Asenapine (Page 2 of 10)

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 sublingual tablets. 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 sublingual tablets 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 TD appear in a patient on asenapine sublingual tablets, drug discontinuation should be considered. However, some patients may require treatment with asenapine sublingual tablets despite the presence of the syndrome.

5.5 Metabolic Changes

Atypical antipsychotic drugs, including asenapine sublingual tablets, 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 sublingual tablets. 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 schizophrenia and bipolar mania trials are presented in Table 1.

TABLE 1: Changes in Fasting Glucose in Adult Patients
Schizophrenia (6-weeks) Bipolar I Disorder (3-weeks)
Placebo Asenapine sublingual tablets Placebo Asenapine sublingual tablets
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily * 5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily
*
Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=90)
Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379).
= Number of patients who had assessments at both Baseline and Endpoint.
§
= Number of patients at risk at Baseline with assessments at both Baseline and Endpoint.
Mean Change from Baseline in Fasting Glucose at Endpoint
Change from Baseline (mg/dL) (N ) -0.2(232) 3.8(158) 1.1(153) 3.2(377) 0 (174) 4.1(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 §) 4.1%(7/170) 4.5%(5/111) 4.5%(5/111) 5.0%(13/262) 2.4%(3/126) 0%(0/53) 1.7%(1/60) 1.8%(4/224)
Borderline to High ≥100 and <126 to ≥126 mg/dL (n/N §) 5.9%(3/51) 6.8%(3/44) 6.3%(2/32) 10.5%(10/95) 0%(0/39) 12.5%(3/24) 15.8%(3/19) 12.8%(10/78)

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

Pediatric Patients: Data from the short-term, placebo-controlled trial in pediatric patients with bipolar I disorder are shown in Table 2.

TABLE 2: Changes in Fasting Glucose in Pediatric Subjects
Bipolar I Disorder (3-weeks)
Placebo Asenapine sublingual tablets 2.5 mg twice daily Asenapine sublingual tablets 5 mg twice daily Asenapine sublingual tablets 10 mg twice daily
*
= Number of subjects who had assessments at both Baseline and Endpoint.
Mean Change from Baseline in Fasting Glucose at Endpoint
Change from Baseline (mg/dL) (N *) -2.24(56) 1.43(51) -0.45(57) 0.34(52)
Proportion of Subjects with Shifts from Baseline to Endpoint
Normal to High>45 & < 100 to ≥126 mg/dL (n/N *) 0%(0/56) 0%(0/51) 1.8%(1/57) 0%(0/52)

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 schizophrenia and bipolar mania trials are presented in Table 3.

TABLE 3: Changes in Lipids in Adult Patients
Schizophrenia (6-weeks) Bipolar I Disorder (3-weeks)
Placebo Asenapine sublingual tablets Placebo Asenapine sublingual tablets
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily * 5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily
*
Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=90)
Includes patients treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily (N=379)
= Number of subjects who had assessments at both Baseline and Endpoint
Mean Change from Baseline (mg/dL)
Total cholesterol (N ) -2.2(351) -2.4(258) 3.3(199) 0.4(539) -1.6(278) -1.6(108) -4.7(95) -0.5(525)
LDL (N ) 0.1(285) -0.2(195) 2.6(195) 1.3(465) 1.4(271) -2.5(101) -4.1(94) -0.3(499)
HDL (N ) 0.5(290) 0.4(199) 1.0(199) 0.5(480) 0.2(278) 0.1(108) 0.7(95) 0.7(525)
Fasting triglycerides (N ) -7.6(233) -1.9(159) 0.1(154) 3.8(380) -16.9(222) 3.9(89) -8.5(85) -3.0(411)
Proportion of Patients with Shifts from Baseline to Endpoint
Total cholesterolNormal to High <200 to ≥240 (mg/dL) (n/N ) 1.3% (3/225) 0.6%(1/161) 2.2%(3/134) 1.7% (6/343) 1.2(2/174) 3.0(2/66) 0(0/63) 2.1(7/333)
LDLNormal to High <100 to ≥160 (mg/dL) (n/N ) 1.7% (2/117) 0.0%(0/80) 1.2%(1/86) 1.0% (2/196) 1.9(2/108) 2.4(1/41) 0(0/41) 0.5(1/223)
HDLNormal to Low ≥40 to <40 (mg/dL) (n/N ) 10.7%(21/196) 13.3%(18/135) 14.7%(20/136) 14.0%(45/322) 7.4(16/215) 4.1 (4/97) 5.1 (4/78) 7.0(29/417)
Fasting triglyceridesNormal to High <150 to ≥200 (mg/dL) (n/N ) 2.4% (4/167) 7.0%(8/115) 8.3%(9/108) 7.7% (20/260) 4.6(7/153) 8.2(5/61) 1.6(1/64) 6.2(17/273)

In short-term schizophrenia trials, the proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 8.3% for asenapine sublingual tablets-treated patients versus 7% for placebo-treated patients. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 13.2% for asenapine sublingual tablets-treated patients versus 10.5% for placebo-treated patients. 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 sublingual tablets-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 sublingual tablets-treated patients versus 8.6% for placebo-treated patients.

