PSYCHIATRISTS’ EDITION ® www.eMPR.com PRESCRIBING ALERT ® Dear Healthcare Professional, At MPR we strive to bring you important drug information in a concise and timely fashion. In keeping with this goal, we are pleased to bring you this PRESCRIBING ALERT for SAPHRIS ® (asenapine) sublingual tablets 5 and 10 mg, discussing its expanded indications. Merck, the marketer of SAPHRIS, has paid for these program materials to be developed and provided to you. SAPHRIS is now indicated for the treatment of schizophrenia in adults, as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and as adjunctive therapy with either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. 1 SAPHRIS was initially approved in 2009 for the acute treatment of schizophrenia in adults and as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. 1 SELECTED SAFETY INFORMATION 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 2.6% in the placebo group • Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature • SAPHRIS is not approved for the treatment of patients with dementia-related psychosis Cerebrovascular Adverse Events • 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 (NMS) • NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including SAPHRIS • NMS can cause hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure • Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems Tardive Dyskinesia (TD) • The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumu- lative dose increase • However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD • If signs and symptoms appear, discontinuation should be considered Hyperglycemia and Diabetes Mellitus • Hyperglycemia, in some cases associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics • Patients with risk factors for diabetes mellitus who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of and 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 also undergo fasting blood glucose testing • In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continu- ation of antidiabetic treatment despite discontinuation of the antipsychotic drug Weight Gain • Patients receiving SAPHRIS should receive regular monitoring of weight. There were differences in mean weight gain between SAPHRIS-treated and placebo-treated patients in short-term schizophrenia trials (1.1 kg vs 0.1 kg) and in bipolar mania trials (1.3 kg vs 0.2 kg). In a 52-week study, the proportion of patients with a ≥7% increase in body weight was 14.7% Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects • SAPHRIS may induce orthostatic hypotension and syncope • SAPHRIS should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, conditions which would predispose them to hypotension, and in the elderly (Selected Safety Information continued on next page)
Transcript
PSYCHIATRISTS’EDITION®
www.eMPR.com
PRESCRIBING ALERT®
Dear Healthcare Professional,
At MPR we strive to bring you important drug information in a concise and timely fashion. In keeping with this goal, we are pleased to bring you this PRESCRIBING ALERT for SAPHRIS® (asenapine) sublingual tablets 5 and 10 mg, discussing its expanded indications. Merck, the marketer of SAPHRIS, has paid for these program materials to be developed and provided to you. SAPHRIS is now indicated for the treatment of schizophrenia in adults, as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and as adjunctive therapy with either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.1 SAPHRIS was initially approved in 2009 for the acute treatment of schizophrenia in adults and as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.1
Selected SAFetY INFORMAtION 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
2.6% in the placebo group• Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or
infectious (eg, pneumonia) in nature• SAPHRIS is not approved for the treatment of patients with dementia-related psychosisCerebrovascular Adverse Events • 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 (NMS) • NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including SAPHRIS• NMS can cause hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or blood pressure, tachycardia, diaphoresis,
and cardiac dysrhythmia. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure
• Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems
Tardive Dyskinesia (TD) • The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumu-
lative dose increase• However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing
should be consistent with the need to minimize TD• If signs and symptoms appear, discontinuation should be consideredHyperglycemia and Diabetes Mellitus • Hyperglycemia, in some cases associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with
atypical antipsychotics• Patients with risk factors for diabetes mellitus who are starting treatment with atypical antipsychotics should undergo fasting blood
glucose testing at the beginning of and 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 also undergo fasting blood
glucose testing• In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continu-
