INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZELDOX®

Composition:

Active substance: ziprasidone;

1 capsule contains 22.65 mg of ziprasidone hydrochloride monohydrate, equivalent to 20 mg of ziprasidone;
1 capsule contains 45.30 mg of ziprasidone hydrochloride monohydrate, equivalent to 40 mg of ziprasidone;
1 capsule contains 90.60 mg of ziprasidone hydrochloride monohydrate, equivalent to 80 mg of ziprasidone;

Excipients: lactose monohydrate; pregelatinized corn starch; magnesium stearate; gelatin capsule shell: titanium dioxide (E 171), sodium dodecyl sulfate, indigo carmine (E 132), gelatin; black ink: shellac, anhydrous ethanol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified water, ammonium hydroxide, potassium hydroxide, black iron oxide (E 172).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

20 mg capsules: hard gelatin capsules, tightly closed, size № 4, blue and white, marked in black ink with "Pfizer" and "ZDX 20";
40 mg capsules: hard gelatin capsules, tightly closed, size № 4, blue, marked in black ink with "Pfizer" and "ZDX 40";
80 mg capsules: hard gelatin capsules, tightly closed, size № 2, blue and white, marked in black ink with "Pfizer" and "ZDX 80".

Pharmacotherapeutic group.

Antipsychotics. Indole derivatives. ATC code N05A E04.

Pharmacological Properties

Pharmacodynamics

Ziprasidone has high affinity for dopamine type 2 (D2) receptors and even greater affinity for serotonin type 2A (5HT2A) receptors. Positron emission tomography has demonstrated that 12 hours after administration of a single 40 mg dose, blockade of serotonin 2A receptors exceeds 80%, while blockade of D2 receptors exceeds 50%. Ziprasidone also interacts with serotonin 5HT2C, 5HT1D, and 5HT1A receptors. Its affinity for these receptors is equal to or even greater than its affinity for D2 receptors. Ziprasidone has moderate affinity for neuronal serotonin and norepinephrine transporters and demonstrates moderate affinity for histamine H(1) and alpha(1) receptors. Its affinity for muscarinic M(1) receptors is negligible.

It has been demonstrated that ziprasidone is an antagonist of serotonin type 2A (5HT2A) receptors and dopamine type 2 (D2) receptors. According to the proposed mechanism, the antipsychotic effect of the drug is partially attributable to this combination of antagonistic actions. Ziprasidone is also a potent antagonist of 5HT2C and 5HT1D receptors, a potent agonist of 5HT1A receptors, and inhibits neuronal reuptake of norepinephrine and serotonin.

Clinical Trials

Schizophrenia. In a 52-week study, ziprasidone demonstrated efficacy in maintaining clinical improvement during continued treatment in patients who had shown a response to initial therapy. No clear dose-response relationship was observed across different ziprasidone treatment groups. The study included patients with both positive and negative symptoms. Efficacy of ziprasidone was demonstrated in both symptom profiles.

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

In a double-blind comparative study of schizophrenia treatment, metabolic parameters such as body weight, fasting insulin levels, total cholesterol, triglycerides, and insulin resistance index were assessed. In patients receiving ziprasidone, no significant deviations from baseline were observed for any of these metabolic parameters.

Results of a large post-marketing safety study. A randomized post-approval study involving 18,239 patients with schizophrenia, including a one-year control observation period, was conducted to evaluate any association between ziprasidone's effect on QTc interval prolongation and increased risk of non-suicide-related mortality. This study was conducted under typical clinical practice conditions; results demonstrated no difference in the incidence of non-suicide-related mortality between ziprasidone and olanzapine treatment groups (primary endpoint). The study also showed no differences between groups regarding secondary endpoints (overall mortality, suicide-related mortality, and sudden death-related mortality). However, in the ziprasidone treatment group, there was a numerically slightly higher number of deaths due to cardiovascular events. Additionally, the ziprasidone group showed a statistically significantly higher rate of hospitalization for any cause, primarily due to increased psychiatric hospitalizations.

Bipolar Mania. The efficacy of ziprasidone in adult patients with mania was established in two double-blind, placebo-controlled studies lasting 3 weeks, comparing ziprasidone with placebo, and in one double-blind 12-week study comparing ziprasidone with haloperidol and placebo. Approximately 850 patients participated in these studies, meeting DSM-IV criteria for bipolar I disorder with acute manic or mixed episodes, with or without psychotic features. In these studies, psychotic features at baseline were observed in 49.7%, 34.7%, or 34.9% of cases. Drug efficacy was assessed using the Mania Rating Scale (MRS). The Clinical Global Impression-Severity (CGI-S) scale was used in these studies as a primary combined or main secondary efficacy variable. Treatment with ziprasidone (40–80 mg twice daily, mean daily dose 120 mg) resulted in statistically significant greater improvement in MRS and CGI-S scores compared to placebo at the final visit (3 weeks). In the 12-week study, haloperidol treatment (mean daily dose 16 mg) resulted in significantly greater reduction in MRS scores compared to ziprasidone treatment (mean daily dose 121 mg). Efficacy of ziprasidone and haloperidol was shown to be comparable in the subset of patients who maintained treatment response from week 3 to week 12.

The efficacy of ziprasidone for treatment of bipolar I disorder in children aged 10 to 17 years was evaluated in one 4-week placebo-controlled study (n=237) involving inpatients or outpatients meeting DSM-IV criteria for manic or mixed episodes of bipolar I disorder with or without psychotic features, with baseline Y-MRS score ≥17 points. In this double-blind, placebo-controlled study, flexible-dose oral ziprasidone (80–160 mg/day in two divided doses (40–80 mg twice daily) for patients with body weight ≥45 kg and 40–80 mg/day in two divided doses (20–40 mg twice daily) for patients with body weight <45 kg) was compared with placebo. On day 1, a single 20 mg dose of ziprasidone was administered, followed by dose escalation over 1–2 weeks, divided into two doses, targeting a range of 120–160 mg/day (for patients with body weight ≥45 kg) or 60–80 mg/day (for patients with body weight <45 kg). Asymmetric dosing was permitted: morning doses were 20 or 40 mg lower than evening doses. Ziprasidone was more effective than placebo in reducing total Y-MRS score from baseline to week 4. During this clinical study, mean daily doses were 119 mg for patients with body weight ≥45 kg and 69 mg for patients with body weight <45 kg.

There are no long-term clinical studies evaluating the efficacy of ziprasidone for prevention of manic/depressive symptom relapse in adult patients.

