Saphris

Dosage Forms And Strengths

• SAPHRIS 2.5 mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with a hexagon on one side.
• SAPHRIS 5 mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with “5” on one side within a circle.
• SAPHRIS 10 mg tablets, black cherry flavor, are round, white to off-white sublingual tablets, with “10” on one side within a circle.

Storage And Handling

SAPHRIS (asenapine) sublingual tablets are supplied as:

2.5 mg Tablets, black cherry flavor

Round, white to off-white sublingual tablets, with a hexagon on one side. Child-resistant packaging

Box of 60 6 blisters with 10 tablets NDC 0456-2402-60

Hospital Unit Dose

Box of 100 10 blisters with 10 tablets NDC 0456-2402-63

5 mg Tablets, black cherry flavor

Round, white to off-white sublingual tablets, with “5” on one side within a circle.

Child-resistant Packaging

Box of 60 6 blisters with 10 tablets NDC 0456-2405-60

Hospital Unit Dose

Box of 100 10 blisters with 10 tablets NDC 0456-2405-63

10 mg Tablets, black cherry flavor

Round, white to off-white sublingual tablets, with “10” on one side within a circle.

Child-resistant Packaging

Box of 60 6 blisters with 10 tablets NDC 0456-2410-60

Hospital Unit Dose

Box of 100 10 blisters with 10 tablets NDC 0456-2410-63

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Distributed by: Allergan USA, Inc. Irvine, CA 92612. Revised: Feb 2017

SAPHRIS is indicated for:

• Schizophrenia in adults
• Bipolar I disorder
  • Acute monotherapy of manic or mixed episodes, in adults and pediatric patients 10 to 17 years of age
  • Adjunctive treatment to lithium or valproate in adults
  • Maintenance monotherapy treatment in adults

Administration Instructions

SAPHRIS 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. SAPHRIS sublingual tablets should not be split, crushed, chewed, or swallowed. Patients should be instructed to not eat or drink for 10 minutes after administration.

Schizophrenia

The recommended dose of SAPHRIS is 5 mg given twice daily. In short-term controlled trials, there was no suggestion of added benefit with a 10 mg twice daily dose, but there was a clear increase in certain adverse reactions. If tolerated, daily dosage can be increased to 10 mg twice daily after one week. The safety of doses above 10 mg twice daily has not been evaluated in clinical studies.

Bipolar I Disorder

Acute Treatment Of Manic Or Mixed Episodes

Monotherapy in Adults: The recommended starting and treatment dose of SAPHRIS is 5 mg to 10 mg twice daily. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials.

Monotherapy in Pediatric Patients: The recommended dose of SAPHRIS 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 SAPHRIS 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 SAPHRIS when the recommended escalation schedule is not followed. The safety of doses greater than 10 mg twice daily has not been evaluated in clinical trials.

Adjunctive Therapy in Adults: The recommended starting dose of SAPHRIS 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 SAPHRIS, whether used as monotherapy or as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients continue treatment beyond the acute episode.

Maintenance Treatment Of Bipolar I Disorder

Monotherapy in Adults: Continue on the SAPHRIS dose that the patient received during stabilization (5 mg to 10 mg twice daily). Depending on the clinical response and tolerability in the individual patient, a dose of 10 mg twice daily can be decreased to 5 mg twice daily. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials.

SAPHRIS is contraindicated in patients with:

• Severe hepatic impairment (Child-Pugh C).
• A history of hypersensitivity reactions to asenapine. Reactions have included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 the drug-treated patients of between 1.6 to 1.7 times that seen 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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis.

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

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis.

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, including SAPHRIS. 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) 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 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.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements can develop in patients treated 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 (TD) is unknown.

The risk of developing TD 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 TD, 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, SAPHRIS should be prescribed in a manner that is most likely to minimize the occurrence of TD. 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 TD appear in a patient on SAPHRIS, drug discontinuation should be considered. However, some patients may require treatment with SAPHRIS despite the presence of the syndrome.

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. W hile 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, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. 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. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Precise risk estimates for hyperglycemia-related adverse events 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 anti-diabetic treatment despite discontinuation of the antipsychotic drug.

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

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

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

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

In short-term schizophrenia trials, the proportion of patients with total cholesterol elevations ≥ 240 mg/dL (at Endpoint) was 8.3% for SAPHRIS-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 SAPHRIS-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 8.7% for SAPHRIS-treated patients versus 8.6% for placebo-treated patients. The proportion of patients with elevations in triglycerides ≥ 200 mg/dL (at Endpoint) was 15.2% for SAPHRIS-treated patients versus 11.4% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial that included primarily patients with schizophrenia, the mean decrease from baseline of total cholesterol was 6 mg/dL and the mean decrease from baseline of fasting triglycerides was 9.8 mg/dL.

