ASENAPINE (Page 2 of 8)

5.4 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including asenapine. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict 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 tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment.

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

Given these considerations, asenapine should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1)who suffer from a chronic illness that is known to respond to antipsychotic drugs; and (2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment.

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

5.5 Metabolic Changes

Atypical antipsychotic drugs, including asenapine, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and 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. There have been reports of hyperglycemia in patients treated with asenapine. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment.

Adult Patients: Pooled data from the short-term placebo-controlled bipolar mania trials are presented in Table 1.

TABLE 1: Changes in Fasting Glucose in Adult Patients
Bipolar I Disorder (3-weeks)
Placebo Asenapine
5 mg twice daily 10 mg twice daily Asenapine 5 or 10 mg twice daily
Mean Change from Baseline in Fasting Glucose at Endpoint
Change from Baseline (mg/dL) (N*) 0 (174)

4.14.1

(84)(84)

3.5 (81) 1.7 (321)
Proportion of Patients with Shifts from Baseline to Endpoint
Normal to High <100 to ≥126 mg/dL (n/N**) 2.4% (3/126)

0%0%

(0/53)(0/53)

1.7% (1/60) 1.8% (4/224)
Borderline to High ≥100 and <126 to ≥126 mg/dL (n/N**) 0% (0/39)

12.5%12.5%

(3/24)(3/24)

15.8% (3/19) 12.8% (10/78)

N* = Number of patients who had assessments at both Baseline and Endpoint. N** = Number of patients at risk at Baseline with assessments at both Baseline and Endpoint. Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379). N* = Number of patients who had assessments at both Baseline and Endpoint.
N** = Number of patients at risk at Baseline with assessments at both Baseline and Endpoint. Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379).

In a 52-week, double-blind, comparator-controlled trial, the mean increase from baseline of fasting glucose was 2.4 mg/dL.

Dyslipidemia

Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.

Adult Patients: Pooled data from the short-term, placebo-controlled bipolar mania trials are presented in Table 3.

Table 3: Changes in Lipids in Adult Patients
Bipolar I Disorder (3-weeks)
Placebo Asenapine
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily
Mean Change from Baseline (mg/dL)

Total CholesterolTotal Cholesterol

(N*)(N*)

-1.6 (278) -1.6 (108) -4.7 (95) -0.5 (525)
LDL (N*) 1.4 (271) -2.5 (101) -4.1 (94) -0.3 (499)
HDL (N*) 0.2 (278) 0.1 (108) 0.7 (95) 0.7 (525)
Fasting triglycerides (N*) -16.9 (222) 3.9 (89) -8.5 (85) -3.0 (411)
Proportion of Patients with Shifts from Baseline to Endpoint
Total cholesterol Normal to High <200 to >240 (mg/dL) (n/N*) 1.2 (2/174) 3.0 (2/66) 0 (0/63) 2.1 (7/333)
LDL Normal to High <100 to >160 (mg/dL) (n/N*) 1.9 (2/108) 2.4 (1/41) 0 (0/41) 0.5 (1/223)

HDLHDL

Normal to Low 40 to <40 (mg/dL) (n/N*) Normal to Low >40 to <40 (mg/dL) (n/N*)

7.4 (16/215) 4.1 (4/97) 5.1 (4/78) 7.0 (29/417)
Fasting triglycerides Normal to High <150 to >200 (mg/dL) (n/N*) 4.6 (7/153) 8.2 (5/61) 1.6 (1/64) 6.2 (17/273)

N* = Number of subjects who had assessments at both Baseline and Endpoint. Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379). N* = Number of subjects who had assessments at both Baseline and Endpoint. Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379).

In short-term, placebo-controlled bipolar mania trials, the proportion of patients with total cholesterol elevations >240 mg/dL (at Endpoint) was 7.8% for asenapine-treated patients versus 7.9% for placebo-treated patients. The proportion of patients with elevations in triglycerides >200 mg/dL (at Endpoint) was 13.1% for asenapine-treated patients versus 8.6% for placebo-treated patients.

Weight Gain

Weight gain has been observed in patients treated with atypical antipsychotics, including asenapine. Monitor weight at baseline and frequently thereafter.

Adult Patients: Pooled data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of >7% of body weight from the short-term, placebo-controlled bipolar mania trials are presented in Table 5.

Table 5: Change in Body Weight in Adult Patients from Baseline
Bipolar I Disorder (3-weeks)
Placebo Asenapine
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily
Change from Baseline (kg) (N*) 0.2 (288) 1.4 (110) 1.3 (98) 1.3 (544)
Proportion of Patients with a >7% Increase in Body Weight
% with >7% increase in body weight 0.4% 6.4% 1.0% 5.5%

N* = Number of subjects who had assessments at both Baseline and Endpoint. Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379). N* = Number of subjects who had assessments at both Baseline and Endpoint. Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379).

In a 52-week, double-blind, comparator-controlled adult trial, the mean weight gain from baseline was 0.9 kg. The proportion of patients with a 7% increase in body weight (at Endpoint) was 14.7%. Table 6 provides the mean weight change from baseline and the proportion of patients with a weight gain of 7% categorized by Body Mass Index (BMI) at baseline. Adult Patients: In a 52-week, double-blind, comparator-controlled adult trial, the mean weight gain from baseline was 0.9 kg. The proportion of patients with a >7% increase in body weight (at Endpoint) was 14.7%. Table 6 provides the mean weight change from baseline and the proportion of patients with a weight gain of >7% categorized by Body Mass Index (BMI) at baseline.

Table 6: Weight Change Results Categorized by BMI at Baseline: Comparator-Controlled 52-Week Study in Adults
BMI <23 Asenapine N=295 BMI 23 — ≤27 Asenapine N=290 BMI >27 Asenapine N=302
Mean change from Baseline (kg) 1.7 1 0
% with ≥7% increase in body weight 22% 13% 9%

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