Pediatric Studies

Bipolar Mania

The safety of ziprasidone was evaluated in 237 children aged 10 to 17 years who participated in clinical trials of bipolar mania with multiple-dose administration. A total of 31 children with bipolar I disorder received oral ziprasidone for at least 180 days.

In a 4-week study involving children aged 10 to 17 years with bipolar mania, no differences were observed between ziprasidone and placebo treatment groups regarding mean change from baseline in body weight, fasting glucose levels, total cholesterol, LDL cholesterol, or triglyceride levels.

The efficacy of ziprasidone in treating bipolar I disorder was evaluated in a post-marketing study involving pediatric patients (n = 171 [safety population]; n = 168 [ITT population]) meeting DSM-5 criteria for bipolar I disorder (manic or mixed type) at baseline. The study compared flexible-dose oral ziprasidone (80–160 mg/day [40–80 mg twice daily] for patients with body weight ≥45 kg; 40–80 mg/day [20–40 mg twice daily] for patients with body weight <45 kg) with placebo over a 4-week period. The study demonstrated that ziprasidone was superior to placebo in reducing total Y-MRS score from baseline to week 4. No significant differences were observed between ziprasidone and placebo groups regarding mean changes in body weight, fasting glucose, total cholesterol, LDL cholesterol, or triglycerides compared to baseline.

No long-term double-blind clinical studies evaluating efficacy and tolerability of ziprasidone in pediatric patients have been conducted.

No long-term clinical studies evaluating the efficacy of ziprasidone for prevention of mania/depression symptom relapse in pediatric patients have been conducted.

Schizophrenia

The pediatric schizophrenia program for ziprasidone included a short-term, 6-week, placebo-controlled study (A1281134) followed by a 26-week open-label extension study (A1281135), designed to obtain information on efficacy, safety, and tolerability of long-term oral ziprasidone (40–80 mg twice daily with food) in adolescents aged 13 to 17 years (inclusive). The study of Zeldox use in pediatric patients with schizophrenia was discontinued by Pfizer due to lack of efficacy (see section "Dosage and Administration").

Pharmacokinetics

Absorption. Peak serum concentration of ziprasidone is typically reached within 6–8 hours after multiple oral doses of ziprasidone taken with food. Absolute bioavailability of a single 20 mg dose taken with food is 60%. Pharmacokinetic studies have demonstrated that in the presence of food, bioavailability of ziprasidone may increase up to 100%. Therefore, the drug is recommended to be taken with food.

Distribution. Volume of distribution is approximately 1.1 L/kg. Ziprasidone is more than 99% bound to serum proteins.

Biotransformation and Elimination. The mean elimination half-life of ziprasidone after oral administration is 6.6 hours. Steady state is achieved within 1–3 days of treatment initiation. Mean clearance of ziprasidone after intravenous administration is 5 mL/min/kg. Approximately 20% of the dose is excreted in urine, and approximately 66% of the drug is eliminated in feces.

Pharmacokinetics of ziprasidone are linear within the dose range of 40–80 mg twice daily taken with food.

After oral administration, ziprasidone is extensively metabolized. The unchanged drug is excreted in very small amounts in urine (<1%) and feces (<4%). Elimination of ziprasidone occurs primarily via three predicted metabolic pathways, resulting in four major circulating metabolites: benzisothiazole piperazine sulfone, benzisothiazole piperazine sulfone, ziprasidone sulfone, and S-methyl-dihydroziprasidone. Unchanged ziprasidone accounts for approximately 44% of total drug-related compounds in serum.

Ziprasidone is primarily metabolized via two pathways: reduction and methylation forming S-methyl-dihydroziprasidone, accounting for approximately two-thirds of metabolism, and oxidation, accounting for one-third of metabolism. In vitro studies using human liver subcellular fractions indicate that S-methyl-dihydroziprasidone is formed in two steps. These studies demonstrated that the first step is primarily mediated by chemical reduction involving glutathione and enzymatic reduction involving aldehyde oxidase. The second step involves methylation by thiopurine methyltransferase. In vitro studies have shown that CYP3A4 is the main cytochrome P450 enzyme catalyzing ziprasidone oxidation, with potentially minor involvement of CYP1A2.

In vitro studies have demonstrated that ziprasidone, S-methyl-dihydroziprasidone, and ziprasidone sulfone have properties that may contribute to QTc interval prolongation. S-methyl-dihydroziprasidone is primarily excreted in feces via biliary excretion. CYP3A4-mediated metabolic transformations play a minor role in the metabolism of this compound. Ziprasidone sulfone is primarily excreted by the kidneys, with CYP3A4-mediated metabolism as a secondary elimination pathway.

Special Patient Populations. Pharmacokinetic screening of patients revealed no significant differences in drug pharmacokinetics between smokers and non-smokers.

No significant differences in ziprasidone pharmacokinetics related to patient age or sex were observed. Pharmacokinetics of ziprasidone in children aged 10 to 17 years were similar to those in adults after adjusting for differences in body weight. When administered to patients with varying degrees of renal impairment, no progressive increase in ziprasidone exposure was observed. These findings are consistent with the fact that renal clearance plays a minimal role in the overall clearance of the drug. After oral administration of 20 mg twice daily for 7 days, exposure levels in patients with mild (creatinine clearance 30–60 mL/min), moderate (10–29 mL/min), and severe (requiring dialysis) renal impairment were 146%, 87%, and 75% of exposure levels in healthy volunteers (creatinine clearance >70 mL/min), respectively. Currently, it is unknown whether metabolite concentrations in serum increase in such patients.

In patients with mild or moderate hepatic impairment (Child-Pugh classes A or B) due to cirrhosis, serum drug concentrations after oral administration increased by 30% compared to healthy volunteers, and elimination half-life increased by approximately 2 hours. The impact of hepatic impairment on serum metabolite concentrations is unknown.

Clinical characteristics.

Indications.

Ziprasidone is indicated for the treatment of schizophrenia in adults.

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

Contraindications.

Hypersensitivity to ziprasidone or to any of the excipients listed in the section "Composition".
Known prolongation of the QT interval.
Congenital QT prolongation syndrome.
Recent acute myocardial infarction.
Decompensated heart failure.
Arrhythmias requiring treatment with class IA or III antiarrhythmic agents.
Concomitant use of medicinal products that prolong the QT interval. Such agents include, in particular, class IA and III antiarrhythmic agents, arsenic trioxide, halofantrine, levomethadyl acetate, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron mesylate, mefloquine, sertindole, or cisapride (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction"), dofetilide, sotalol, quinidine, chlorpromazine, droperidol, pentamidine, probucol, or tacrolimus.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic and pharmacodynamic studies on the interaction between ziprasidone and other drugs that prolong the QT interval have not been conducted. An additive effect of such drugs and ziprasidone cannot be excluded. Therefore, ziprasidone should not be administered concomitantly with medicinal products that prolong the QT interval (class IA and III antiarrhythmics, arsenic trioxide, halofantrine, levomethadyl acetate, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron mesylate, mefloquine, sertindole, or cisapride (see section "Contraindications")).