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

Weight Gain

Increases in weight have been observed in pre-marketing clinical trials with SAPHRIS. Patients receiving SAPHRIS should receive regular monitoring of weight.

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

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 5 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

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 SAPHRS 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

Hypersensitivity Reactions

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

Orthostatic Hypotension, Syncope, And Other Hemodynamic Effects

SAPHRIS may induce orthostatic hypotension and syncope in some patients, especially early in treatment, because of its α1-adrenergic antagonist activity. In short-term schizophrenia adult trials, syncope was reported in 0.2% (1/572) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of SAPHRIS, compared to 0.3% (1/378) of patients treated with placebo. In short-term bipolar mania adult trials, syncope was reported in 0.3% (1/379) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of SAPHRIS, compared to 0% (0/203) of patients treated with placebo. During adult pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with SAPHRIS. In a 3-week, bipolar mania pediatric trial, syncope was reported in 1% (1/104) of patients treated with SAPHRIS 2.5 mg twice daily, 1% (1/99) of patients treated with SAPHRIS 5 mg twice daily, and 0% (0/99) for patients treated with SAPHRIS 10 mg twice daily compared to 0% (0/101) for patients treated with placebo.

Patients should be instructed about non-pharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). SAPHRIS should be used with caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications); and (2) in the elderly. SAPHRIS should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.

Leukopenia, Neutropenia, And Agranulocytosis

In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including SAPHRIS. 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)/absolute neutrophil count (ANC) and history of drug induced leukopenia/neutropenia. In patients with a pre-existing low W BC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of SAPHRIS at the first sign of a clinically significant decline in W BC 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 SAPHRIS in patients with severe neutropenia (absolute neutrophil count < 1000/mm³) and follow their W BC until recovery.

QT Prolongation

The effects of SAPHRIS on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved SAPHRIS doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with schizophrenia, with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, SAPHRIS was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with SAPHRIS 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 SAPHRIS clinical trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for SAPHRIS 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.

The use of SAPHRIS should be avoided in combination with other drugs known to prolong QTc including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin). SAPHRIS 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.

Hyperprolactinemia

Like other drugs that antagonize dopamine D2 receptors, SAPHRIS 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. In SAPHRIS adult clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo. In a 3-week, bipolar mania pediatric trial, the incidence of adverse events related to abnormal prolactin levels were 0% in the SAPHRIS 2.5 mg twice daily treatment group, 2% in the SAPHRIS 5 mg twice daily treatment group, and 1% in the SAPHRIS 10 mg twice daily treatment group versus to 1% for patients treated with placebo.

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. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

Seizures

Seizures were reported in 0% and 0.3% (0/572, 1/379) of adult patients treated with doses of 5 mg and 10 mg twice daily of SAPHRIS, respectively, compared to 0% (0/503, 0/203) of patients treated with placebo in short-term schizophrenia and bipolar mania trials, respectively. During adult pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1953) of patients treated with SAPHRIS. There were no reports of seizures in pediatric patients treated with SAPHRIS in a 3-week-term, bipolar mania trial.

As with other antipsychotic drugs, SAPHRIS 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.

Potential For Cognitive And Motor Impairment

Somnolence was reported in patients treated with SAPHRIS. It was usually transient with the highest incidence reported during the first week of treatment. In short-term, fixed-dose, placebo-controlled schizophrenia adult trials, somnolence was reported in 15% (41/274) of patients on SAPHRIS 5 mg twice daily and in 13% (26/208) of patients on SAPHRIS 10 mg twice daily compared to 7% (26/378) of placebo patients. In short-term, placebo-controlled bipolar mania adult trials of therapeutic doses (5-10 mg twice daily), somnolence was reported in 24% (90/379) of patients on SAPHRIS compared to 6% (13/203) of placebo patients. During adult pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with SAPHRIS. Somnolence (including sedation) led to discontinuation in 0.6% (12/1953) of patients in short-term, placebo-controlled trials.

In a 3-week, placebo-controlled, bipolar I pediatric trial, the incidence of somnolence (including sedation and hypersomnia) for placebo, SAPHRIS 2.5 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. Somnolence led to discontinuation in 0%, 3%, 1%, and 2% of patients treated with placebo, and SAPHRIS 2.5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, respectively.

Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SAPHRIS therapy does not affect them adversely.

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. In the short-term placebo-controlled trials for both schizophrenia and acute bipolar disorder, the incidence of adverse reactions suggestive of

SIDE EFFECTS

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Use in Elderly Patients with Dementia-Related Psychosis
• Neuroleptic Malignant Syndrome
• Tardive Dyskinesia
• Metabolic Changes
• Hypersensitivity Reactions
• Orthostatic Hypotension, Syncope, and other Hemodynamic Effects
• Falls
• Leukopenia, Neutropenia, and Agranulocytosis
• QT Interval Prolongation
• Hyperprolactinemia
• Seizures
• Potential for Cognitive and Motor Impairment
• Body Temperature Regulation
• Dysphagia

The most common adverse reactions ( ≥ 5% and at least twice the rate of placebo) reported with acute treatment in adults with schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of SAPHRIS in the maintenance treatment of schizophrenia in adults was similar to that seen with acute treatment.

The most common adverse reactions ( ≥ 5% and at least twice the rate of placebo) reported with acute monotherapy treatment of manic or mixed episodes associated with bipolar I disorder in adults were somnolence, oral hypoesthesia dizziness, extrapyramidal symptoms (excluding akathisia) and akathisia; and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia. The rates were lower at the 5mg twice daily dose than the 10mg twice daily dose for all of these most common adverse reactions. The safety profile of SAPHRIS in the maintenance treatment of manic or mixed episodes associated with bipolar I disorder in adults was similar to that seen with acute treatment.

The adult information below is derived from a clinical trial database for SAPHRIS consisting of over 5355 patients and/or healthy subjects exposed to one or more sublingual doses of SAPHRIS. A total of 1427 SAPHRIS-treated patients were treated for at least 24 weeks and 785 SAPHRIS-treated patients had at least 52 weeks of exposure at therapeutic doses.

In a 3-week monotherapy trial, the most common adverse reactions ( ≥ 5% and at least twice the rate of placebo) reported in pediatric patients with bipolar I disorder treated with SAPHRIS were somnolence, dizziness, dysgeusia, oral hypoesthesia, nausea, increased appetite, fatigue, and increased weight. No new major safety findings were reported from a 50-week, open-label, uncontrolled safety trial.

A total of 651 pediatric patients were treated with SAPHRIS. Of these patients, 352 pediatric patients were treated with SAPHRIS for at least 180 days and 58 pediatric patients treated with SAPHRIS had at least 1 year of exposure. The safety of SAPHRIS was evaluated in 403 pediatric patients with bipolar I disorder who participated in a 3-week, placebo-controlled, double-blind trial, of whom 302 patients received SAPHRIS at fixed doses ranging from 2.5 mg to 10 mg twice daily.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment-emergent adverse event of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

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.

Adult Patients with Schizophrenia: The following findings are based on the short-term placebo-controlled pre-marketing trials for schizophrenia (a pool of three 6-week fixed-dose trials and one 6-week flexible-dose trial) in which sublingual SAPHRIS was administered in doses ranging from 5 to 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9% of SAPHRIS-treated patients and 10% of placebo-treated patients discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in patients treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in SAPHRIS-Treated Patients with Schizophrenia: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 8.

Table 8: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials

Dose-Related Adverse Reactions: In the short term schizophrenia trials the incidence of akathisia appeared to be dose-related (see Table 8).

Monotherapy In Adult Patients With Bipolar Mania

The following findings are based on the short-term placebo-controlled trials for bipolar mania (a pool of two 3-week flexible-dose trials and one 3-week fixed-dose trial) in which sublingual SAPHRIS was administered in doses of 5 mg or 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: Approximately 10% (61/620) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 7% (22/329) on placebo. There were no adverse reactions associated with discontinuation in patients treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate

Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Monotherapy) patients with Bipolar I Disorder: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 9.

Table 9: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Respective Placebo Group in 3-Week Bipolar Mania Fixed and Flexible Dose Trials

Monotherapy In Pediatric Patients With Bipolar Mania

The following findings are based on a 3-week , placebo-controlled trial for bipolar mania in which SAPHRIS was administered at doses of 2.5 mg, 5 mg, or 10 mg twice daily.

