Asenapine

gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

5 mg, 5 mg, or 10 mg twice daily. 1% (5/99) of patients treated with asenapine 10 mg twice daily discontinued treatment due to adverse reactions compared to 4% (4/101) on placebo. 5 mg twice daily group, 1% in the 5 mg twice daily group, and 2% in the 10 mg twice daily group), abdominal pain (2% in the 10 mg twice daily group), and nausea (2% in the 10 mg twice daily group) No placebo-treated patients dropped out for these events.

Adverse Reactions Occurring with Asenapine at an Incidence of 2% or More in Asenapine-treated Bipolar I Patients: Adverse reactions associated with the use of asenapine (incidence of ≥2% in any asenapine dose group and greater than placebo) that occurred during acute therapy are shown in Table 10 .

5, 5, and 10 mg N=101 % N=104 % N=99 % N=99 % N=302 % Cardiac Disorders Tachycardia 1 0 3 0 1 1 Gastrointestinal Disorders Oral hypoesthesia 2 4 25 25 30 27 Nausea 3 6 6 6 6 Vomiting 3 4 4 4 4 Abdominal pain 3 7 9 3 5 6 Glossodynia 0 0 2 0 1 General Disorders and Administrative Site Disorders Fatigue 4 5 4 8 14 9 Irritability 1 1 1 2 1 Injury, Poisoning, and Procedural Complications Muscle strain 0 0 0 2 1 Investigations Increased weight 0 6 2 2 3 Hyperinsulinemia 5 0 1 3 1 2 ALT increased 0 0 0 2 1 AST increased 0 0 0 2 1 Metabolism and Nutrition Disorders Increased appetite 2 10 9 6 8 Dehydration 1 0 2 0 1 Musculoskeletal and Connective Tissue Disorders Myalgia 0 0 2 1 1 Nervous System Disorders Somnolence 6 12 46 53 49 49 Headache 6 8 11 9 9 Dizziness 3 6 10 5 7 Dysgeusia 2 4 5 9 6 Akathisia 0 2 2 1 2 Parkinsonism 0 1 0 2 1 Psychiatric Disorders Insomnia 3 3 4 3 3 Suicidal ideation 1 4 1 3 3 Anger 0 0 0 2 1 Reproductive System and Breast Disorders Dysmenorrhea 1 0 2 0 1 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal pain 2 0 3 1 1 Nasal congestion 1 0 2 0 1 Dyspnea 0 0 2 0 1 Skin and Subcutaneous Tissue Disorders Rash 1 0 1 2 1 1 Includes the preferred terms tachycardia and heart rate increased.

2 Includes the preferred terms oral hypoesthesia, oral paresthesia, and oral dysesthesia. 3 Includes the preferred terms abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. 4 Includes the preferred terms fatigue and lethargy.

5 Includes the preferred terms hyperinsulinemia and blood insulin increased. 6 Includes the preferred terms somnolence, sedation, and hypersomnia.

Dose-Related Adverse Reactions:

In the short term pediatric bipolar I trial the incidence of fatigue appeared to be dose-related (see Table 10 ).

Adjunctive Therapy in Adult Patients with Bipolar Mania:

The following findings are based on a 12 week placebo-controlled trial (with a 3 week efficacy endpoint) in adult patients with bipolar mania in which sublingual asenapine was administered in doses of 5 mg or 10 mg twice daily as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment:

Approximately 16% (25/158) of asenapine-treated patients discontinued treatment due to an adverse reaction, compared with about 11% (18/166) on placebo. 3%). Adverse Reactions Occurring at an Incidence of 2% or More Among Asenapine-Treated (Adjunctive) Bipolar I Patients: Adverse reactions associated with the use of asenapine (incidence of 2% or greater, rounded to the nearest percent, and asenapine incidence greater than placebo) that occurred during acute adjunctive therapy at 3 weeks, a time when most of the patients were still participating in the trial, are shown in Table 11 .

