolic hypertension, unstable blood pressure; unknown - fainting, venous thromboembolism.

From the respiratory system, chest and mediastinal organs: infrequently - shortness of breath, sore throat; rarely hiccups.

From the digestive system: often - nausea, vomiting, constipation, dyspepsia, dry mouth, excessive secretion of saliva: infrequently - diarrhea, dysphagia, gastritis, discomfort from the digestive tract, swelling of the tongue, thickening of the tongue, flatulence; rarely - gastroesophageal reflux, loose stools.

On the part of the skin and subcutaneous tissue: infrequently - urticaria, rash, maculopapular rash, acne; rarely - psoriasis, allergic dermatitis, alopecia, facial swelling, erythema, papular rashes, skin irritation; unknown - hypersensitivity, angioedema, drug reaction, accompanied by eosinophilia and systemic manifestations (DRESS).

From the musculoskeletal system and connective tissue: often - musculoskeletal rigidity; infrequently - discomfort from the musculoskeletal system, muscle cramps, pain in the limbs, stiffness of the joints; rarely - trismus.

From the kidneys and urinary system: rarely - urinary incontinence, dysuria; unknown - enuresis.

From the reproductive system and mammary glands: rarely - erectile dysfunction, increased erection, galactorrhea, gynecomastia; unknown - priapism.

Immunity disorders: unknown - anaphylactic reactions.

On the part of the liver and biliary tract: infrequently - increased levels of liver enzymes; rarely, abnormal results of liver function tests.

General disorders and reactions at the injection site: often - asthenia, increased fatigue; infrequently - discomfort in the chest, gait disturbance, pain, thirst; rarely - pyrexia, sensation of heat.

Laboratory studies: rarely - an increase in LDH in the blood.

Pregnancy, postpartum and perinatal conditions: unknown - drug withdrawal syndrome in a newborn (see. Use during pregnancy and lactation).

In short- and long-term studies of schizophrenia using ziprasidone, episodes of tonic-clonic seizures and hypotension were rare, in less than 1% of patients receiving ziprasidone.

Ziprasidone causes a dose-dependent increase in the duration of the Q – T interval of mild or moderate severity (see PHARMACOLOGICAL PROPERTIES).In clinical trials of schizophrenia, an extension of the Q – T interval from 30 to 60 ms was noted by 12.3% (976 out of 7941) ECG in the ziprasidone treatment group and 7.5% (73 out of 975) ECG in the placebo group. An interval extension of 60 ms was detected in the ziprasidone treatment group by 1.6% (128 of 7941) ECGs and 1.2% (12 of 975) ECGs in the placebo group. An increase in the duration of the Q – Tc interval to values ​​in excess of 500 ms was observed in 3 of 3266 (0.1%) patients taking ziprasidone, and 1 of 538 (0.2%) patients in the placebo group. Clinical trials of bipolar mania have shown comparable results.

During long-term supportive treatment within the clinical studies of schizophrenia, patients taking ziprasidone sometimes showed an increase in prolactin levels, but in most cases this increase returned to normal without discontinuation of treatment. In addition, potential clinical manifestations (such as gynecomastia and breast enlargement) have been reported rarely.

Children with bipolar mania and schizophrenia. In placebo-controlled studies of bipolar disorder (patient age 10-17 years), the most frequent adverse reactions (reported at a frequency of 10%) were sedation, drowsiness, headache, fatigue, nausea, and dizziness. In placebo-controlled studies of schizophrenia (patients aged 13-17 years), the most common adverse reactions (reported at a frequency of 10%) were drowsiness and extrapyramidal disorders. The frequency, type and severity of adverse reactions in this category of patients were generally similar to those in adult patients with bipolar disorders or schizophrenia who received ziprasidone.

In a clinical study of bipolar disorder and schizophrenia in children, the use of ziprasidone was associated with a dose-dependent lengthening of the Q – T interval of mild or moderate severity, which was similar in nature to the lengthening found in the adult patient population. During placebo-controlled clinical trials of bipolar disorder involving children, the development of tonic-clonic seizures and arterial hypotension were not reported.

Clinical research experience. Since clinical trials are conducted under very different conditions, the incidence of adverse reactions during clinical trials of one drug cannot be directly compared with that obtained in clinical trials of another drug and the same frequency can be expected in practice.

In clinical trials of ziprasidone, approximately 5700 patients and / or healthy volunteers who received 1 dose of ziprasidone or more participated. Among them, more than 4,800 were patients who participated in multiple dose efficacy studies; the duration of their treatment was about 1831 patient-years. The conditions and duration of treatment with ziprasidone included open and double-blind studies, studies in inpatient and outpatient patients, as well as short-term and long-term use of the drug. Information about adverse reactions during treatment was obtained by registering voluntary reports of adverse reactions, as well as the result of physical examinations, determination of basic vital signs, body weight, laboratory tests, ECG and the results of ophthalmic examinations. This frequency of adverse reactions reflects the proportion of patients in whom at least 1 time the specified adverse reaction caused by treatment was observed. The reaction was considered to be caused by treatment if it was first detected or worsened during therapy after assessing the initial state.