Pediatric Patients: Data from the short-term, placebo-controlled bipolar mania trial are presented in Table 4

TABLE 4: Changes in Fasting Lipids in Pediatric Subjects
Bipolar I Disorder (3-weeks)
Placebo Asenapine sublingual tablets2.5 mg twice daily Asenapine sublingual tablets5 mg twice daily Asenapine sublingual tablets10 mg twice daily
*
= Number of patients who had assessments at both Baseline and Endpoint
Mean Change from Baseline (mg/dL)
Total fasting cholesterol (N *) -2.3(57) 3.7(50) 7.2(57) 9.3(52)
Fasting LDL (N *) -2.5(57) -0.2(50) 3.0(57) 4.9(51)
Fasting HDL (N *) 1.6 (57) 2.3 (50) 1.5(57) 1.7(52)
Fasting triglycerides (N *) -6.6(57) 8.7(50) 13.4(57) 14.7(52)
Proportion of Subjects with Shifts from Baseline to Endpoint
Total fasting cholesterol Normal to High <170 to >=200 (mg/dL) (n/N *) 1.8% (1/57) 0% (0/50) 1.8%(1/57) 0%(0/52)
Fasting LDL Normal to High <110 to >=130 (n/N *) 1.8% (1/57) 2.0% (1/50) 1.8%(1/57) 0%(0/51)
Fasting HDL Normal to Low ≥40 to <40 (mg/dL) (n/N *) 3.5% (2/57) 6.0% (3/50) 3.5%(2/57) 9.6%(5/52)
Fasting triglycerides Normal to High <150 to ≥200 (mg/dL) (n/N *) 0% (0/57) 4.0% (2/50) 3.5%(2/57) 1.9%(1/52)

Weight Gain

Weight gain has been observed in patients treated with atypical antipsychotics, including asenapine sublingual tabelts. 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 schizophrenia and bipolar mania trials are presented in Table 5.

Table 5: Change in Body Weight in Adult Patients from Baseline
Schizophrenia (6-weeks) Bipolar I Disorder (3-weeks)
Placebo Asenapine sublingual tablets Placebo Asenapine sublingual tablets
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily * 5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily
*
Includes subjects treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily (N=90)
Includes patients treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily (N=379).
= Number of subjects who had assessments at both Baseline and Endpoint.
Change from Baseline (kg) (N ) 0.0(348) 1.0(251) 0.9(200) 1.1(532) 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 1.6% 4.4% 4.8%. 4.9% 0.4% 6.4% 1.0% 5.5%

Adult Patients: In a 52-week, double-blind, comparator-controlled adult trial that included primarily patients with schizophrenia, 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 with Schizophrenia
BMI <23Asenapine sublingual tablets N=295 BMI 23 — ≤27Asenapine sublingual tabletsN=290 BMI >27Asenapine sublingual tablets N=302
Mean change from Baseline (kg) 1.7 1 0
% with ≥7% increase in body weight 22% 13% 9%

Pediatric Patients: Data on mean changes in body weight and the proportion of pediatric patients meeting a weight gain criterion of ≥7% of body weight from the short-term, placebo-controlled bipolar mania trial are presented in Table 7. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients by comparisons to age-and sex-matched population standards.

The distance of a z-score from 0 represents the distance of a percentile from the median, measured in standard deviations (SD). After adjusting for age and sex, the mean change from baseline to endpoint in weight z-score for asenapine sublingual tablets 2.5 mg, 5 mg, and 10 mg twice daily, was 0.11, 0.08 and 0.09 SD versus 0.02 SD for placebo, respectively.

When treating pediatric patients, weight gain should be monitored and assessed against that expected for normal growth.

Table 7: Change in Body Weight in Pediatric Subjects from Baseline
Bipolar I Disorder (3-weeks)
Placebo Asenapine sublingual tablets2.5 mgtwice daily Asenapine sublingual tablets5 mgtwice daily Asenapine sublingual tablets10 mgtwice daily
*
= Number of subjects who had assessments at both Baseline and Endpoint.
Change from Baseline (kg) (N *) 0.5(89) 1.7(92) 1.6(90) 1.4(87)
Proportion of Subjects with a ≥7% Increase in Body Weight
% with ≥7% increase in body weight 1.1% 12.0% 8.9% 8.0%

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