Special Warning : אזהרת שימוש

5      WARNINGS AND PRECAUTIONS
5.1    Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SAPHRIS is not approved for the treatment of patients with dementia- related psychosis and is not recommended for use in this particular group of patients [see Boxed Warning].

5.2    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 and is not recommended for use in this particular group of patients [see also Boxed Warning and Warnings and Precautions (5.1)].

5.3    Neuroleptic Malignant Syndrome
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, 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.



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5.4   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.
The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia.
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.

5.5   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 or bipolar disorder 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 


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included in these studies. Because SAPHRIS was not marketed at the time these studies were performed, it is not known if SAPHRIS is associated with this increased risk. 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.

5.6   Weight Gain

Increases in weight have been observed in pre-marketing clinical trials with SAPHRIS. Patients receiving SAPHRIS should receive regular monitoring of weight [see Patient Counseling Information (17.6)].

In short-term schizophrenia and bipolar mania trials, there were differences in mean weight gain between SAPHRIS-treated and placebo-treated patients. In short-term, placebo-controlled schizophrenia trials, the mean weight gain was 1.1 kg for SAPHRIS-treated patients compared to 0.1 kg for placebo- treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.9% for SAPHRIS-treated patients versus 2% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean weight gain for SAPHRIS-treated patients was 1.3 kg compared to 0.2 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 5.8% for SAPHRIS-treated patients versus 0.5% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia or schizoaffective disorder, 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 1 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 1: Weight Change Results Categorized by BMI at Baseline: Comparator-Controlled 52-Week Study in Schizophrenia
BMI <23              BMI 23 - ≤27            BMI >27
SAPHRIS               SAPHRIS                SAPHRIS
N=295                 N=290                  N=302
Mean change



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from Baseline                  1.7                     1                      0 (kg)
% with ≥7% increase in body               22%                    13%                    9% weight


5.7   Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and angioedema, 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.


5.8   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. Elderly patients are particularly at risk for experiencing orthostatic hypotension. In short-term schizophrenia 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 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 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.

Four normal volunteers in clinical pharmacology studies treated with either intravenous, oral, or sublingual SAPHRIS experienced hypotension, bradycardia, and sinus pauses. These spontaneously resolved in 3 cases, but the fourth subject received external cardiac massage. The risk of this sequence of hypotension, bradycardia, and sinus pause might be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.

Patients should be instructed about nonpharmacologic 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 


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nervous system depression [see Drug Interactions (7)]. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.

5.9   Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/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) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and SAPHRIS should be discontinued at the first sign of decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue SAPHRIS and have their WBC followed until recovery.

5.10 QT Prolongation

The effects of SAPHRIS on the QT/QTc interval were evaluated in a dedicated 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 


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bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval.

5.11 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 clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo [see Adverse Reactions (6.2)].

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.

5.12 Seizures

Seizures were reported in 0% and 0.3% (0/572, 1/379) of 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 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. 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, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

5.13 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 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 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 pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison 


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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.

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.

5.14 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 body temperature increases was low (≤1%) and comparable to placebo. During pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, the incidence of adverse reactions suggestive of body temperature increases (pyrexia and feeling hot) was ≤1%. Appropriate care is advised when prescribing SAPHRIS for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.15 Suicide

The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for SAPHRIS should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

5.16 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Dysphagia was reported in 0.2% and 0% (1/572, 0/379) of patients treated with therapeutic doses (5-10 mg twice daily) of SAPHRIS as compared to 0% (0/378, 0/203) of patients treated with placebo in short- term schizophrenia and bipolar mania trials, respectively. During pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, dysphagia was reported in 0.1% (2/1953) of patients treated with SAPHRIS.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. SAPHRIS is not indicated for the treatment of dementia- related psychosis, and should not be used in patients at risk for aspiration pneumonia [see also Warnings and Precautions (5.1)].



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5.17 Use in Patients with Concomitant Illness

Clinical experience with SAPHRIS in patients with certain concomitant systemic illnesses is limited [see Clinical Pharmacology (12.3)].

SAPHRIS has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical trials.
Because of the risk of orthostatic hypotension with SAPHRIS, caution should be observed in cardiac patients [see Warnings and Precautions (5.6)].


6     ADVERSE REACTIONS
6.1   Overall Adverse Reactions Profile
The following adverse reactions are discussed in more detail in other sections of the labeling: 
•   Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1 and 5.2)]

•   Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)] 
•   Tardive Dyskinesia [see Warnings and Precautions (5.4)]

•   Hyperglycemia and Diabetes Mellitus [see Warnings and Precautions (5.5)] 
•   Weight Gain [see Warnings and Precautions (5.6)]

•   Hypersensitivity Reactions [see Warnings and Precautions (5.7) and Patient Counseling Information]

•   Orthostatic Hypotension, Syncope, and other Hemodynamic Effects [see Warnings and Precautions (5.8)]

•   Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.9)] 
•   QT Interval Prolongation [see Warnings and Precautions (5.10)]

•   Hyperprolactinemia [see Warnings and Precautions (5.11)]
•   Seizures [see Warnings and Precautions (5.12)]

•   Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)] 
•   Body Temperature Regulation [see Warnings and Precautions (5.14)] 
•   Suicide [see Warnings and Precautions (5.15)]

•   Dysphagia [see Warnings and Precautions (5.16)]


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•   Use in Patients with Concomitant Illness [see Warnings and Precautions (5.17)] 
The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with acute treatment in schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of SAPHRIS in the maintenance treatment of schizophrenia 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 were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and weight increased and during the adjunctive therapy trial in bipolar disorder were somnolence and oral hypoesthesia.

