Ziprasidone Hydrochloride (Page 3 of 10)

5.5 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation should be considered. However, some patients may require treatment with ziprasidone despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with ziprasidone. Although fewer patients have been treated with ziprasidone, it is not known if this more limited experience is the sole reason for the paucity of such reports. 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 reactions is not completely understood. Precise risk estimates for hyperglycemia-related adverse reactions 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 patient 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 antidiabetic treatment despite discontinuation of the suspect drug.

Pooled data from short-term, placebo-controlled studies in schizophrenia are presented in Tables 1 and 2. Note that for the flexible dose studies in schizophrenia, each subject is categorized as having received either low (20 mg to 40 mg BID) or high (60 mg to 80 mg BID) dose based on the subject’s modal daily dose. In the tables showing categorical changes, the percentages (% column) are calculated as 100x (n/N).

Table 1: Glucose * Mean Change from Baseline in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Schizophrenia
*
“Random” glucose measurements — fasting/non-fasting status unknown

Mean Random Glucose Change from Baseline mg/dL (N)

Ziprasidone

Placebo

5 mg BID

20 mg BID

40 mg BID

60 mg BID

80 mg BID

100 mg BID

-1.1 (N = 45)

+2.4 (N = 179)

-0.2 (N = 146)

-0.5 (N = 119)

-1.7 (N = 104)

+4.1 (N = 85)

+1.4 (N = 260)

Table 2: Glucose * Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Schizophrenia
*
“Random” glucose measurements – fasting/non-fasting status unknown

Laboratory Analyte

Category Change (at least once) from Baseline

Treatment Arm

N

n (%)

Random Glucose

Normal to High (< 100 mg/dL to ≥ 126 mg/dL)

Ziprasidone

438

77 (17.6%)

Placebo

169

26 (15.4%)

Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL)

Ziprasidone

159

54 (34.0%)

Placebo

66

22 (33.3%)

In long-term (at least one year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline in random glucose for ziprasidone 20 mg to 40 mg BID was -3.4 mg/dL (N = 122); for ziprasidone 60 mg to 80 mg BID was +1.3 mg/dL (N = 10); and for placebo was +0.3 mg/dL (N = 71).

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