Adverse Reactions Leading to Discontinuation of Treatment: A total of 6.7% (7/104) of patients treated with SAPHRIS 2.5 mg twice daily, 5.1% (5/99) of patients treated with SAPHRIS 5 mg twice daily, and 5.1% (5/99) of patients treated with SAPHRIS 10 mg twice daily discontinued treatment due to adverse reactions compared to 4% (4/101) on placebo. The most common adverse reactions that led to discontinuation in pediatric patients treated with SAPHRIS (rates at least 2% in any SAPHRIS arm and at least twice the placebo rate) were somnolence (3% in the 2.5mg twice daily group, 1% in the 5mg twice daily group, and 2% in the 10mg twice daily group), abdominal pain (2% in the 10mg twice daily group), and nausea (2% in the 10mg twice daily group) No placebo-treated patients dropped out for these events.

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

Table 10: Adverse Reactions Reported in 2% or More of Pediatric Patients (Ages 10 to 17 Years) in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial

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 SAPHRIS 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 SAPHRIS-treated patients discontinued treatment due to an adverse reaction, compared with about 11% (18/166) on placebo. The most common adverse reactions associated with discontinuation in subjects treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were depression (2.5%), suicidal ideation (2.5%), bipolar I disorder (1.9%), insomnia (1.9%) and depressive symptoms (1.3%).

Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Adjunctive) Bipolar I Patients: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS 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 SAPHRIS-Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials

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. An elevated risk of acute dystonia is observed in males and younger age groups.

Extrapyramidal Symptoms

In the short-term, placebo-controlled schizophrenia and 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-SAPHRIS 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores.

In the short-term, placebo-controlled schizophrenia adult trials, the incidence of reported EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 10% versus 7% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 6% versus 3% for placebo. In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 8% versus 4% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 7% versus 3% for placebo. The incidence rates of all EPS events (including akathisia) were lower at the 5mg twice daily dose (11% of N=122) than the 10mg twice daily dose (25% of N=119) in a fixed-dose study.

In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the incidences of EPS-related events, excluding events related to akathisia, were 4%, 3%, and 5% for patients treated with SAPHRIS 2.5 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.

For events of akathisia, incidences were 2%, 2%, and 1% for pediatric patients treated with SAPHRIS 2.5 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 SAPHRIS and usually resolves within 1 hour.

Laboratory Test Abnormalities

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania adult trials were more common in treated patients. In short-term, placebo-controlled schizophrenia adult trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 1.6 units/L compared to a decrease of 0.4 units/L for placebo-treated patients. The proportion of patients with transaminase elevations ≥ 3 times ULN (at Endpoint) was 0.9% for SAPHRIS-treated patients versus 1.3% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 6.1units/L compared to a decrease of 3.9units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥ 3 times upper limit of normal (ULN) (at Endpoint) was 2.1% for SAPHRIS-treated patients versus 0.7% for placebo-treated patients. The incidence rate of transaminase elevations ≥ 3 times ULN is 3% of N=95 for 10mg twice daily dose, and 0% of N=108 for the 5mg twice daily dose and 0% of N=115 for placebo in a fixed-dose study.

In a 52-week, double-blind, comparator-controlled trial that included primarily adult patients with schizophrenia, the mean increase from baseline of ALT was 1.7 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. The proportion of pediatric patients with ALT elevations ≥ 3 times upper limit of normal (ULN) was 2.4% for patients treated with SAPHRIS 10 mg twice daily versus none for the other SAPHRIS dose groups and placebo-treated patients.

Prolactin: In short-term, placebo-controlled adult schizophrenia trials, the mean decreases in prolactin levels were 6.5 ng/mL for SAPHRIS-treated patients compared to 10.7 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥ 4 times ULN (at Endpoint) were 2.6% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 6.7ng/mL for SAPHRIS-treated patients compared to a decrease of 1.0 ng/mL for placebo-treated patients. The proportion of patients with prolactin e

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SAPHRIS during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-9612388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Studies have not been conducted with SAPHRIS in pregnant women. There are no available human data informing the drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. No teratogenicity was observed in animal reproduction studies with intravenous administration of asenapine to rats and rabbits during organogenesis at doses 0.7 and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 10 mg sublingually twice daily. In a pre-and post-natal study in rats, intravenous administration of asenapine at doses up to 0.7 times the MRHD produced increases in post-implantation loss and early pup deaths, and decreases in subsequent pup survival and weight gain. Advise pregnant women of the potential risk to a fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Data

Animal Data

In animal studies, asenapine increased post-implantation loss and decreased pup weight and survival at doses similar to or less than recommended clinical doses. In these studies there was no increase in the incidence of structural abnormalities caused by asenapine.