ation of antidiabetic treatment despite discontinuation of the antipsychotic drugWeight Gain• Patients receiving SAPHRIS should receive regular monitoring of weight. There were differences in mean weight gain between
SAPHRIS-treated and placebo-treated patients in short-term schizophrenia trials (1.1 kg vs 0.1 kg) and in bipolar mania trials (1.3 kg vs 0.2 kg). In a 52-week study, the proportion of patients with a ≥7% increase in body weight was 14.7%
Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects • SAPHRIS may induce orthostatic hypotension and syncope • SAPHRIS should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, conditions which would
predispose them to hypotension, and in the elderly
(Selected Safety Information continued on next page)
• 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, events of leukopenia/neutropenia have been reported temporally related to antipsy-
chotic agents, including SAPHRIS • Patients with a preexisting low white blood cell count (WBC) or a history of 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 a decline in WBC in the absence of other causative factors
QT Prolongation • 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 experience a QTc
of ≥500 msec• SAPHRIS should be avoided in combination with other drugs known to prolong QTc interval, in patients with congenital prolongation
of QT interval or a history of cardiac arrhythmias, and in circumstances that may increase the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval
Hyperprolactinemia • Like other drugs that antagonize dopamine D2 receptors, SAPHRIS can elevate prolactin levels, and the elevation can persist during
chronic administration. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds
Seizures • SAPHRIS should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold (eg, Alzheim-
er’s dementia)Potential for Cognitive and Motor Impairment • Somnolence was reported in patients treated with SAPHRIS • 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 adverselyBody Temperature Regulation • Appropriate care is advised when prescribing SAPHRIS for patients who will be experiencing conditions that may contribute to an
elevation in core body temperature, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration
Suicide • The possibility of suicide attempt is inherent in psychotic illnesses and bipolar disorder. Close supervision of high-risk patients should
accompany drug therapy • Prescriptions for SAPHRIS should be written for the smallest quantity of tablets in order to reduce the risk of overdose Dysphagia • Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. 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
pneumoniaHepatic Impairment • SAPHRIS is not recommended in patients with severe hepatic impairmentDrug Interactions • The risks of using SAPHRIS in combination with other drugs have not been extensively evaluated. Given the primary CNS effects of
SAPHRIS, caution should be used when it is taken in combination with other centrally acting drugs or alcohol • Coadministration of SAPHRIS with strong CYP1A2 inhibitors (fluvoxamine) or compounds which are both CYP2D6 substrates and
inhibitors (paroxetine) should be done with cautionCommonly Observed Adverse Reactions (≥5% and at least twice that for placebo)• In short-term schizophrenia trials with SAPHRIS 5 or 10 mg BID vs placebo: akathisia (6% vs 3%), oral hypoesthesia (numbing of the
tongue [5% vs 1%]), and somnolence (13% vs 7%). The safety profile of SAPHRIS in the maintenance treatment of schizophrenia was similar to that seen with acute treatment
• In short-term bipolar mania (monotherapy) trials with SAPHRIS 5 or 10 mg BID vs placebo: somnolence (24% vs 6%), dizziness (11% vs 3%), extrapyramidal symptoms other than akathisia (7% vs 2%) and weight increase (5% vs less than 1%)
• In the bipolar mania (adjunctive) therapy trial with SAPHRIS 5 or 10 mg BID vs placebo at 3 weeks: somnolence (22% vs 10%) and oral hypoesthesia (5% vs 0%)
Please click here for Prescribing Information, including Boxed Warning.
More information about the use of SAPHRIS is available in the current edition of MPR.
Sincerely,
Grace L. McBride Editorial Director MPR Custom Programs
RefeRence1. SAPHRIS [package insert]. Kenilworth, NJ: Schering Corporation, a subsidiary of Merck & co., Inc.; 2011.
Pharmacologic class: Atypical antipsychotic (dibenzo-oxepino pyrrole).Active ingredient: Asenapine 5 mg, 10 mg; sublingual tablets.indications: Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, as monotherapy or as adjunctive therapy, with either lithium or valproate. Treatment of schizophrenia in adults.Pharmacology: Although the mechanism of action of asenapine in the treatment of schizophrenia and bipolar disorder is not known, it may be due to its antagonistic effects at dopamine D2 and serotonin 5-HT2A receptor sites.Adults†: Do not remove tablet until ready to administer. Use dry hands when handling tablet. Place tablet under tongue and allow it to dissolve completely. Do not crush, chew, or swallow tablet. Do not eat or drink for 10 minutes after administration.children: not recommended.
