QT Interval: Ziprasidone causes a mild to moderate prolongation of the QT interval.
In the pre-marketing clinical trials database, the incidence of QTc prolongation above 500 msec was 3 in a total of 3266 (0.1%) in ziprasidone-treated patients and 1 in a total of 538 (0.2%) in placebo-treated patients.
Some drugs including Class IA and III antiarrhythmics that prolong the QT interval greater than 500 msec have been associated with the rare occurrence of Torsade de pointes, a life-threatening arrhythmia (See Contraindications).
There have been rare post-marketing reports of torsade de pointes in patients with multiple confounding risk factors taking ziprasidone. A causal relationship with ziprasidone has not been established.
Ziprasidone should be used with caution in patients with the following risk factors, which can increase the risk for occurrence of this arrhythmia: bradycardia; electrolyte imbalance; concomitant use with other drugs that prolong QT.
If cardiac symptoms suggestive of arrhythmias are observed or reported during treatment, then appropriate cardiac diagnostics should be performed. If the QTc interval is greater than 500 msec, it is recommended that treatment be stopped (See Contraindications).
Venous Thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with ziprasidone and preventive measures undertaken.
Neuroleptic Malignant Syndrome (NMS): Neuroleptic Malignant Syndrome (NMS), a potentially fatal complex, has been reported in association with antipsychotic drugs, including ziprasidone. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs must be discontinued.
Severe Cutaneous Adverse Reactions: Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone exposure. DRESS consists of a combination of three or more of the following: cutaneous 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 severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with ziprasidone exposure.
Severe cutaneous adverse reactions are sometimes fatal. Discontinue ziprasidone if severe cutaneous adverse reactions occur.
Tardive Dyskinesia: There is a potential for ziprasidone to cause tardive dyskinesia and other tardive extrapyramidal syndromes after long-term treatment. If signs and symptoms of tardive dyskinesia appear, dose reduction or discontinuation of ziprasidone should be considered.
Falls: Antipsychotic drugs (which includes ziprasidone) may cause somnolence, postural hypotension, and motor and sensory instability, which could lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, a fall risk assessment should be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Seizures: Caution is recommended when treating patients with a history of seizures.
CNS Drugs/Alcohol: Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting agents, including alcohol and drugs acting on the dopaminergic and serotonergic systems.
Medicinal Products Containing Lactose: As the capsule contains the excipient lactose (See Description), patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Increased Risk of Cerebrovascular Accidents in the Dementia Population: An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomized placebo-controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Zeldox should be used with caution in patients with risk factors for stroke.
Increased Mortality in Elderly Patients with Dementia-related Psychosis: Elderly patients with dementia-related psychosis have been shown to be at an increased risk of death and/or potentially, cerebrovascular adverse events compared with placebo when treated with some antipsychotic drugs. Study data with ziprasidone in the treatment of elderly patients with dementia are insufficient to conclude whether or not there is an increased risk of death with ziprasidone versus placebo in this patient population. Ziprasidone is not approved for the treatment of elderly patients with dementia-related psychosis.
Priapism: Cases of priapism have been reported with antipsychotic use, including ziprasidone. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment.
Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, ziprasidone may elevate prolactin levels. Disturbances, such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density.
Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia and weakness.
Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Effects on Ability to Drive and Use Machines: Ziprasidone may cause somnolence. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ziprasidone does not affect them adversely.