Ziprasidone Hydrochloride (Page 5 of 10)

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Monitoring of weight is recommended. Pooled data from short-term, placebo-controlled studies in schizophrenia are presented in Table 5.

Table 5: Weight Mean Changes in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

Ziprasidone

Placebo

5 mg BID

20 mg BID

40 mg BID

60 mg BID

80 mg BID

100 mg BID

Mean Weight (kg) Changes from Baseline (N)

+0.3 (N = 40)

+1.0 (N = 167)

+1.0 (N = 135)

+0.7 (N = 109)

+1.1

(N = 97)

+0.9

(N = 74)

-0.4

(227)

Proportion of Patients with ≥ 7% Increase in Weight from Baseline (N)

0.0%

(N = 40)

9.0%

(N = 167)

10.4% (N = 135)

7.3% (N = 109)

15.5% (N = 97)

10.8% (N = 74)

4.0% (N = 227)

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline weight for ziprasidone 20 mg to 40 mg BID was -2.3 kg (N = 124); for ziprasidone 60 mg to 80 mg BID was +2.5 kg (N = 10); and for placebo was -2.9 kg (N = 72). In the same long-term studies, the proportion of subjects with 7% increase in weight from baseline for ziprasidone 20 mg to 40 mg BID was 5.6% (N = 124); for ziprasidone 60 mg to 80 mg BID was 20.0% (N = 10), and for placebo was 5.6% (N = 72). In a long-term (at least one year), placebo-controlled, fixed-dose study in schizophrenia, the mean change from baseline weight for ziprasidone 20 mg BID was -2.6 kg (N = 72); for ziprasidone 40 mg BID was -3.3 kg (N = 69); for ziprasidone 80 mg BID was -2.8 kg (N = 70) and for placebo was -3.8 kg (N = 70). In the same long-term fixed-dose schizophrenia study, the proportion of subjects with 7% increase in weight from baseline for ziprasidone 20 mg BID was 5.6% (N = 72); for ziprasidone 40 mg BID was 2.9% (N = 69); for ziprasidone 80 mg BID was 5.7% (N = 70) and for placebo was 2.9% (N = 70).

Schizophrenia

The proportions of patients meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of four 4- and 6-week placebo-controlled schizophrenia clinical trials, revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight change in placebo patients. In this set of clinical trials, weight gain was reported as an adverse reaction in 0.4% and 0.4% of ziprasidone and placebo patients, respectively. During long-term therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (> 7% of body weight) in patients with low BMI (< 23) compared to normal (23 to 27) or overweight patients (> 27). There was a mean weight gain of 1.4 kg for those patients with a “low” baseline BMI, no mean change for patients with a “normal” BMI, and a 1.3 kg mean weight loss for patients who entered the program with a “high” BMI.

5.7 Rash

In premarketing trials with ziprasidone, about 5% of patients developed rash and/or urticaria, with discontinuation of treatment in about one-sixth of these cases. The occurrence of rash was related to dose of ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness, e.g., elevated WBCs. Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these reactions were reported to recover completely. Upon appearance of rash for which an alternative etiology cannot be identified, ziprasidone should be discontinued.

5.8 Orthostatic Hypotension

Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α 1 -adrenergic antagonist properties. Syncope was reported in 0.6% of the patients treated with ziprasidone.

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

5.9 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue ziprasidone at the first sign of decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm 3) should discontinue ziprasidone and have their WBC followed until recovery.

5.10 Seizures

During clinical trials, seizures occurred in 0.4% of patients treated with ziprasidone. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. As with other antipsychotic drugs, ziprasidone should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

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