Ziprasidone Hydrochloride (Page 2 of 7)

5.3 Neuroleptic Malignant Syndrome (NMS)

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

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

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. DRESS is sometimes fatal. Discontinue ziprasidone if DRESS is suspected.

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 is presented in Table 1. Note that for the flexible dose study in schizophrenia, each subject is categorized as having received either low (20 to 40 mg BID) or high (60 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

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)

*”Random” glucose measurements—fasting/non-fasting status unknown

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

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%)

*”Random” glucose measurements – fasting/non-fasting status unknown

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline in random glucose for ziprasidone 20-40 mg BID was -3.4 mg/dL (N=122); for ziprasidone 60-80 mg BID was +1.3 mg/dL (N=10); and for placebo was +0.3 mg/dL (N=71).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo-controlled studies in schizophrenia is presented in Table 3.

Table 3: Lipid* Mean Change from Baseline in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

Mean Lipid Change from Baseline mg/dL (N)

Laboratory Analyte

Ziprasidone

Placebo

5 mg BID

20 mg BID

40 mg BID

60 mg BID

80 mg BID

100 mg BID

Triglycerides

-12.9 (N=45)

-9.6 (N=181)

-17.3 (N=146)

-0.05 (N=120)

-16.0 (N=104)

+0.8 (N=85)

-18.6 N=260)

Total Cholesterol

-3.6 (N=45)

-4.4 (N=181)

-8.2 (N=147)

-3.6 (N=120)

-10.0 (N=104)

-3.6 (N=85)

-4.7 (N=261)

*” Random” lipid measurements, fasting/non-fasting status unknown

Table 4: Lipid* Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

Laboratory Analyte

Category Change (at least once) from Baseline

Treatment Arm

N

n (%)

Triglycerides

Increase by ≥50 mg/dL

Ziprasidone

681

232 (34.1%)

Placebo

260

53 (20.4%)

Normal to High (<150 mg/dL to ≥200 mg/dL)

Ziprasidone

429

63 (14.7%)

Placebo

152

12 (7.9%)

Borderline to High (≥150 mg/dL and <200 mg/dL to ≥200 mg/dL)

Ziprasidone

92

43 (46.7%)

Placebo

41

12 (29.3%)

Total Cholesterol

Increase by ≥40 mg/dL

Ziprasidone

682

76 (11.1%)

Placebo

261

26 (10.0%)

Normal to High (<200 mg/dL to ≥240 mg/dL)

Ziprasidone

380

15 (3.9%)

Placebo

145

0 (0.0%)

Borderline to High (≥200 mg/dL and <240 mg/dL to ≥240 mg/dL)

Ziprasidone

207

56 (27.1%)

Placebo

82

22 (26.8%)

*” Random” lipid measurements, fasting/non-fasting status unknown

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline in random triglycerides for ziprasidone 20-40 mg BID was +26.3 mg/dL (N=15); for ziprasidone 60-80 mg BID was -39.3 mg/dL (N=10); and for placebo was +12.9 mg/dL (N=9). In long-term (at least 1 year), placebo- controlled, flexible-dose studies in schizophrenia, the mean change from baseline in random total cholesterol for ziprasidone 20 to 40 mg BID was +2.5 mg/dL (N=14); for ziprasidone 60 to 80 mg BID was -19.7 mg/dL (N=10); and for placebo was -28.0 mg/dL (N=9).

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 is 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 to 40 mg BID was -2.3 kg (N=124); for ziprasidone 60 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 to 40 mg BID was 5.6% (N=124); for ziprasidone 60 to 80 mg BID was 20.0% (N=10), and for placebo was 5.6% (N=72). In a long-term (at least 1 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.

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