Interaction studies between ziprasidone and other medicinal products in pediatric patients have not been conducted.

Medicinal products affecting the CNS/alcohol. Given the primary effects of ziprasidone, caution should be exercised when combining ziprasidone with other agents affecting the central nervous system and with alcohol.

Effect of ziprasidone on other medicinal products.

An in vivo study with dextromethorphan demonstrated mild inhibition of CYP2D6 at plasma concentrations 50% lower than those observed after administration of 40 mg ziprasidone twice daily. In vitro data indicate that ziprasidone may be a moderate inhibitor of CYP2D6 and CYP3A4. However, it is unlikely that ziprasidone administration will have a clinically significant effect on the pharmacokinetics of drugs metabolized by these cytochrome P450 isoenzymes.

Ziprasidone may cause hypotension and thus may potentiate the effects of certain antihypertensive agents.

Ziprasidone may exert antagonistic effects to levodopa and dopamine antagonists.

Oral contraceptives. Administration of ziprasidone resulted in minor changes in the pharmacokinetics of estrogenic (ethinylestradiol, a CYP3A4 substrate) or progestogenic components.

Lithium. Concomitant administration of ziprasidone did not affect the pharmacokinetics of lithium. Since both ziprasidone and lithium are associated with changes in cardiac conduction, combination of these agents may pose a risk of pharmacodynamic interactions, including arrhythmias. However, in controlled clinical trials, concomitant use of ziprasidone and lithium was not associated with increased clinical risk compared to lithium monotherapy.

Data on concomitant use with carbamazepine (a mood stabilizer) are limited.

Pharmacokinetic interactions between ziprasidone and valproate are unlikely due to the absence of shared metabolic pathways for these agents. In a study of concomitant administration of ziprasidone and valproate, the mean valproate concentration remained within the therapeutic range compared to that observed during concomitant administration of valproate and placebo.

Effect of other medicinal products on ziprasidone.

Ketoconazole (a CYP3A4 inhibitor that also inhibits P-glycoprotein) at a dose of 400 mg/day increased serum ziprasidone concentration by < 40%. Concentrations of S-methyldihydroziprasidone and ziprasidone sulfoxide at the predicted Tmax for ziprasidone were increased by 55% and 8%, respectively. No additional prolongation of the QTc interval was observed. Changes in pharmacokinetics due to concomitant use of potent CYP3A4 inhibitors are unlikely to be clinically significant; therefore, dose adjustment is not required. In vitro and animal studies suggest that ziprasidone may act as a substrate for P-glycoprotein. The significance of this for humans in vivo remains unknown. Since ziprasidone is a substrate for CYP3A4, and induction of CYP3A4 and P-glycoprotein are linked, concomitant use with inducers of CYP3A4 and P-glycoprotein such as carbamazepine, rifampicin, and St. John's wort preparations may lead to decreased ziprasidone concentrations.

Administration of carbamazepine at doses of 200 mg twice daily for 21 days resulted in approximately a 35% reduction in ziprasidone exposure.

Antacids. Repeated administration of aluminum- and magnesium-containing antacids or cimetidine did not result in clinically significant effects on the pharmacokinetics of ziprasidone when administered after food.

Serotonergic medicinal products. In individual cases, serotonin syndrome has been reported temporally associated with the use of ziprasidone in combination with other serotonergic medicinal products (e.g., selective serotonin reuptake inhibitors) (see section "Adverse reactions"). Manifestations of serotonin syndrome may include confusion, agitation, fever, diaphoresis, ataxia, hyperreflexia, myoclonic jerks, and diarrhea.

Plasma protein binding. Ziprasidone is highly bound to plasma proteins. In vitro, warfarin or propranolol (medicinal products highly bound to plasma proteins) did not affect the plasma protein binding of ziprasidone; similarly, ziprasidone did not alter the binding characteristics of these two drugs to human plasma proteins. Thus, potential interactions of ziprasidone with other drugs via displacement mechanisms are unlikely.

In vitro studies. In vitro enzyme inhibition studies using human liver microsomes demonstrated that ziprasidone exerts minimal inhibitory effects on CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and thus is unlikely to affect the metabolism of drugs primarily metabolized by these enzymes. Drug interactions with ziprasidone due to displacement are unlikely.

Cimetidine. Cimetidine, administered at a dose of 800 mg once daily for 2 days, did not affect the pharmacokinetics of ziprasidone.

Dextromethorphan. Results from a study in healthy volunteers, consistent with in vitro findings, demonstrated that ziprasidone does not affect the metabolism of dextromethorphan, a reference substrate for the CYP2D6 enzyme, to its major metabolite dextrorphan. No statistically significant change in the urinary dextromethorphan/dextrorphan ratio was observed.

Concomitant use with other medicinal products. A population pharmacokinetic analysis of patients with schizophrenia included in controlled clinical trials did not reveal evidence of any clinically significant pharmacokinetic interaction with benztropine, propranolol, or lorazepam.

Interaction with food. The absolute bioavailability of the 20 mg dose of the drug when taken with food is approximately 60%. Absorption of ziprasidone is doubled when taken with food.

Special precautions for use.

In order to identify patients in whom ziprasidone is contraindicated, a medical history (including assessment of family history) and a physical examination should be obtained prior to initiating treatment (see section "Contraindications").

QT interval. Ziprasidone causes dose-dependent mild to moderate QT interval prolongation (see sections "Adverse reactions" and "Pharmacodynamics").

Concomitant use of ziprasidone and drugs that prolong the QT interval is not recommended (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Caution is required when treating patients with marked bradycardia. Electrolyte imbalances (such as hypokalemia and hypomagnesemia) increase the risk of developing malignant arrhythmias. Such imbalances should be corrected prior to initiating ziprasidone therapy. Prior to initiating treatment in patients with stable cardiac disease, consideration should be given to performing an ECG.

If cardiac symptoms such as palpitations, vertigo, syncope, or seizures occur, the risk of malignant arrhythmia should be considered and cardiac evaluation, including ECG, should be performed. If the QTc interval duration exceeds 500 ms, treatment with the medicinal product should be discontinued (see section "Contraindications").

