August 30, 2015
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Saphris

"Jan. 7, 2011 -- Many people taking powerful psychiatric medications that increase their risk of weight gain and diabetes are prescribed those drugs when there's little evidence that they will get any benefit from them, a new study shows.

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Saphris




Warnings
Precautions

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 [see BOXED WARNING and Cerebrovascular Adverse Events, Including Stroke, In Elderly Patients with Dementia-Related Psychosis below].

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 [see also BOXED WARNING and Increased Mortality In Elderly Patients With Dementia-Related Psychosis above].

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

  Schizophrenia (6-weeks) Bipolar (3-weeks)
Placebo SAPHRIS Placebo SAPHRIS 5 or 10 mg twice daily†
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily§
Mean Change from Baseline in Fasting Glucose at Endpoint
Change from Baseline (mg/dL) (N*) -0.2 (232) 3.8 (158) 1.1 (153) 3.2 (377) -0.6 (89) -0.6 (156)
Proportion of Patients with Shifts from Baseline to Endpoint
Normal to High < 100 to ≥ 126 mg/dL (n/N**) 4.1% (7/170) 4.5% (5/111) 4.5% (5/111) 5.0% (13/262) 3.3% (2/61) 2.7% (3/111)
Borderline to High ≥ 100 and < 126 to ≥ 126 mg/dL (n/N**) 5.9% (3/51) 6.8% (3/44) 6.3% (2/32) 10.5% (10/95) 0.0% (0/23) 11.4% (4/35)
N* = Number of patients who had assessments at both Baseline and Endpoint.
N** = Number of patients at risk at Baseline with assessments at both Baseline and Endpoint.
§ Includes patients treated with flexible dose of SAPHRIS 5 or 10 mg twice daily (N=90).
†SAPHRIS 5 mg or 10 mg twice daily with flexible dosing.

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

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

TABLE 2: Changes in Fasting Glucose in Pediatric Subjects

  Bipolar I Disorder (3-weeks)
Placebo SAPHRIS 2.5 mg twice daily SAPHRIS 5 mg twice daily SAPHRIS 10 mg twice daily
Change fromBaseline (mg/dL) (N*) Mean Change from Baseline in Fasting Glucose at Endpoint
-2.24(56) 1.43 (51) -0.45(57) 0.34(52)
Normal to High > 45 & < 100 to ≥ 126 mg/dL (n/N*) Proportion of Subjects with Shifts from Baseline to Endpoint
0% (0/56) 0% (0/51) 1.8% (1/57) 0% (0/52)

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

  Schizophrenia (6-weeks) Bipolar (3-weeks)
Placebo SAPHRIS Placebo SAPHRIS 5 or 10 mg twice daily†
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily§
Mean Change from Baseline (mg/dL)
Total cholesterol(N*) -2.2 (351) -2.4 (258) 3.3 (199) 0.4 (539) -1.5 (163) 1.1 (322)
LDL (N*) 0.1 (285) -0.2 (195) 2.6 (195) 1.3 (465) 1.9 (158) 1.6 (304)
HDL (N*) 0.5(290) 0.4(199) 1.0(199) 0.5(480) 0.0(163) 0.9(322)
Fasting triglycerides (N*) -7.6 (233) -1.9 (159) 0.1 (154) 3.8 (380) -17.9 (129) -3.5 (237)
Proportion of Patients with Shifts from Baseline to Endpoint
Total cholesterol Normal to High < 200 to ≥ 240 (mg/dL) (n/N*) 1.3% (3/225) 0.6% (1/161) 2.2% (3/134) 1.7% (6/343) 1.1% (1/95) 2.5% (5/204)
LDL Normal to High < 100 to ≥ 160 (mg/dL) (n/N*) 1.7% (2/117) 0.0% (0/80) 1.2% (1/86) 1.0% (2/196) 1.9% (1/53) 0.0% (0/141)
HDL Normal to Low ≥ 40 to < 40 (mg/dL) (n/N*) 10.7% (21/196) 13.3% (18/135) 14.7% (20/136) 14.0% (45/322) 7.4% (9/122) 8.7% (21/242)
Fasting triglycerides Normal to High < 150 to ≥ 200 (mg/dL) (n/N*) 2.4% (4/167) 7.0% (8/115) 8.3% (9/108) 7.7% (20/260) 5.1% (4/78) 7.4% (11/148)
N* = Number of subjects who had assessments at both Baseline and Endpoint.
§ Includes subjects treated with flexible dose of SAPHRIS 5 or 10 mg twice daily (N=90).
†SAPHRIS 5 mg or 10 mg twice daily with flexible dosing.