Asenapine was not teratogenic in reproduction studies in rats and rabbits at intravenous doses up to 1.5 mg/kg in rats and 0.44 mg/kg in rabbits administered during organogenesis. These doses are 0.7 and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 10 mg twice daily given sublingually on a mg/m² basis. Plasma levels of asenapine were measured in the rabbit study, and the area under the curve (AUC) at the highest dose tested was 2 times that in humans receiving the MRHD.

In a study in which rats were treated from day 6 of gestation through day 21 postpartum with intravenous doses of asenapine of 0.3, 0.9, and 1.5 mg/kg/day (0.15, 0.4, and 0.7 times the MRHD of 10 mg twice daily given sublingually on a mg/m² basis), increases in post-implantation loss and early pup deaths were seen at all doses, and decreases in subsequent pup survival and weight gain were seen at the two higher doses. A cross-fostering study indicated that the decreases in pup survival were largely due to prenatal drug effects. Increases in post-implantation loss and decreases in pup weight and survival were also seen when pregnant rats were dosed orally with asenapine.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Use in Elderly Patients with Dementia-Related Psychosis
• Neuroleptic Malignant Syndrome
• Tardive Dyskinesia
• Metabolic Changes
• Hypersensitivity Reactions
• Orthostatic Hypotension, Syncope, and other Hemodynamic Effects
• Falls
• Leukopenia, Neutropenia, and Agranulocytosis
• QT Interval Prolongation
• Hyperprolactinemia
• Seizures
• Potential for Cognitive and Motor Impairment
• Body Temperature Regulation
• Dysphagia

The most common adverse reactions ( ≥ 5% and at least twice the rate of placebo) reported with acute treatment in adults with schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of SAPHRIS in the maintenance treatment of schizophrenia in adults was similar to that seen with acute treatment.

The most common adverse reactions ( ≥ 5% and at least twice the rate of placebo) reported with acute monotherapy treatment of manic or mixed episodes associated with bipolar I disorder in adults were somnolence, oral hypoesthesia dizziness, extrapyramidal symptoms (excluding akathisia) and akathisia; and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia. The rates were lower at the 5mg twice daily dose than the 10mg twice daily dose for all of these most common adverse reactions. The safety profile of SAPHRIS in the maintenance treatment of manic or mixed episodes associated with bipolar I disorder in adults was similar to that seen with acute treatment.

The adult information below is derived from a clinical trial database for SAPHRIS consisting of over 5355 patients and/or healthy subjects exposed to one or more sublingual doses of SAPHRIS. A total of 1427 SAPHRIS-treated patients were treated for at least 24 weeks and 785 SAPHRIS-treated patients had at least 52 weeks of exposure at therapeutic doses.

In a 3-week monotherapy trial, the most common adverse reactions ( ≥ 5% and at least twice the rate of placebo) reported in pediatric patients with bipolar I disorder treated with SAPHRIS were somnolence, dizziness, dysgeusia, oral hypoesthesia, nausea, increased appetite, fatigue, and increased weight. No new major safety findings were reported from a 50-week, open-label, uncontrolled safety trial.

A total of 651 pediatric patients were treated with SAPHRIS. Of these patients, 352 pediatric patients were treated with SAPHRIS for at least 180 days and 58 pediatric patients treated with SAPHRIS had at least 1 year of exposure. The safety of SAPHRIS was evaluated in 403 pediatric patients with bipolar I disorder who participated in a 3-week, placebo-controlled, double-blind trial, of whom 302 patients received SAPHRIS at fixed doses ranging from 2.5 mg to 10 mg twice daily.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment-emergent adverse event of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

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.

Adult Patients with Schizophrenia: The following findings are based on the short-term placebo-controlled pre-marketing trials for schizophrenia (a pool of three 6-week fixed-dose trials and one 6-week flexible-dose trial) in which sublingual SAPHRIS was administered in doses ranging from 5 to 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9% of SAPHRIS-treated patients and 10% of placebo-treated patients discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in patients treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in SAPHRIS-Treated Patients with Schizophrenia: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 8.

Table 8: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials

Dose-Related Adverse Reactions: In the short term schizophrenia trials the incidence of akathisia appeared to be dose-related (see Table 8).

Monotherapy In Adult Patients With Bipolar Mania

The following findings are based on the short-term placebo-controlled trials for bipolar mania (a pool of two 3-week flexible-dose trials and one 3-week fixed-dose trial) in which sublingual SAPHRIS was administered in doses of 5 mg or 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: Approximately 10% (61/620) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 7% (22/329) on placebo. There were no adverse reactions associated with discontinuation in patients treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate

Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Monotherapy) patients with Bipolar I Disorder: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 9.