Since marketing authorization, rare cases of ventricular tachycardia of the torsade de pointes type have been reported in patients receiving ziprasidone who had multiple risk factors.

Paediatric population

The safety and efficacy of ziprasidone in the treatment of schizophrenia in children and adolescents have not been established (see section "Pharmacodynamics").

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with the use of antipsychotic drugs. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and signs of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure.

Diagnosing such patients is difficult. It is important to exclude conditions where the clinical picture includes both a serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). In differential diagnosis, central anticholinergic toxicity, heat stroke, drug-induced fever, and primary central nervous system (CNS) pathology should also be excluded.

Management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and any other non-essential drugs; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any serious concomitant illnesses for which specific treatment exists. There are no generally accepted specific pharmacological treatment regimens for NMS.

If antipsychotic treatment is required after recovery from NMS, re-initiation of the drug should be carefully considered. Close monitoring of the patient is necessary, as recurrences of NMS have been reported.

Tardive Dyskinesia. Tardive dyskinesia and other late extrapyramidal syndromes may potentially develop after prolonged treatment with ziprasidone. Patients with bipolar disorders are particularly susceptible to developing such symptoms. The risk increases with longer duration of treatment and with increasing patient age. If symptoms or signs of tardive dyskinesia occur, consideration should be given to reducing the dose of ziprasidone or discontinuing the drug.

Seizures. Caution is required when treating patients with a history of seizures.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Cases of DRESS have been reported. This reaction consists of a combination of three or more of the following manifestations: skin reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy, and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. Other serious skin adverse reactions, including Stevens-Johnson syndrome, have been reported in association with the use of ziprasidone.

Serious skin adverse reactions may occasionally be fatal. If such reactions develop, ziprasidone should be discontinued.

Hepatic impairment

Ziprasidone should be used with caution in patients with severe hepatic impairment, as experience with treatment in such patients is limited (see sections "Method of administration and dosage" and "Pharmacokinetics").

Medicinal products containing lactose. Since the medicinal product contains lactose, it should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Increased risk of cerebrovascular disorders in patients with dementia. In randomized, placebo-controlled clinical trials of atypical antipsychotic drugs in patients with dementia, there was approximately a threefold increase in the risk of cerebrovascular adverse events. The mechanism of this phenomenon is unknown. An increase in risk with other antipsychotic drugs or in other patient populations cannot be excluded. Zeldox® should be used with caution in patients with existing risk factors for stroke.

Increased mortality in elderly patients with dementia. Data from two large observational studies demonstrated a slightly increased risk of death and/or cerebrovascular adverse events in elderly patients with dementia treated with antipsychotic drugs compared to patients not receiving antipsychotic drugs. At present, data are insufficient to determine the exact magnitude of risk. The causes of the increased risk are unknown.

Zeldox® is not approved for the treatment of behavioural disorders associated with dementia.

Venous thromboembolism. Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients receiving antipsychotic drugs often have acquired risk factors for venous thromboembolism, all possible risk factors should be identified before and during treatment with ziprasidone, and preventive measures should be taken.

Metabolic changes. The use of atypical antipsychotic drugs is associated with metabolic changes that may increase the risk of cardiovascular and cerebrovascular disorders. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. While all drugs in this class have the potential to cause metabolic changes, each individual drug has its own specific risk profile.

Hyperglycemia and diabetes mellitus. Cases of hyperglycemia and diabetes mellitus, sometimes severe, leading to ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with atypical antipsychotic drugs. Several cases of hyperglycemia or diabetes mellitus have been reported in patients treated with Zeldox®. Although fewer patients have received Zeldox®, it is unknown whether this more limited experience is the sole reason for the relatively low number of such reports. Assessing the relationship between the use of atypical antipsychotic drugs and glucose abnormalities is complicated by the possibility of an increased baseline risk of diabetes in patients with schizophrenia and the increasing prevalence of diabetes in the general population. Given these confounding factors, the relationship between atypical antipsychotic drugs and hyperglycemia-related adverse reactions is not fully understood. It is not possible to provide a precise estimate of the risk of hyperglycemia-related adverse reactions in patients treated with atypical antipsychotic drugs.

Patients with established diabetes mellitus who are initiated on atypical antipsychotic drugs should undergo regular monitoring for worsening glycemic control. Patients initiated on atypical antipsychotic drugs who have risk factors for diabetes mellitus (such as obesity, family history of diabetes) should have fasting blood glucose levels measured at the beginning of treatment and periodically monitored during treatment. All patients receiving atypical antipsychotic drugs should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotic drugs should have fasting blood glucose levels measured. In some cases, hyperglycemia resolves after discontinuation of atypical antipsychotic drugs. However, some patients require ongoing antidiabetic treatment despite discontinuation of antipsychotic drugs.

Dyslipidemia. Unfavourable changes in lipid levels have been observed in patients treated with atypical antipsychotic drugs.

Weight gain. Weight gain has been observed with the use of atypical antipsychotic drugs. Monitoring of patient weight is recommended.

Rash. In pre-marketing studies of ziprasidone, rash and/or urticaria occurred in approximately 5% of patients, leading to discontinuation of the study in about one out of every six cases. The occurrence of rash was dose-related, although these results could also be explained by longer exposure time with higher doses. In several patients with rash, signs and symptoms of concomitant systemic illness, such as elevated white blood cell count, were observed. The condition of most patients improved rapidly with additional use of antihistamines or steroids and/or after discontinuation of ziprasidone; all patients with such reactions recovered completely. If a rash develops for which no alternative etiology can be identified, ziprasidone should be discontinued.

Orthostatic hypotension. Ziprasidone may cause orthostatic hypotension, accompanied by dizziness, tachycardia, and in some patients, syncope, particularly during the initial dose titration period, likely reflecting the drug's α1-adrenergic receptor antagonism. Syncope was reported in 0.6% of patients treated with ziprasidone.

Ziprasidone should be used with particular caution in patients with known cardiovascular disorders (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disorders, or conditions predisposing to hypotension (dehydration, hypovolemia, and treatment with antihypertensive drugs).

Falls. Ziprasidone may cause somnolence, dizziness, postural hypotension, and gait disturbances, which may lead to falls. This medicinal product should be used with caution in patients at increased risk (e.g., elderly or debilitated patients), and consideration should be given to reducing the initial dose (see section "Method of administration and dosage").

Leukopenia, neutropenia, and agranulocytosis. Cases of leukopenia/neutropenia temporally associated with the use of antipsychotic drugs have been reported in clinical trials and since marketing authorization. Cases of agranulocytosis (including fatal cases) have also been reported.