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

  Bipolar I Disorder (3-weeks)
Placebo SAPHRIS 2.5 mg twice daily SAPHRIS 5 mg twice daily SAPHRIS 10 mg twice daily
Mean Change from Baseline (mg/dL)  
Total fasting cholesterol (N*) -2.3 (57) 3.7 (50) 7.2 (57) 9.3 (52)
Fasting LDL (N*) -2.5 (57) -0.2 (50) 3.0 (57) 4.9 (51)
Fasting HDL (N*) 1.6 (57) 2.3 (50) 1.5 (57) 1.7 (52)
Fasting triglycerides (N*) -6.6 (57) 8.7 (50) 13.4 (57) 14.7 (52)
Proportion of Subjects with Shifts from Baseline to Endpoint
Total fasting cholesterol Normal to High < 170 to > =200 (mg/dL) (n/N*) 1.8% (1/57) 0% (0/50) 1.8% (1/57) 0% (0/52)
Fasting LDL Normal to High < 110 to > =130 (n/N*) 1.8% (1/57) 2.0% (1/50) 1.8% (1/57) 0% (0/51)
Fasting HDL Normal to Low ≥ 40 to < 40 (mg/dL) (n/N*) 3.5% (2/57) 6.0% (3/50) 3.5% (2/57) 9.6% (5/52)
Fasting triglycerides Normal to High < 150 to ≥ 200 (mg/dL) (n/N*) 0%(0/57) 4.0%(2/50) 3.5%(2/57) 1.9%(1/52)
N* = Number of patients who had assessments at both Baseline and Endpoint

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 INFORMATION].

Adult Patients: Pooled data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the short-term, placebo-controlled schizophrenia and bipolar mania trials are presented in Table 5.

Table 5: Change in Body Weight in Adult Patients from Baseline

  Schizophrenia (6-weeks) Bipolar (3-weeks)
Placebo SAPHRIS Placebo SAPHRIS 5 or 10 mg twice daily†
5 mg twice daily 10 mg twice daily 5 or 10 mg twice daily§
Change from Baseline (kg) (N*) 0.0 (348) 1.0 (251) 0.9 (200) 1.1 (532) 0.2 (171) 1.3 (336)
Proportion of Patients with a > 7% Increase in Body Weight
% with ≥ 7% increase in body weight 1.6% 4.4% 4.8% 4.9% 0.5% 5.8%
N* = Number of subjects who had assessments at both Baseline and Endpoint.
§ Includes subjects treated with flexible dose of SAPHRIS 5 or 10 mg twice daily (N=90).
†SAPHRIS 5 mg or 10 mg twice daily with flexible dosing.

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

  BMI < 23 SAPHRIS
N=295
BMI 23 - ≤ 27 SAPHRIS
N=290
BMI > 27 SAPHRIS
N=302
Mean change from Baseline (kg) 1.7 1 0
% with ≥ 7% increase in body weight 22% 13% 9%

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

The distance of a z-score from 0 represents the distance of a percentile from the median, measured in standard deviations (SD). After adjusting for age and sex, the mean change from baseline to endpoint in weight z-score for 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

  Bipolar I Disorder (3-weeks)
Placebo SAPHRIS 2.5 mg twice daily SAPHRIS 5 mg twice daily SAPHRIS 10 mg twice daily
Change from Baseline (kg) (N*) 0.5 (89) 1.7 (92) 1.6 (90) 1.4 (87)
  Proportion of Subjects with a ≥ 7% Increase in Body Weight
% with ≥ 7% increase in body weight 1.1% 12.0% 8.9% 8.0%
N* = Number of subjects who had assessments at both Baseline and Endpoint.

