Asenapine

ASENAPINE — asenapine tablet
Alembic Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

Asenapine is indicated for:
• Bipolar I disorder [see Clinical Studies (14.2)]
• Acute monotherapy of manic or mixed episodes, in pediatric patients 10 to 17 years of age
• Adjunctive treatment to lithium or valproate in adults

2 DOSAGE AND ADMINISTRATION

2.1 Administration Instructions

Asenapine is a sublingual tablet. To ensure optimal absorption, patients should be instructed to place the tablet under the tongue and allow it to dissolve completely. The tablet will dissolve in saliva within seconds. Asenapine sublingual tablets should not be split, crushed, chewed, or swallowed [see Clinical Pharmacology (12.3)]. Patients should be instructed to not eat or drink for 10 minutes after administration [see Clinical Pharmacology (12.3)].

2.3 Bipolar I Disorder

Acute Treatment of Manic or Mixed Episodes:

Monotherapy in Pediatric Patients:The recommended dose of asenapine is 2.5 mg to 10 mg twice daily in pediatric patients 10 to 17 years of age, and dose may be adjusted for individual response and tolerability. The starting dose of asenapine is 2.5 mg twice daily. After 3 days, the dose can be increased to 5 mg twice daily, and from 5 mg to 10 mg twice daily after 3 additional days. Pediatric patients aged 10 to 17 years appear to be more sensitive to dystonia with initial dosing with asenapine when the recommended escalation schedule is not followed [see Use in Specific Populations (8.4)]. The safety of doses greater than 10 mg twice daily has not been evaluated in clinical trials [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

Adjunctive Therapy in Adults: The recommended starting dose of asenapine is 5 mg twice daily when administered as adjunctive therapy with either lithium or valproate. Depending on the clinical response and tolerability in the individual patient, the dose can be increased to 10 mg twice daily. The safety of doses above 10 mg twice daily as adjunctive therapy with lithium or valproate has not been evaluated in clinical trials.

For patients on asenapine, used as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients continue treatment beyond the acute episode.

3 DOSAGE FORMS AND STRENGTHS

2.5 mg: White to off white, round tablets debossed with ‘L’ on one side and ‘70’ on the other side.

5 mg: White to off white, round tablets debossed with “464” on one side and plain on other side.
10 mg: White to off white round tablets debossed with “465” on one side and plain on other side.

4 CONTRAINDICATIONS

Asenapine is contraindicated in patients with:

• Severe hepatic impairment (Child-Pugh C) [see Specific Populations (8.7), Clinical Pharmacology (12.3)].
• A history of hypersensitivity reactions to asenapine. Reactions have included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash [see Warnings and Precautions (5.6), Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Asenapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

5.2 Cerebrovascular Adverse Events, Including Stroke, In Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Asenapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

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, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue asenapine and provide intensive symptomatic treatment and monitoring.

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 TD 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	5 mg or 10 mg twice daily †
Mean Change from Baseline in Fasting Glucose at Endpoint
Change from Baseline (mg/dL) (N*)	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**)	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**)	0% (0/39)	12.5% (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 mg 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.

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	Asenapine2.5 mg twice daily	Asenapine5 mg twice daily	Asenapine10 mg twice daily
Mean Change from Baseline in Fasting Glucose to 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	0%	0%	1.8%	0%
(n/N*)	(0/56)	(0/51)	(1/57)	(0/52)

N^* = Number of subjects who had assessments at both Baseline and Endpoint

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 mg or 10 mg twice daily †
Mean Change from Baseline (mg/dL)
Total cholesterol (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 (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 (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)
HDL Normal to Low ≥40 to <40 (mg/dL) (n/N*)	7.4 (16/215)	4.1 (4/97)	5.1 (4/78)	7 (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 mg 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.

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	Asenapine2.5 mg twice daily	Asenapine5 mg twice daily	Asenapine10 mg twice daily
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 (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% (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% (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% (2/50)	3.5% (2/57)	1.9% (1/52)

N* = Number of patients who had assessments at both Baseline and Endpoint

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 mg 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%	5.5%

N^* = Number of subjects who had assessments at both Baseline and Endpoint.

^† Includes patients treated with flexible dose of asenapine 5 mg or 10 mg twice daily (n=379).

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 Adult Patients

	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%

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 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 2.5 mg twice daily	Asenapine 5 mg twice daily	Asenapine 10 mg twice daily
Mean Change from Baseline in Fasting Glucose to 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%	8.9%	8%

N^* = Number of subjects who had assessments at both Baseline and Endpoint.