Table 9: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Respective Placebo Group in 3-Week Bipolar Mania Fixed and Flexible Dose Trials

Monotherapy In Pediatric Patients With Bipolar Mania

The following findings are based on a 3-week , placebo-controlled trial for bipolar mania in which SAPHRIS was administered at doses of 2.5 mg, 5 mg, or 10 mg twice daily.

Adverse Reactions Leading to Discontinuation of Treatment: A total of 6.7% (7/104) of patients treated with SAPHRIS 2.5 mg twice daily, 5.1% (5/99) of patients treated with SAPHRIS 5 mg twice daily, and 5.1% (5/99) of patients treated with SAPHRIS 10 mg twice daily discontinued treatment due to adverse reactions compared to 4% (4/101) on placebo. The most common adverse reactions that led to discontinuation in pediatric patients treated with SAPHRIS (rates at least 2% in any SAPHRIS arm and at least twice the placebo rate) were somnolence (3% in the 2.5mg twice daily group, 1% in the 5mg twice daily group, and 2% in the 10mg twice daily group), abdominal pain (2% in the 10mg twice daily group), and nausea (2% in the 10mg twice daily group) No placebo-treated patients dropped out for these events.

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

Table 10: Adverse Reactions Reported in 2% or More of Pediatric Patients (Ages 10 to 17 Years) in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial

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 SAPHRIS 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 SAPHRIS-treated patients discontinued treatment due to an adverse reaction, compared with about 11% (18/166) on placebo. The most common adverse reactions associated with discontinuation in subjects treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were depression (2.5%), suicidal ideation (2.5%), bipolar I disorder (1.9%), insomnia (1.9%) and depressive symptoms (1.3%).

Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Adjunctive) Bipolar I Patients: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS 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 SAPHRIS-Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials

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. An elevated risk of acute dystonia is observed in males and younger age groups.

Extrapyramidal Symptoms

In the short-term, placebo-controlled schizophrenia and 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-SAPHRIS 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores.

In the short-term, placebo-controlled schizophrenia adult trials, the incidence of reported EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 10% versus 7% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 6% versus 3% for placebo. In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 8% versus 4% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 7% versus 3% for placebo. The incidence rates of all EPS events (including akathisia) were lower at the 5mg twice daily dose (11% of N=122) than the 10mg twice daily dose (25% of N=119) in a fixed-dose study.

In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the incidences of EPS-related events, excluding events related to akathisia, were 4%, 3%, and 5% for patients treated with SAPHRIS 2.5 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.

For events of akathisia, incidences were 2%, 2%, and 1% for pediatric patients treated with SAPHRIS 2.5 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 SAPHRIS and usually resolves within 1 hour.

Laboratory Test Abnormalities

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania adult trials were more common in treated patients. In short-term, placebo-controlled schizophrenia adult trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 1.6 units/L compared to a decrease of 0.4 units/L for placebo-treated patients. The proportion of patients with transaminase elevations ≥ 3 times ULN (at Endpoint) was 0.9% for SAPHRIS-treated patients versus 1.3% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 6.1units/L compared to a decrease of 3.9units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥ 3 times upper limit of normal (ULN) (at Endpoint) was 2.1% for SAPHRIS-treated patients versus 0.7% for placebo-treated patients. The incidence rate of transaminase elevations ≥ 3 times ULN is 3% of N=95 for 10mg twice daily dose, and 0% of N=108 for the 5mg twice daily dose and 0% of N=115 for placebo in a fixed-dose study.

In a 52-week, double-blind, comparator-controlled trial that included primarily adult patients with schizophrenia, the mean increase from baseline of ALT was 1.7 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. The proportion of pediatric patients with ALT elevations ≥ 3 times upper limit of normal (ULN) was 2.4% for patients treated with SAPHRIS 10 mg twice daily versus none for the other SAPHRIS dose groups and placebo-treated patients.

Prolactin: In short-term, placebo-controlled adult schizophrenia trials, the mean decreases in prolactin levels were 6.5 ng/mL for SAPHRIS-treated patients compared to 10.7 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥ 4 times ULN (at Endpoint) were 2.6% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 6.7ng/mL for SAPHRIS-treated patients compared to a decrease of 1.0 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥ 4 time

Human Experience

In adult pre-marketing clinical studies involving more than 3350 patients and/or healthy subjects, accidental or intentional acute overdosage of SAPHRIS was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of SAPHRIS was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion.