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 [see DRUG INTERACTIONS]. 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 [see ADVERSE REACTIONS].

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 body temperature increases was low ( ≤ 1%) and comparable to placebo (0%). During 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.

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.

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 adult trials, respectively. During adult 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 Increased Mortality in Elderly Patients with Dementia- Related Psychosis].

Use In Patients With Concomitant Illness

Clinical experience with SAPHRIS in patients with certain concomitant systemic illnesses is limited [see CLINICAL PHARMACOLOGY].

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 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects].

Patient Counseling Information

Dosage and Administration

Counsel patients on proper sublingual administration of SAPHRIS and advise them to read the FDA-approved patient labeling (Instructions for Use). When initiating treatment with SAPHRIS, provide dosage escalation instructions [see DOSAGE AND ADMINISTRATION].

Hypersensitivity Reactions

Counsel patients on the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.) and to seek immediate emergency assistance if they develop any of these signs and symptoms [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Application Site Reactions

Inform patients that application site reactions, primarily in the sublingual area, including oral ulcers, blisters, peeling/sloughing and inflammation have been reported. Instruct patients to monitor for these reactions [see ADVERSE REACTIONS]. Inform patients that numbness or tingling of the mouth or throat may occur directly after administration of SAPHRIS and usually resolves within 1 hour (see ADVERSE REACTIONS).

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Patients should contact their health care provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see WARNINGS AND PRECAUTIONS].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see WARNINGS AND PRECAUTIONS].

Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see WARNINGS AND PRECAUTIONS].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and also at times of re-initiating treatment or increases in dose [see WARNINGS AND PRECAUTIONS].

Leukopenia/Neutropenia

Advise patients with a pre-existing low W BC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking SAPHRIS [see WARNINGS AND PRECAUTIONS].

Interference with Cognitive and Motor Performance

Caution patients 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 [see WARNINGS AND PRECAUTIONS].

Heat Exposure and Dehydration

Counsel patients regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].

Concomitant Medications

Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-thecounter medications since there is a potential for interactions [see DRUG INTERACTIONS].

Pregnancy

Advise patients that SAPHRIS may cause fetal harm as well as extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SAPHRIS during pregnancy [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a lifetime carcinogenicity study in CD-1 mice asenapine was administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD of 10 mg twice daily. The incidence of malignant lymphomas was increased in female mice, with a no-effect dose resulting in plasma levels estimated to be 1.5 times those in humans receiving the MRHD. The mouse strain used has a high and variable incidence of malignant lymphomas, and the significance of these results to humans is unknown. There were no increases in other tumor types in female mice. In male mice, there were no increases in any tumor type.

In a lifetime carcinogenicity study in Sprague-Dawley rats, asenapine did not cause any increases in tumors when administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD.

Mutagenesis

No evidence for genotoxic potential of asenapine was found in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assays in human lymphocytes, the in vitro sister chromatid exchange assay in rabbit lymphocytes, or the in vivo micronucleus assay in rats.

Impairment of Fertility

Asenapine did not impair fertility in rats when tested at doses up to 11 mg/kg twice daily given orally. This dose is 10 times the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/m² basis.

Use In Specific Populations

Pregnancy

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 [see Data]. 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.

Lactation

Risk Summary

Lactation studies have not been conducted to assess the presence of asenapine in human milk, the effects of asenapine on the breastfed infant, or the effects of asenapine on milk production. Asenapine is excreted in rat milk .The development and health benefits of breastfeeding should be considered along with the mother's clinical need for SAPHRIS and any potential adverse effects on the breastfed infant from SAPHRIS or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of SAPHRIS in pediatric patients below the age of 10 years of age have not been evaluated.

Bipolar I Disorder

The safety and efficacy of SAPHRIS as monotherapy in the treatment of bipolar I disorder were established in a 3week, placebo-controlled, double-blind trial of 403 pediatric patients 10 to 17 years of age, of whom 302 patients received SAPHRIS at fixed doses ranging from 2.5 mg to 10 mg twice daily [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, and Clinical Studies]. In a Phase 1 study, pediatric patients aged 10 to 17 years appeared to be more sensitive to dystonia with initial dosing with asenapine when the recommended dose escalation schedule was not followed. No new major safety findings were reported from a 50-week, open-label, uncontrolled safety trial in pediatric patients with bipolar disorder treated with SAPHRIS monotherapy. The safety and efficacy of SAPHRIS as adjunctive therapy in the treatment of bipolar I disorder have not been established in the pediatric population. In general, the pharmacokinetics of asenapine in pediatric patients (10 to17 years) and adults are similar [see CLINICAL PHARMACOLOGY].