Possible risk factors for developing leukopenia/neutropenia include pre-existing low white blood cell count and a history of drug-induced leukopenia/neutropenia. Patients with pre-existing low white blood cell count or a history of drug-induced leukopenia/neutropenia should undergo frequent monitoring of complete blood counts during the first few months of therapy; treatment with Zeldox® should be discontinued at the first sign of decreased white blood cell count in the absence of other etiological factors.

Patients with neutropenia should be closely monitored for fever or other signs of infection, and appropriate treatment should be initiated immediately if such symptoms occur. Zeldox® should be discontinued in patients with severe neutropenia (absolute neutrophil count < 1000/mm³), and white blood cell counts should be monitored until recovery.

Dysphagia. Esophageal dyskinesia and aspiration have been associated with the use of antipsychotic drugs. Aspiration pneumonia is often a cause of morbidity and mortality in elderly patients, particularly in patients with progressive dementia due to Alzheimer's disease. Ziprasidone and other antipsychotic drugs should be used with caution in patients at risk of aspiration pneumonia.

Body temperature regulation. Although disturbances in the body's ability to reduce core body temperature were not reported during pre-approval studies with ziprasidone, such events have been associated with the use of antipsychotic drugs. Caution should be exercised when prescribing ziprasidone to patients who may be exposed to conditions that could lead to elevated core body temperature, such as strenuous exercise, exposure to high ambient temperatures, use of concomitant drugs with anticholinergic activity, or conditions leading to dehydration.

Suicide. Patients with psychotic or bipolar disorders may be at risk of suicide; therefore, pharmacological therapy in high-risk patients should be accompanied by close monitoring. Prescriptions for ziprasidone should be written for the smallest necessary quantity to reduce the risk of overdose.

Laboratory tests. In patients at risk of significant electrolyte disturbances who are planned for ziprasidone therapy, serum potassium and magnesium levels should be measured at baseline. Low serum potassium and magnesium levels should be corrected before initiating treatment. In patients starting diuretics during ziprasidone treatment, serum potassium and magnesium levels should be periodically monitored. Ziprasidone should be discontinued in patients in whom the QTc interval is persistently > 500 msec.

Patients with concomitant diseases. Clinical experience with the use of ziprasidone in patients with multiple concomitant systemic diseases is limited.

Ziprasidone has not been adequately evaluated or used in patients with recent myocardial infarction or with cardiac conditions characterized by unstable cardiac function. Patients with such diagnoses were excluded from pre-approval clinical trials. Due to the risk of QTc interval prolongation and orthostatic hypotension, ziprasidone should be used with caution in patients with cardiac disorders.

Ability to impair cognitive and motor functions. Somnolence was the most commonly reported adverse reaction in patients treated with ziprasidone. In 4- and 6-week placebo-controlled studies, somnolence was reported in 14% of patients receiving ziprasidone compared to 7% of patients receiving placebo. In short-term clinical studies, somnolence led to discontinuation of treatment in 0.3% of patients. Since ziprasidone may impair consciousness, thinking, or motor skills, patients should be advised to exercise caution when performing tasks requiring alertness, such as driving vehicles (including automobiles) or operating dangerous machinery, until they are fully confident that ziprasidone treatment does not adversely affect them.

Priapism. Cases of priapism have been reported with the use of antipsychotic drugs, including ziprasidone. This adverse reaction, as with other psychotropic drugs, is not dose-dependent and does not correlate with duration of treatment.

Hyperprolactinemia. Like other dopamine D2 receptor antagonists, ziprasidone may increase prolactin levels. With drugs that elevate prolactin levels, disorders such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported. Prolonged hyperprolactinemia associated with hypogonadism may lead to decreased bone density.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive toxicity studies of ziprasidone demonstrated adverse effects on reproduction when administered at doses associated with toxic effects on the maternal organism and/or sedative effects. No teratogenic effects of the drug were observed.

Studies on the use of the drug in pregnant women have not been conducted.

Since experience with the use of ziprasidone in pregnant women is limited, ziprasidone is not recommended during pregnancy except when the expected benefit to the mother outweighs the potential risk to the fetus.

Neonates whose mothers were treated with antipsychotic drugs (including ziprasidone) during the third trimester of pregnancy are at risk of developing postnatal adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms; the severity and duration of such events after delivery may vary. Excitement, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, such neonates should be closely monitored. Zeldox® should not be used during pregnancy except when use of the drug is clearly necessary. If discontinuation of the drug during pregnancy is required, abrupt discontinuation should be avoided.

Breastfeeding. Adequate and well-controlled studies in breastfeeding women have not been conducted. In one case, ziprasidone was detected in breast milk. Patients should be advised to avoid breastfeeding while taking ziprasidone. If use of this medicinal product is necessary, breastfeeding should be discontinued.

Fertility

Adequate and well-controlled studies in men and women receiving ziprasidone have not been conducted.

Contraception. Women of childbearing potential receiving ziprasidone should be advised to use appropriate contraceptive methods.

Ability to affect reaction speed when driving or operating machinery.

Ziprasidone may cause somnolence and affect reaction speed when driving vehicles or operating other machinery. Patients who may need to drive or operate machinery should be warned accordingly.

Dosage and Administration

Adults. The recommended dose for the acute treatment of schizophrenia and bipolar mania is 40 mg twice daily with food. Depending on individual clinical response, the daily dose may subsequently be increased to the maximum level of 80 mg twice daily. If clinically indicated, the maximum recommended daily dose may be administered as early as day 3 of treatment. It is very important not to exceed the maximum daily dose, as the safety profile for doses exceeding 160 mg per day has not been established, and ziprasidone use is associated with dose-dependent QT interval prolongation (see sections "Contraindications" and "Special Warnings and Precautions for Use").

For maintenance treatment of patients with schizophrenia, ziprasidone should be administered at the lowest effective dose. In many cases, a dose of 20 mg twice daily may be sufficient.

Elderly patients. A dose reduction is generally not required for patients aged 65 years and older; however, dose adjustment should be considered in the presence of relevant clinical factors.

Patients with renal impairment. Dose adjustment is not required in patients with renal impairment (see section "Pharmacokinetics").

Patients with hepatic impairment. Lower doses should be considered when administering the drug to patients with hepatic insufficiency (see sections "Special Warnings and Precautions for Use" and "Pharmacokin游戏副本).

Pediatric population.