Management Of Overdosage

There is no specific antidote to SAPHRIS. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Consult with a Certified Poison Control Center for up-to-date guidance and advice on the management of overdosage (1-800-222-1222.)

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of SAPHRIS-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 receptors (Ki values of 2.5, 2.7, 0.07, 0.18, 0.03, 1.6, 0.25, and 0.11 nM, respectively), dopamine D2A, D2B, D3, D4, and D1 receptors (Ki values of 1.3, 1.4, 0.42, 1.1, and 1.4 nM, respectively), α1A, α2A, α2B, and α2C -adrenergic receptors (Ki values of 1.2, 1.2, 0.33 and 1.2 nM, respectively), and histamine H1 receptors (Ki value 1.0 nM), and moderate affinity for H2 receptors (Ki value of 6.2 nM). In in vitro assays asenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors (e.g., Ki value of 8128 nM for M1).

The effects of asenapine on the pharmacokinetics of other co-administered drugs are summarized in Figure 2. Coadministration of paroxetine with SAPHRIS caused a two-fold increase in the maximum plasma concentrations and systemic exposure of paroxetine. Asenapine enhances the inhibitory effects of paroxetine on its own metabolism by CYP2D6.

Figure 2: Effect of Asenapine on Other Drug Pharmacokinetics

Studies In Special Populations

Exposures of asenapine in special populations are summarized in Figure 3. Additionally, based on population pharmacokinetic analysis, no effects of sex, race, BMI, and smoking status on asenapine exposure were observed. Exposure in elderly patients is 30-40% higher as compared to adults.

Figure 3: Effect of Intrinsic Factors on Asenapine Pharmacokinetics

Clinical Studies

Efficacy of SAPHRIS was established in the following trials:

• Two fixed-dose, short-term trials and one flexible-dose, maintenance trial in adult patients with schizophrenia as monotherapy
• One fixed-dose and two flexible-dose, short-term trials of monotherapy in adults with manic or mixed episodes associated with bipolar I disorder
• One flexible-dose, maintenance trial of monotherapy in adults with bipolar I disorder
• One fixed-dose, short term trial of monotherapy in children (10 to 17 years) with manic or mixed episodes associated with bipolar I disorder
• One flexible-dose, short-term trial in adult patients with manic or mixed episode associated with bipolar I disorder as adjunctive treatment to lithium or valproate

Schizophrenia

The efficacy of SAPHRIS in the treatment of schizophrenia in adults was evaluated in three fixed-dose, short-term (6 week), randomized, double-blind, placebo-controlled, and active-controlled (haloperidol, risperidone, and olanzapine) trials of adult patients who met DSM-IV criteria for schizophrenia and were having an acute exacerbation of their schizophrenic illness. In two of the three trials SAPHRIS demonstrated superior efficacy to placebo. In a third trial, SAPHRIS could not be distinguished from placebo; however, an active control in that trial was superior to placebo.

In the two positive trials for SAPHRIS, the primary efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The primary endpoint was change from baseline to endpoint on the PANSS total score. The results of the SAPHRIS trials in schizophrenia follow:

In trial 1, a 6-week trial (n=174), comparing SAPHRIS (5 mg twice daily) to placebo, SAPHRIS 5 mg twice daily was statistically superior to placebo on the PANSS total score (Trial 1 in Table 13).

In trial 2, a 6-week trial (n=448), comparing two fixed doses of SAPHRIS (5 mg and 10 mg twice daily) to placebo, SAPHRIS 5 mg twice daily was statistically superior to placebo on the PANSS total score. SAPHRIS 10 mg twice daily showed no added benefit compared to 5 mg twice daily and was not significantly different from placebo (Trial 2 in Table 13).

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex or race.