The information below is derived from a clinical trial database for SAPHRIS consisting of over 4565 patients and/or normal subjects exposed to one or more sublingual doses of SAPHRIS. A total of 1314 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.

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.

The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses, and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

6.2      Clinical Studies Experience
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 subjects and 10% of placebo subjects discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in subjects 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 Schizophrenic Patients: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to 


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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 2.

TABLE 2: Adverse Reactions Reported in 2% or More of Subjects in One of the SAPHRIS Dose Groups and Which Occurred at Greater Incidence Than in the Placebo Group in 6- Week Schizophrenia Trials
SAPHRIS              SAPHRIS             All SAPHRIS§
Placebo            5 mg                10 mg                 5 mg or
System Organ Class/ twice                twice              10 mg twice
Preferred Term daily                daily                  daily
N=378           N=274                N=208                  N=572
Gastrointestinal disorders
Constipation                                        6%                 7%                  4%                     5% Dry mouth                                           1%                 3%                  1%                     2% Oral hypoesthesia                                   1%                 6%                  7%                     5% Salivary hypersecretion                             0%                <1%                  4%                     2% Stomach discomfort                                  1%                <1%                  3%                     2% Vomiting                                            5%                 4%                  7%                     5% General disorders
Fatigue                                             3%                 4%                  3%                     3% Irritability                                       <1%                 2%                  1%                     2% Investigations
Weight increased                                   <1%                 2%                  2%                     3% Metabolism disorders
Increased appetite                                 <1%                 3%                  0%                     2% Nervous system disorders
Akathisia*                                          3%                 4%                 11%                      6% Dizziness                                           4%                 7%                  3%                      5% Extrapyramidal symptoms                             7%                 9%                 12%                     10% (excluding akathisia)†
Somnolence‡                                          7%               15%                 13%                     13% Psychiatric disorders
Insomnia                                           13%                16%                 15%                     15% Vascular disorders
Hypertension                                        2%                 2%                  3%                     2% *Akathisia includes: akathisia and hyperkinesia.
†Extrapyramidal symptoms included dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor, and extrapyramidal disorder (excluding akathisia).
‡Somnolence includes the following events: somnolence, sedation, and hypersomnia.
§Also includes the Flexible-dose trial (N=90).


Dose-Related Adverse Reactions: Of all the adverse reactions listed in Table 2, the only apparent dose-related adverse reaction was akathisia.

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) 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% (38/379) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an 


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adverse reaction, compared with about 6% (12/203) 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 anxiety (1.1%) and oral hypoesthesia (1.1%) compared to placebo (0%).

Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Monotherapy) Bipolar 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 monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 3.

TABLE 3: Adverse Reactions Reported in 2% or More of Subjects in One of the SAPHRIS Dose Groups and Which Occurred at Greater Incidence Than in the Placebo Group in 3- Week Bipolar Mania Trials
SAPHRIS
Placebo                  5 mg or 10 mg twice
System Organ Class/Preferred Term
N=203                          daily*
N=379
Gastrointestinal disorders
Dry mouth                            1%                                                         3% Dyspepsia                            2%                                                         4% Oral hypoesthesia                   <1%                                                         4% Toothache                            2%                                                         3% General disorders
Fatigue                              2%                                                         4% Investigations
Weight increased                    <1%                                                         5% Metabolism disorders
Increased appetite                   1%                                                         4% Musculoskeletal and connective tissue disorders
Arthralgia                           1%                                                         3% Pain in extremity                   <1%                                                         2% Nervous system disorders
Akathisia                            2%                                                         4% Dizziness                            3%                                                        11% Dysgeusia                           <1%                                                         3% Headache                            11%                                                        12% Other extrapyramidal symptoms        2%                                                         7% (excluding akathisia)†
Somnolence‡                          6%                                                        24% Psychiatric disorders
Anxiety                              2%                                                         4% Depression                           1%                                                         2% Insomnia                             5%                                                         6% * SAPHRIS 5 mg to 10 mg twice daily with flexible dosing.
†Extrapyramidal symptoms included: dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, and tremor (excluding akathisia).
‡Somnolence includes the following events: somnolence, sedation, and hypersomnia.



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 


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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 1 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 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 4.