Schizophrenia. The safety and efficacy of ziprasidone for the treatment of schizophrenia in pediatric patients have not been established (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

Dependence

Ziprasidone has not been systematically studied in animal or human studies regarding its potential for abuse, dependence, or physical addiction. During clinical trials, no behavioral changes indicating increased drug craving were observed; however, observations were not systematic. Based on this limited experience, the extent of off-label use or abuse after ziprasidone market release cannot be predicted. Therefore, patients should be carefully evaluated for a history of drug dependence, and such patients should be closely monitored for signs of misuse or abuse of ziprasidone (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Overdose.

Experience with ziprasidone overdose is limited. The highest documented single dose of ziprasidone is 12,800 mg. In this case, extrapyramidal symptoms were reported; QTc interval duration was 446 ms (without cardiac consequences). Overdose is typically associated with extrapyramidal symptoms, somnolence, tremor, and anxiety.

Overdose may lead to central nervous system depression, seizures, or dystonic reactions involving the head and neck, which could pose a risk of aspiration if emesis is induced. Immediate cardiovascular monitoring, including electrocardiographic monitoring, should be initiated to detect potential arrhythmias. There is no specific antidote for ziprasidone overdose.

Adverse Reactions

Ziprasidone was administered orally to approximately 6500 adult patients during clinical trials (see section "Pharmacodynamics"). The most commonly reported adverse reactions in clinical trials of schizophrenia were insomnia, somnolence, headache, and agitation. The most commonly reported adverse reactions in clinical trials of bipolar mania were sedative effect, headache, and somnolence.

The adverse reactions listed below were identified in controlled trials of schizophrenia and bipolar mania.

Adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), unknown (cannot be estimated from available data).

The adverse reactions listed below may also be related to the underlying diseases and/or concomitant medication use.

Immune system disorders

Uncommon: hypersensitivity.

Rare: anaphylactic reaction.

Infections and infestations

Common: rhinitis.

Blood and lymphatic system disorders

Rare: lymphopenia, increased eosinophil count.

Endocrine disorders

Uncommon: hyperprolactinaemia.

Metabolism and nutrition disorders

Uncommon: increased appetite.

Rare: hypocalcaemia.

Psychiatric disorders

Very common: insomnia.

Common: mania, agitation, anxiety, restlessness.

Uncommon: panic attacks, night terrors, nervousness, depressive symptoms, decreased libido.

Rare: hypomania, bradyphrenia, anorgasmia, flattened affect.

Nervous system disorders

Very common: somnolence, headache.

Common: dystonia, extrapyramidal disorders, parkinsonism, tardive dyskinesia, dyskinesia, hypertonia, akathisia, tremor, dizziness, sedative effect.

Uncommon: syncope, grand mal seizures, ataxia, akinesia, restless legs syndrome, gait disturbance, salivation, paraesthesia, hypoaesthesia, dysarthria, attention disturbance, hypersomnia, lethargy.

Rare: neuroleptic malignant syndrome, serotonin syndrome, facial nerve paralysis, paresis.

Eye disorders

Common: blurred vision, visual disturbance.

Uncommon: spasm of accommodation, photophobia, dry eyes.

Rare: amblyopia, eye pruritus.

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus, ear pain.

Cardiac disorders

Common: tachycardia.

Uncommon: palpitations.

Rare: ventricular tachycardia of the torsade de pointes type.

Vascular disorders

Common: hypertension.

Uncommon: hypertensive crisis, orthostatic hypotension, hypotension.

Rare: systolic hypertension, diastolic hypertension, unstable blood pressure.

Unknown: venous embolism.

Respiratory, thoracic and mediastinal disorders

Uncommon: throat tightness, dyspnoea, oropharyngeal pain.

Rare: laryngospasm, hiccup.

Gastrointestinal disorders

Common: vomiting, diarrhoea, nausea, constipation, excessive salivation, dry mouth, dyspepsia.

Uncommon: dysphagia, gastritis, gastroesophageal reflux, abdominal discomfort, tongue disorder, flatulence.

Rare: loose stools.

Skin and subcutaneous tissue disorders

Common: rash.

Uncommon: urticaria, maculopapular rash, acne, alopecia.

Rare: drug reaction with eosinophilia and systemic symptoms (DRESS), psoriasis, angioedema, allergic dermatitis, facial swelling, erythema, papular rash, skin irritation.

Musculoskeletal and connective tissue disorders

Common: muscle rigidity.

Uncommon: torticollis, muscle spasms, limb pain, musculoskeletal discomfort, joint stiffness.

Rare: trismus.

Renal and urinary disorders

Uncommon: urinary incontinence, dysuria.

Rare: urinary retention, enuresis.

Pregnancy, puerperium and perinatal conditions

Rare: neonatal withdrawal syndrome.

Reproductive system and breast disorders

Common: male sexual dysfunction.

Uncommon: galactorrhoea, gynaecomastia, amenorrhoea.

Rare: priapism, prolonged erection, erectile dysfunction.

General disorders and administration site conditions

Common: pyrexia, pain, asthenia, fatigue.

Uncommon: chest discomfort, thirst.

Rare: feeling of warmth.

Investigations

Common: weight decreased, weight increased.

Uncommon: QT interval prolongation on electrocardiogram, liver function test abnormalities.

Rare: increased blood lactate dehydrogenase.

In short- and long-term schizophrenia trials with ziprasidone, tonic-clonic seizures and hypotension were observed infrequently, in less than 1% of patients receiving ziprasidone.

Ziprasidone causes dose-dependent mild to moderate QT interval prolongation (see section "Pharmacodynamics"). In clinical trials of schizophrenia, QT interval prolongation of 30 to 60 ms was observed in 12.3% (976 of 7941) of ECG tracings in the ziprasidone treatment group and in 7.5% (73 of 975) of ECG tracings in the placebo group. QT interval prolongation of > 60 ms was observed in 1.6% (128 of 7941) of ECG tracings in the ziprasidone treatment group and in 1.2% (12 of 975) of ECG tracings in the placebo group. QTc interval increases to values greater than 500 ms were observed in 3 of 3266 (0.1%) patients receiving ziprasidone and in 1 of 538 (0.2%) patients in the placebo group. Results from clinical trials of bipolar mania demonstrated comparable findings.

During long-term maintenance treatment in clinical trials of schizophrenia, increased prolactin levels were occasionally observed in patients receiving ziprasidone, but in most cases, such increases normalized without discontinuation of treatment. Furthermore, potential clinical manifestations (e.g., gynaecomastia and breast enlargement) were rarely observed.