Table 13: Short-Term Schizophrenia Trials Establishing Efficacy in Adults

Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. All patients were initially administered 5 mg twice daily for 1 week and then titrated up to 10 mg twice daily. A total of 700 patients entered open-label treatment with SAPHRIS for a period of 26 weeks. Of these, a total of 386 patients who met pre-specified criteria for continued stability (mean length of stabilization was 22 weeks) were randomized to a double-blind, placebo-controlled, randomized withdrawal phase. SAPHRIS was statistically superior to placebo in time to relapse or impending relapse defined as increase in PANSS ≥ 20% from baseline and a Clinical Global Impression-Severity of Illness (CGI-S) score ≥ 4 (at least 2 days within 1 week) or PANSS score ≥ 5 on “hostility” or “uncooperativeness” items and CGI-S score ≥ 4 ( ≥ 2 days within a week), or PANSS score ≥ 5 on any two of the following items: “unusual thought content,” “conceptual disorganization,” or “hallucinatory behavior” items, and CGI-S score ≥ 4 ( ≥ 2 days within 1 week) or investigator judgment of worsening symptoms or increased risk of violence to self (including suicide) or other persons. The Kaplan-Meier curves of the time to relapse or impending relapse during the double-blind, placebo-controlled, randomized withdrawal phase of this trial for SAPHRIS and placebo are shown in Figure 4.

Figure 4: Kaplan-Meier Estimation of Percent Relapse/Impending Relapse for SAPHRIS and placebo

Bipolar I Disorder

Monotherapy

Adults: The efficacy of SAPHRIS in the treatment of acute mania was established in two similarly designed 3-week, randomized, double-blind, placebo-controlled, and active-controlled (olanzapine) trials of adult patients who met DSM-IV criteria for Bipolar I Disorder with an acute manic or mixed episode with or without psychotic features.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). Patients were also assessed on the Clinical Global Impression - Bipolar (CGI-BP) scale. In both trials, all patients randomized to SAPHRIS were initially administered 10 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. Ninety percent of patients remained on the 10 mg twice daily dose. SAPHRIS was statistically superior to placebo on the YMRS total score and the CGI-BP Severity of Illness score (mania) in both studies (Trials 1 and 2 in Table 14).

In another 3-week, randomized, double-blind, placebo-controlled trial (n=359), comparing two fixed doses of SAPHRIS (5 mg and 10 mg twice daily) to placebo, both doses were statistically superior to placebo on the YMRS total score and CGI-BP Severity of Illness overall score. (Trial 3 in Table 14).

An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, or race.

Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. All patients were initially administered 5 or 10 mg twice daily, and the option to titrate down to 5 mg twice daily was provided based on tolerability. A total of 549 patients entered open-label treatment with SAPHRIS for a period of 12 to16 weeks. Of these, a total of 252 patients who met pre-specified criteria for continued stability were randomized to and treated in a double-blind, placebo-controlled, randomized withdrawal phase. SAPHRIS was statistically superior to placebo in time to relapse defined as 1) YMRS or MADRS score ≥ 16; 2) requirement or initiation of any non-study medication to treat mixed, manic, or depressive symptoms, including an antipsychotic, antidepressant, or mood-stabilizing agent; 3) requirement or initiation of psychiatric hospitalization; 4) investigator judgment to discontinue the study due to a mood event. The Kaplan-Meier curves of the time to relapse during the double-blind, placebo-controlled, randomized withdrawal phase of this trial for SAPHRIS and placebo are shown in Figure 5.

Figure 5: Kaplan-Meier Estimation of Percent Relapse for SAPHRIS and Placebo

Pediatric patients: The efficacy of SAPHRIS in the treatment of acute mania was established in a single, 3-week, placebo-controlled, double-blind trial of 403 pediatric patients 10 to 17 years of age, of whom 302 patients received SAPHRIS at fixed doses of 2.5 mg, 5 mg and 10 mg twice daily. All patients were started on 2.5 mg twice daily. For those assigned to 5 mg twice daily, the dose was increased to 5 mg twice daily after 3 days. For those assigned to 10 mg twice daily, the dose was increased from 2.5 to 5 mg twice daily after 3 days, and then to 10 mg twice daily after 3 additional days.

SAPHRIS was statistically superior to placebo in improving YMRS total score and the CGI-BP Severity of Illness overall score as measured by the change from baseline to week 3 (Trial 3 Pediatric in Table 14). An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, and race.

Adjunctive Therapy

The efficacy of SAPHRIS as an adjunctive therapy in acute mania was established in a 12week, placebo-controlled trial with a 3-week primary efficacy endpoint involving 326 adult patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially responsive to lithium or valproate monotherapy after at least 2 weeks of treatment. All patients randomized to SAPHRIS were initially administered 5 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. SAPHRIS was statistically superior to placebo in the reduction of manic symptoms (measured by the YMRS total score) as an adjunctive therapy to lithium or valproate monotherapy at Week 3 (Trial 5 Adjunctive in Table 14).

Table 14: Acute Bipolar I Trials Establishing Efficacy in Adults and Pediatric Patients