Table 11:

Adverse Reactions Reported in 2% or More of Adult Patients In Any Asenapine-Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials System Organ Class/Preferred Term Placebo N=166 % Asenapine 5 mg or 10 mg twice daily * N=158 % Gastrointestinal disorders Dyspepsia 2 3 Oral hypoesthesia 0 5 General disorders Fatigue 2 4 Edema peripheral <1 3 Investigations Increased weight 0 3 Nervous system disorders Dizziness 2 4 Other extrapyramidal symptoms (excluding akathisia) † 5 6 Somnolence ‡ 10 22 Psychiatric disorders Insomnia 8 10 Vascular disorders Hypertension <1 3 * Asenapine 5 mg to 10 mg twice daily with flexible dosing.

† Extrapyramidal symptoms included: dystonia, parkinsonism, oculogyration, and tremor (excluding akathisia). ‡ Somnolence includes the following events: somnolence and sedation.

Dystonia:

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue.

While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. 3)] .

Extrapyramidal Symptoms:

In the short-term, placebo-controlled bipolar mania adult trials, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Assessments of Involuntary Movement Scales (for dyskinesias).

The mean change from baseline for the all-asenapine 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores. In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for asenapine-treated patients was 8% versus 4% for placebo; and the incidence of akathisia-related events for asenapine-treated patients was 7% versus 3% for placebo.

The incidence rates of all EPS events (including akathisia) were lower at the 5 mg twice daily dose (11% of N=122) than the 10 mg twice daily dose (25% of N=119) in another study. 5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 3% for placebo-treated patients.

EPS-related events include: bradykinesia, dyskinesia, dystonia, oromandibular dystonia, muscle contractions involuntary, muscle twitching, musculoskeletal stiffness, parkinsonism, protrusion tongue, resting tremor, and tremor. 5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 0% for placebo-treated patients.

Other Findings:

Oral hypoesthesia and/or oral paresthesia may occur directly after administration of asenapine and usually resolves within 1 hour.

Laboratory Test Abnormalities:

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term bipolar mania adult trials were more common in treated patients. 9 units/L in placebo-treated patients. 7% for placebo-treated patients. The incidence rate of transaminase elevations ≥3 times ULN is 3% of N=95 for 10 mg twice daily dose, and 0% of N=108 for the 5 mg twice daily dose and 0% of N=115 for placebo in another study.

7 units/L. In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, transient elevations in serum transaminases (primarily ALT) were more common in treated patients. 4% for patients treated with asenapine 10 mg twice daily versus none for the other asenapine dose groups and placebo-treated patients.

7 ng/mL for asenapine-treated patients compared to a decrease of 1 ng/mL for placebo-treated patients. 8% for placebo-treated patients. 9 ng/mL. 5 ng/mL for placebo-treated patients. There were no reports of prolactin elevations ≥4 times ULN (at Endpoint) for patients treated with asenapine or placebo.

5 mg twice daily, 2% of patients treated with asenapine 5 mg twice daily, and 1% of patients treated with asenapine 10 mg twice daily compared to 1% of placebo-treated patients. There were no reports of gynecomastia in this trial. 7% for placebo-treated patients in pre-marketing short-term, fixed-dose trials in bipolar mania and another indication.

The clinical relevance of this finding is unknown. 5 mg, 5 mg, and 10 mg twice daily, respectively, versus 3% for placebo-treated patients.

Other Adverse Reactions Observed During the Premarketing Evaluation of Asenapine:

Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual asenapine at multiple doses of ≥5 mg twice daily during any phase of a trial within the database of adult patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds.

Reactions already listed for adult patients in other parts of Adverse Reactions (6) , or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) are not included. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).

5 mg, 5 mg, or 10 mg twice daily during any phase of a trial within the database of pediatric patients. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of asenapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure.

In many cases, the occurrence of these adverse reactions led to discontinuation of therapy. Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, blisters, peeling/sloughing, and inflammation.