Children. In placebo-controlled trials of bipolar disorder (patients aged 10–17 years), the most commonly reported adverse reactions (reported with a frequency > 10%) were sedative effect, somnolence, headache, fatigue, nausea, dizziness, vomiting, decreased appetite, and extrapyramidal disorders. In placebo-controlled trials of schizophrenia (patients aged 13–17 years), the most commonly reported adverse reactions (reported with a frequency > 10%) were somnolence and extrapyramidal disorders. The pediatric safety profile of ziprasidone was generally similar to that of adults. However, a higher incidence of sedation and somnolence was observed in the pediatric population.

In a clinical trial involving children, ziprasidone administration was associated with dose-dependent mild to moderate QT interval prolongation, similar in nature to that observed in the adult population. In placebo-controlled clinical trials of bipolar disorder involving children, no cases of tonic-clonic seizures or hypotension were reported.

Clinical trial experience. Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of one drug cannot be directly compared to that of another drug, nor can it be expected to reflect the frequency observed in clinical practice.

Approximately 5700 patients and/or healthy volunteers participated in clinical trials of ziprasidone and received at least one dose of ziprasidone. Among them, over 4800 were patients enrolled in multiple-dose efficacy trials, with a treatment duration of approximately 1831 patient-years. Conditions and duration of ziprasidone treatment included open-label and double-blind trials, inpatients and outpatients, and short- and long-term use. Information on adverse reactions during treatment was collected through spontaneous reporting of adverse events, as well as physical examinations, vital sign measurements, body weight, laboratory tests, ECGs, and ophthalmological examinations. The reported frequency of adverse reactions reflects the proportion of patients in whom the specified adverse reaction was observed at least once, and was considered treatment-related. A reaction was considered treatment-related if it occurred for the first time or worsened during therapy after baseline assessment.

Adverse reactions observed in short-term, placebo-controlled trials of oral ziprasidone.

The information below is based on results from short-term, placebo-controlled pre-approval trials in patients with schizophrenia (pooled data from two 6-week and two 4-week fixed-dose trials) and bipolar mania (pooled data from two 3-week flexible-dose trials), in which ziprasidone was administered at doses of 10 to 200 mg/day.

The adverse reactions listed below, associated with ziprasidone use, were most frequently observed (incidence ≥ 5%) and were not observed with equivalent frequency in placebo-treated patients (incidence in the ziprasidone group at least twice that in the placebo group):

Schizophrenia trials: somnolence, respiratory tract infections;
Bipolar disorder trials: somnolence, extrapyramidal symptoms (including extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis, and choreic movements. None of these individual adverse reactions occurred with a frequency greater than 10% in bipolar mania trials), dizziness (including dizziness and presyncope), akathisia, visual disturbance, asthenia, vomiting.

Schizophrenia

Adverse reactions leading to discontinuation. Approximately 4.1% (29/702) of patients receiving ziprasidone discontinued treatment due to adverse reactions, compared to approximately 2.2% (6/273) of placebo-treated patients. The most common reaction leading to discontinuation was rash, including 7 cases of discontinuation due to rash among ziprasidone-treated patients (1%), compared to no such cases in the placebo group.
Adverse reactions occurring with a frequency of 2% or greater. Below are treatment-emergent adverse reactions observed in ≥ 2% of patients during short-term therapy (up to 6 weeks), primarily in patients with schizophrenia receiving ziprasidone, and with a higher frequency in ziprasidone-treated patients than in placebo-treated patients (frequency rounded to the nearest whole number).

Patients reporting adverse reactions with ziprasidone (N=702) and placebo (N=273), respectively (listed as "ziprasidone-treated patients"/"placebo-treated patients", %):

General disorders: asthenia – 5/3; accidental injury – 4/2; chest pain – 3/2;
Cardiovascular disorders: tachycardia – 2/1;
Gastrointestinal disorders: nausea – 10/7; constipation – 9/8; dyspepsia – 8/7; diarrhoea – 5/4; dry mouth – 4/2; anorexia – 2/1;
Nervous system disorders: extrapyramidal symptoms (term includes the following adverse reactions: extrapyramidal syndrome, hypertonia, dystonia, dyskinesias, hypokinesia, tremor, paralysis, and choreic movements. None of these individual adverse reactions occurred with a frequency greater than 5% in schizophrenia treatment) – 14/8; somnolence – 14/7; akathisia – 8/7; dizziness (term includes dizziness and presyncope) – 8/6;
Respiratory disorders: respiratory tract infection – 8/3; rhinitis – 4/2; cough increased – 3/1;
Skin and appendage disorders: rash – 4/3; fungal skin infection – 2/1;
Sensory organ disorders: visual disturbance – 3/2.
- Dose dependency of adverse reactions. Analysis of dose-response relationships from four schizophrenia trials revealed a clear dose dependency for the following adverse reactions: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and visual disturbance.
- Extrapyramidal symptoms. The incidence of reported extrapyramidal symptoms (including extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis, and choreic movements) in patients receiving ziprasidone in short-term, placebo-controlled schizophrenia trials was 14% compared to 8% in the placebo group. Objective data from these trials using the Simpson–Angus Scale (for EPS) and Barnes Akathisia Scale generally showed no difference between ziprasidone and placebo.
- Dystonia. Drug class effects (symptoms of dystonia, prolonged abnormal contraction of muscle groups) may occur in susceptible patients during the first few days of treatment. Dystonia symptoms include neck muscle spasms, sometimes progressing to throat tightness, difficulty swallowing, difficulty breathing, and/or tongue protrusion. These symptoms may occur with low doses but are more frequent and severe with higher doses of first-generation antipsychotics. Increased risk of acute dystonia is observed in male patients and younger patients.
- Changes in vital signs. Ziprasidone use is associated with orthostatic hypotension.
- ECG changes. Ziprasidone use is associated with QTc interval prolongation. In schizophrenia trials, ziprasidone use was associated with a mean increase in heart rate of 1.4 beats per minute compared to an increase of 0.2 beats per minute in the placebo group.
- Other adverse reactions observed during pre-approval evaluation of oral ziprasidone. Below are treatment-emergent adverse reactions reported in patients with schizophrenia receiving ziprasidone in multiple-dose trials (> 4 mg/day) using COSTART terminology (database: 3834 patients). All recorded reactions were included except: reactions already listed in the product information; reactions that were general and therefore uninformative; reactions reported only once; reactions considered to have a low likelihood of occurrence in acute, life-threatening conditions; reactions that are part of the disease being treated or are common background events; and reactions considered unlikely to be related to drug use. Although the reported reactions occurred during ziprasidone treatment, they were not necessarily caused by it. Adverse reactions were further categorized by system organ class and listed in decreasing order of frequency according to the following definitions: common – adverse reactions observed in at least 1/100 patients (≥ 1.0% of patients) (only those not listed in placebo-controlled trial results are included in this list); uncommon – adverse reactions observed in 1/100 to 1/1000 patients (0.1–1.0% of patients); rare – adverse reactions observed in fewer than 1/1000 patients (< 0.1% of patients).