Schizophrenia

Efficacy of SAPHRIS was not demonstrated in an 8-week, placebo-controlled, double-blind trial, in 306 adolescent patients aged 12 to17 years with schizophrenia at doses of 2.5 and 5 mg twice daily. The most common adverse reactions (proportion of patients equal or greater than 5% and at least twice placebo) reported were somnolence, akathisia, dizziness, and oral hypoesthesia or paresthesia. The proportion of patients with an equal or greater than 7% increase in body weight at endpoint compared to baseline for placebo, SAPHRIS 2.5 mg twice daily, and SAPHRIS 5 mg twice daily was 3%, 10%, and 10%, respectively.

The clinically relevant adverse reactions identified in the pediatric schizophrenia trial were generally similar to those observed in the pediatric bipolar and adult bipolar and schizophrenia trials. No new major safety findings were reported from a 26-week, open-label, uncontrolled safety trial in pediatric patients with schizophrenia treated with SAPHRIS monotherapy.

Juvenile Animal Data

Subcutaneous administration of asenapine to juvenile rats for 56 days from day 14 of age to day 69 of age at 0.4, 1.2, and 3.2 mg/kg/day (0.2, 0.6 and 1.5 times the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/m² basis) resulted in significant reduction in body weight gain in animals of both sexes at all dose levels from the start of dosing until weaning. Body weight gain remained reduced in males to the end of treatment, however, recovery was observed once treatment ended. Neurobehavioral assessment indicated increased motor activity in animals at all dose levels following the completion of treatment, with the evidence of recovery in males. There was no recovery after the end of treatment in female activity pattern as late as day 30 following the completion of treatment (last retesting). Therefore, a No Observed Adverse Effect Level (NOAEL) for the juvenile animal toxicity of asenapine could not be determined. There were no treatment-related effects on the startle response, learning/memory, organ weights, microscopic evaluations of the brain and, reproductive performance (except for minimally reduced conception rate and fertility index in males and females administered 1.2 and 3.2 mg/kg/day).

Geriatric Use

Clinical studies of SAPHRIS in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Of the approximately 2250 patients in pre-marketing clinical studies of SAPHRIS, 1.1% (25) were 65 years of age or over. Multiple factors that might increase the pharmacodynamic response to SAPHRIS, causing poorer tolerance or orthostasis, could be present in elderly patients, and these patients should be monitored carefully. Based on a pharmacokinetic study in elderly patients, dosage adjustments are not recommended based on age alone [see CLINICAL PHARMACOLOGY].

Elderly patients with dementia-related psychosis treated with SAPHRIS are at an increased risk of death compared to placebo. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].

Renal Impairment

No dosage adjustment for SAPHRIS is required on the basis of a patient'srenal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute). The exposure of asenapine was similar among subjects with varying degrees of renal impairment and subjects with normal renal function [see CLINICAL PHARMACOLOGY]. The effect of renal function on the excretion of other metabolites and the effect of dialysis on the pharmacokinetics of asenapine has not been studied.

Hepatic Impairment

SAPHRIS is contraindicated in patients with severe hepatic impairment (Child-Pugh C) because asenapine exposure is 7-fold higher in subjects with severe hepatic impairment than the exposure observed in subjects with normal hepatic function.

No dosage adjustment for SAPHRIS is required in patients with mild to moderate hepatic impairment (Child-Pugh A and B) because asenapine exposure is similar to that in subjects with normal hepatic function[see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Other Specific Populations

No dosage adjustment for SAPHRIS is required on the basis of a patient's sex, race (Caucasian and Japanese), or smoking status [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 3/26/2015
This monograph has been modified to include the generic and brand name in many instances.

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