TABLE 4: Adverse Reactions Reported in 2% or More Among SAPHRIS-Treated (Adjunctive) Bipolar Mania Patients and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks

SAPHRIS
Placebo
System Organ Class/Preferred Term                             5 mg or 10 mg twice daily* N=166
N=158

Gastrointestinal disorders

Dyspepsia                                    2%                       3% 
Oral hypoesthesia                            0%                       5% 
General disorders

Fatigue                                      2%                       4% 
Edema peripheral                            <1%                       3% 
Investigations

Weight increased                             0%                       3% 
Nervous system disorders

Dizziness                                    2%                       4% 
Other extrapyramidal symptoms                5%                       6% †
(excluding akathisia)
‡                              10%                      22%
Somnolence

Psychiatric disorders

Insomnia                                     8%                      10% 
Vascular disorders

Hypertension                                <1%                       3% 


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* SAPHRIS 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: Antipsychotic Class Effect: 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 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 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 trials, the incidence of EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 7% versus 2% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 4% versus 2% for placebo.
Other Findings:
Asenapine has anesthetic properties. Oral hypoesthesia and oral paraesthesia may occur directly after administration and usually resolve within 1 hour.

Hepatic enzymes: Transient, asymptomatic elevations of hepatic transaminases, alanine transferase (ALT), aspartate transferase (AST) have been seen commonly, especially in early treatment.

Laboratory Test Abnormalities:
Glucose: The effects on fasting serum glucose levels in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes [see also Warnings and Precautions (5.5)]. In the short-term placebo-controlled schizophrenia trials, the mean increase in fasting glucose levels for SAPHRIS-treated patients was 3.2 mg/dL compared to a decrease of 1.6 mg/dL for placebo-treated patients. The proportion of patients with fasting glucose elevations ≥126 mg/dL (at Endpoint), was 7.4% for SAPHRIS-treated patients versus 6% for placebo-treated patients. In the short-term, placebo- controlled bipolar mania trials, the mean decreases in fasting glucose levels for both SAPHRIS-treated and placebo-treated patients were 0.6 mg/dL. The proportion of patients with fasting glucose elevations 


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≥126 mg/dL (at Endpoint), was 4.9% for SAPHRIS-treated patients versus 2.2% for placebo-treated patients.

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

Lipids: The effects on total cholesterol and fasting triglycerides in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes. In short-term, placebo-controlled schizophrenia trials, the mean increase in total cholesterol levels for SAPHRIS-treated patients was 0.4 mg/dL compared to a decrease of 3.6 mg/dL for placebo-treated patients. 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. In short-term, placebo-controlled bipolar mania trials, the mean increase in total cholesterol levels for SAPHRIS-treated patients was 1.1 mg/dL compared to a decrease of 1.5 mg/dL in placebo-treated patients. 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. In short- term, placebo-controlled schizophrenia trials, the mean increase in triglyceride levels for SAPHRIS- treated patients was 3.8 mg/dL compared to a decrease of 13.5 mg/dL 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 mean decrease in triglyceride levels for SAPHRIS-treated patients was 3.5 mg/dL versus 17.9 mg/dL for placebo-treated subjects. 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 of patients with schizophrenia and schizoaffective disorder, 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.

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania trials were more common in treated patients but mean changes were not clinically relevant. In short-term, placebo-controlled schizophrenia 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 trials, the mean increase in transaminase levels for SAPHRIS- treated patients was 8.9 units/L compared to a decrease of 4.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times upper limit of normal (ULN) (at Endpoint) was 2.5% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients. No cases of more severe liver injury were seen.



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In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean increase from baseline of ALT was 1.7 units/L.

Prolactin: The effects on prolactin levels in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes in baseline. In short-term, placebo-controlled 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 trials, the mean increase in prolactin levels was 4.9 ng/mL for SAPHRIS-treated patients compared to a decrease of 0.2 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.3% for SAPHRIS- treated patients versus 0.7% for placebo-treated patients.

In a long-term (52-week), double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean decrease in prolactin from baseline for SAPHRIS-treated patients was 26.9 ng/mL.

Creatine Kinase (CK): The proportion of patients with CK elevations >3 times ULN at any time were 6.4% and 11.1% for patients treated with SAPHRIS 5 mg bid and 10 mg bid, respectively, as compared to 6.7% for placebo-treated patients in short-term, fixed-dose trials in schizophrenia and bipolar mania. The clinical relevance of this finding is unknown.

Other Adverse Reactions Observed During the Premarketing Evaluation of SAPHRIS: Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual SAPHRIS 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 in other parts of Adverse Reactions (6), or those considered in Warnings and Precautions (5) or Overdosage (10) are not included. Although the reactions reported occurred during treatment with SAPHRIS, they were not necessarily caused by it. 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 (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; and those occurring in fewer than 1/1000 patients.

Blood and lymphatic disorders: <1/1000 patients: thrombocytopenia; ≥1/1000 patients and <1/100 patients: anemia

Cardiac disorders: ≥1/1000 patients and <1/100 patients: tachycardia, temporary bundle branch block

Eye disorders: ≥1/1000 patients and <1/100 patients: accommodation disorder 


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Gastrointestinal disorders: ≥1/1000 patients and <1/100 patients: oral paraesthesia, glossodynia, swollen tongue

General disorders: <1/1000 patients: idiosyncratic drug reaction

Investigations: ≥1/1000 patients and <1/100 patients: hyponatremia
Nervous system disorders: ≥1/1000 patients and <1/100 patients: dysarthria 

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