Choking has been reported by patients, some of whom may have also experienced oropharyngeal muscular dysfunction or hypoesthesia.

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.

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 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. 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). 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 . 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. 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).

9% for placebo-treated patients. 6% for placebo-treated patients.

Pediatric Patients:

Data from the short-term, placebo-controlled bipolar mania trial are presented in Table 4 . 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. 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). 9 kg. 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.

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).

02 SD for placebo, respectively. When treating pediatric patients, weight gain should be monitored and assessed against that expected for normal growth. 9% 8% N * = Number of subjects who had assessments at both Baseline and Endpoint.

6 Hypersensitivity Reactions Hypersensitivity reactions have been observed in patients treated with asenapine. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.

7 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. 2% (1/620) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of asenapine, compared to 0% (0/329) of patients treated with placebo.

6% (11/1953) of patients treated with asenapine. 5 mg twice daily, 1% (1/99) of patients treated with asenapine 5 mg twice daily, and 0% (0/99) for patients treated with asenapine 10 mg twice daily compared to 0% (0/101) for patients treated with placebo.

Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medications, patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.

1)] . Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. 8 Falls Asenapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 9 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including asenapine.

Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug induced leukopenia/neutropenia.

In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) during the first few months of therapy. In such patients, consider discontinuation of asenapine at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue asenapine in patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) and follow their WBC until recovery.

10 QT Prolongation The effects of asenapine on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved asenapine doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with electrocardiographic assessments throughout the dosing interval at baseline and steady state.

At these doses, asenapine was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with asenapine experienced QTc increases ≥60 msec from baseline measurements, nor did any patient experience a QTc of ≥500 msec.

Electrocardiogram (ECG) measurements were taken at various time points during the asenapine clinical trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for asenapine and placebo in these short-term trials.

There were no reports of Torsade de Pointes or any other adverse reactions associated with delayed ventricular repolarization. , gatifloxacin, moxifloxacin). Asenapine should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval.

11 Hyperprolactinemia Like other drugs that antagonize dopamine D 2 receptors, asenapine can elevate prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. 4% versus 0% for placebo. 1)]. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer.

Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. 3% (0/572, 1/379) of adult patients treated with doses of 5 mg and 10 mg twice daily of asenapine, respectively, compared to 0% (0/203) of patients treated with placebo in pre-marketing short-term bipolar mania trials.

3% (5/1953) of patients treated with asenapine. There were no reports of seizures in pediatric patients treated with asenapine in a 3-week-term, bipolar mania trial. As with other antipsychotic drugs, asenapine should be used with caution 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 patients 65 years or older. 13 Potential for Cognitive and Motor Impairment Somnolence was reported in patients treated with asenapine. It was usually transient with the highest incidence reported during the first week of treatment.

In short-term, placebo-controlled bipolar mania adult trials of therapeutic doses (5 to 10 mg twice daily), somnolence was reported in 23% (145/620) of patients on asenapine compared to 5% (18/329) of placebo patients. In another study, somnolence occurred at a lower rate in the 5 mg twice daily dose 20% (24/122) versus the 10 mg twice daily dose 26% (31/119) compared to 4% (5/126) in placebo patients.

During adult pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with asenapine. 6% (12/1953) of patients in short-term, placebo-controlled trials.

5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, was 12% (12/101), 46% (48/104), 53% (52/99), and 49% (49/99), respectively. 5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, respectively. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that asenapine therapy does not affect them adversely.

14 Body Temperature Regulation Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. In the pre-marketing short-term placebo-controlled trials for acute bipolar I disorder and another indication, the incidence of adverse reactions suggestive of body temperature increases was low (≤1%) and comparable to placebo (0%).

During pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, the incidence of adverse reactions suggestive of body temperature increases (pyrexia and feeling hot) was ≤1%. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use asenapine with caution in patient who may experience these conditions.

15 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with asenapine. Asenapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.