General disorders

Common: abdominal pain, influenza-like syndrome, increased temperature, accidental fall, facial swelling, fever, photosensitivity reaction, flank pain, hypothermia, traffic accident.

Cardiovascular disorders

Common: tachycardia, hypertension, postural hypotension.

Uncommon: bradycardia, angina pectoris, atrial fibrillation.

Rare: first-degree AV block, intraventricular block, phlebitis, pulmonary embolism, cardiomegaly, cerebral stroke, haemorrhagic stroke, deep thrombophlebitis, myocarditis, thrombophlebitis.

Gastrointestinal disorders

Common: anorexia, vomiting.

Uncommon: rectal bleeding, dysphagia, tongue oedema.

Rare: gastrointestinal haemorrhage, jaundice, faecal impaction, increased gamma-glutamyltransferase, haematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of the mouth, fatty liver degeneration, melena.

Endocrine disorders

Rare: hypothyroidism, hyperthyroidism, thyroiditis.

Blood and lymphatic system disorders

Uncommon: anaemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy.

Rare: thrombocytopenia, hypochromic anaemia, lymphocytosis, monocytosis, basophilia, lymphoedema, polycythaemia, thrombocytosis.

Metabolism and nutrition disorders

Uncommon: thirst, increased transaminase levels, peripheral oedema, hyperglycaemia, increased creatine phosphokinase, increased alkaline phosphatase, hypercholesterolaemia, dehydration, increased lactate dehydrogenase, albuminuria, hypokalaemia.

Rare: increased blood urea nitrogen, increased creatinine, hyperlipidaemia, hypocholesterolaemia, hyperkalaemia, hypochloraemia, hypoglycaemia, hyponatraemia, hypoproteinaemia, decreased glucose tolerance, gout, hyperchloraemia, hyperuricaemia, hypocalcaemia, hypoglycaemic reaction, hypomagnesaemia, ketosis, respiratory alkalosis.

Musculoskeletal and connective tissue disorders

Common: myalgia.

Uncommon: tenosynovitis.

Rare: myopathy.

Nervous system disorders

Common: anxiety, extrapyramidal syndrome, tremor, dystonia, hypertonia, dyskinesia, hostility, choreic movements, paraesthesia, confusion, vertigo, hypokinesia, hyperkinesia, gait disturbance, oculogyric crisis, hypoaesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, tardive dyskinesia, choreoathetosis, diplopia, incoordination, neuropathy.

Uncommon: paralysis.

Rare: myoclonus, nystagmus, torticollis, perioral paraesthesia, opisthotonus, increased reflexes, trismus.

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea.

Uncommon: pneumonia, epistaxis.

Rare: haemoptysis, laryngospasm.

Skin and appendage disorders

Uncommon: maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash.

Sensory organ disorders

Common: fungal skin infection.

Uncommon: conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia. Rare: eye haemorrhage, visual field defect, keratitis, keratoconjunctivitis.

Renal and genital disorders

Uncommon: impotence, ejaculation disorder, amenorrhoea, haematuria, hypermenorrhoea, lactation in women, polyuria, urinary retention, metrorrhagia, male sexual dysfunction, anorgasmia, glucosuria.

Rare: gynaecomastia, vaginal haemorrhage, nocturia, oliguria, female sexual dysfunction, uterine haemorrhage.

Bipolar disorders

Acute treatment of manic or mixed episodes

Adverse reactions leading to discontinuation. Approximately 6.5% (18/279) of patients receiving ziprasidone in short-term, placebo-controlled trials discontinued treatment due to adverse reactions, compared to approximately 3.7% (5/136) of placebo-treated patients. The most common reactions leading to discontinuation among ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash, and vomiting, with two discontinuations each for these reactions in ziprasidone-treated patients (1%), compared to no discontinuations in the placebo group, except for one patient each in the placebo group for dystonia and rash (1%), and no patients in the placebo group for the remaining adverse reactions.
Adverse reactions occurring with a frequency of 2% or greater in patients receiving oral ziprasidone in short-term, placebo-controlled trials. Below are treatment-emergent adverse reactions observed in ≥ 2% of patients during acute treatment (up to 3 weeks), primarily in patients with bipolar mania receiving ziprasidone, and with a higher frequency in ziprasidone-treated patients than in placebo-treated patients (frequency rounded to the nearest whole number).

Patients reporting adverse reactions with ziprasidone (N=279) and placebo (N=136), respectively (listed as "ziprasidone-treated patients"/"placebo-treated patients", %):

General disorders: headache – 18/17; asthenia – 6/2; accidental injury – 4/1;
Cardiovascular disorders: hypertension – 3/2;
Gastrointestinal disorders: nausea – 10/7; diarrhoea – 5/4; dry mouth – 5/4; vomiting – 5/2; increased salivation – 4/0; tongue oedema – 3/1; dysphagia – 2/0;
Musculoskeletal disorders: myalgia – 2/0;
Nervous system disorders: somnolence – 31/12; extrapyramidal symptoms (term includes the following adverse reactions: extrapyramidal syndrome, hypertonia, dystonia, dyskinesias, hypokinesia, tremor, paralysis, and choreic movements. None of these individual adverse reactions occurred with a frequency greater than 10% in bipolar mania trials) – 31/12; dizziness (term includes dizziness and presyncope) – 16/7; akathisia – 10/5; anxiety – 5/4; hypoaesthesia – 2/1; speech disorder – 2/0;
Respiratory disorders: pharyngitis – 3/1; dyspnoea – 2/1;
Skin and appendage disorders: fungal skin infection – 2/1;
Sensory organs: visual disturbance – 6/3.

No clinically significant differences in adverse reaction frequency by gender were identified in interaction analyses.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine.

Shelf life.

4 years.

Storage conditions.

Store in the original packaging, out of the reach of children, at a temperature not exceeding 25 ºC.

Packaging.

Hard capsules 20 mg, 40 mg, and 80 mg. 14 hard capsules in a blister, 2 blisters in a cardboard box, or 10 hard capsules in a blister, 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pfizer Manufacturing Deutschland GmbH /
Pfizer Manufacturing Deutschland GmbH.

Manufacturer's address and place of business.

Mooswaldallee 1, 79108 Freiburg Im Breisgau, Germany /
Mooswaldallee 1, 79108 Freiburg Im Breisgau, Germany.