Adverse reactions observed in short-term, placebo-controlled studies of oral administration of ziprasidone.The information below is based on results obtained from short-term, placebo-controlled pre-registration studies involving schizophrenia patients (a combination of two 6-week and two 4-week studies with fixed doses of the drug) and bipolar mania (a combination of two 3-week studies with variable doses), which were used ziprasidone in doses of 10-200 mg / day.

The following adverse reactions associated with the use of ziprasidone were most often observed (with a frequency of ≥5%) and were not observed with an equivalent frequency in patients receiving placebo (the frequency for the ziprasidone treatment group is at least twice that for the placebo group):

schizophrenia research: drowsiness, respiratory tract infections;

investigation of bipolar disorder: drowsiness, extrapyramidal symptoms (including hypertension, dystonia, dyskinesia, hypokinesia, tremor, paralysis and convulsive movements. None of these adverse reactions are separately detected with a frequency exceeding 10% in studies of bipolar mania), dizziness (including dizziness and fainting), akathisia; visual impairment; asthenia, vomiting.

Schizophrenia. Adverse reactions associated with discontinuation of treatment. About 4.1% (29/702) of patients receiving ziprasidone discontinued use of the drug due to adverse reactions compared with approximately 2.2% (6/273) of patients receiving placebo. The most common reaction associated with discontinuation of the drug was rash, including 7 cases of drug discontinuation due to rash in patients who received ziprasidone (1%), compared with the absence of those in the placebo group.

Adverse reactions occurring with a frequency of ≥2%. The following are adverse reactions that were caused by treatment and were observed in ≥2% of patients during emergency therapy (lasting up to 6 weeks), mainly in patients with schizophrenia treated with ziprasidone, and whose frequency in patients treated with ziprasidone was higher than in patients receiving placebo (the frequency indicator is rounded to the nearest whole number).

Patients who report adverse reactions with ziprasidone (n = 702) and placebo (n = 273), respectively (shown as "patients who used ziprasidone" / "patients who used placebo",%):

organism as a whole: asthenia - 5/3; accidental injury - 4/2; chest pain - 3/2;

disorders of the cardiovascular system: tachycardia - 2/1;

disorders of the digestive system: nausea - 10/7; constipation - 9/8; dyspepsia - 8/7; diarrhea - 5/4; dry mouth - 4/2; anorexia - 2/1;

disorders of the nervous system: extrapyramidal symptoms (the term includes such adverse reactions: extrapyramidal symptoms, hypertension, dystonia, dyskinesia, hypokinesia, tremor, paralysis and convulsive movements. None of these adverse reactions are separately noted with a frequency exceeding 5%, with treatment of schizophrenia) - 14/8; drowsiness - 14/7; akathisia - 8/7; dizziness (the term includes dizziness and fainting) - 8/6;

disorders of the respiratory system: respiratory tract infections - 8/3; rhinitis - 4/2; severe cough - 3/1;

violations of the skin and its appendages: rash - 4/3; fungal skin lesion - 2/1;

disorders of the sensory organs: visual impairment - 3/2.

Dependence of adverse reactions on the dose. An analysis of the dose-dependent response from 4 studies in patients with schizophrenia showed a visible dependence of adverse reactions on the dose of the drug in such cases: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertension, drowsiness, tremor, rhinitis, rash, and visual impairment.

Extrapyramidal symptoms.The incidence of extrapyramidal symptoms (including adverse reactions such as extrapyramidal symptoms, hypertension, dystonia, dyskinesia, hypokinesia, tremors, paralysis, and convulsive movements) in patients treated with ziprasidone in short-term placebo-controlled studies of schizophrenia was 14% compared with 8 % in the placebo group. The objectively obtained data of these studies on the Simpson-Angus scale (for extrapyramidal symptoms) and the Barnes scale (for akathisia) as a whole did not reveal a difference between ziprasidone and placebo.

Dystonia. The effects of a class of drugs (symptoms of dystonia, prolonged abnormal contraction of muscle groups) can be noted in predisposed patients during the first few days of treatment. Symptoms of dystonia include cramping of the neck muscles, sometimes progressing to constriction in the throat, difficulty swallowing, difficulty breathing and / or protrusion of the tongue. These symptoms can be observed when using low doses, but when using high doses of first-generation antipsychotic drugs, they are detected more often and with a greater degree of severity. An increased risk of acute dystonia is noted in male patients and in younger people.

Changes in key vital signs. The use of ziprasidone is associated with orthostatic arterial hypotension.

ECG changes. The use of ziprasidone is associated with an increase in the Q – Tc interval. In schizophrenia studies, the use of