WArning: increAsed mortAlitY in elderlY PAtients With dementiA-relAted PsYchosiselderly 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 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. sAPhris is not approved for the treatment of patients with dementia-related psychosis.
selected Warnings & Precautions†: Cerebrovascular Adverse Events: Increased incidence of cerebrovascu-lar adverse events (eg, stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs. Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. Tardive Dyskinesia: Discontinue if clinically appropriate. Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of
sAPhris®
(asenapine) sublingual tablets
Now approved for 2 expanded indications
1
Prescribing Alert
(continued on next page)
Please click here for Prescribing Information, including Boxed Warning.
*Merck, the marketer of SAPHRIS, has paid for these program materials to be developed and provided to you.
†Please see Prescribing Information for details.
hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with, and at risk for, diabetes. Weight Gain: Patients should receive regular monitoring of weight. Orthostatic Hypotension and Syncope: Dizziness, tachycardia or bradycardia, and syncope may occur, especially early in treatment. Use with caution in patients with known cardiovascular or cerebrovascular disease, and in antipsychotic-naïve patients. Leukopenia, Neutropenia, and Agranulocytosis: Have been reported with antipsychotics. Patients with a pre-existing low WBC or a history of leukopenia/neutropenia should have CBC monitored frequently during the first few months of therapy; discontinue at the first sign of a decline in WBC in the absence of other causative factors. QT Prolongation: Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment: Use caution when operating machinery. Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients.interactions: Avoid drugs that can prolong QT interval. Caution should be used when taken in combination with other centrally acting drugs, alcohol or with strong CYP1A2 inhibitors (fluvoxamine) or drugs that are both substrates and inhibitors of CYP2D6 (paroxetine).Adverse reactions†: Schizophrenia: akathisia, oral hypoesthesia, somnolence. Bipolar I disorder (monotherapy): somnolence, dizziness, extrapyramidal symptoms other than akathisia, weight increased. Bipolar I disorder (adjunctive therapy): somnolence, oral hypoesthesia.how supplied: Sublingual tablets—60; Sublingual tablets (black cherry flavor)—60
SAPHRIS® (asenapine) is now also indicated for: • Adjunctive therapy with lithium or valproate in the acute treatment of manic or mixed episodes
associated with bipolar I disorder in adults1
• Maintenance treatment of schizophrenia in adults1
Proven efficacy as adjunctive therapy with either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults
• Evaluated in a 12-week, randomized, double-blind, placebo-controlled, multicenter, parallel group trial with a 3-week primary end point1
• Compared SAPHRIS in combination with a mood stabilizer (lithium or valproate) to placebo in patients with acute manic or mixed episodes of bipolar I disorder who had not completely responded to lithium or valproate1
• Primary efficacy end point showed significant improvement in the Young Mania Rating Scale (YMRS) total score at week 31 (Figure 1)
• While there is no body of evidence available to answer the question of how long the bipolar patient should remain on SAPHRIS, whether used as monotherapy or as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients be continued beyond the acute response1
• If SAPHRIS is used for extended periods in bipolar disorder, the physician should periodically reevaluate the long-term risks and benefits of the drug for the individual patient1
SELECTED SAFETY INFORMATIONIncreased 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 atypi-cal 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 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis.Cerebrovascular Adverse Events: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebro-vascular 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.
Prescribing Alert
(continued on next page)2
Please click here for Prescribing Information, including Boxed Warning.
significAnt imProvement in Ymrs totAl score vs lithium or vAlProAte Alone
Source: Data on file.2
Figure 1
-9
-6
-3
0
-12
-1530 7 14 21
-9.7
-7.7
Days
Placebo + lithium or valproate (n=163)
Mea
n c
han
ge f
rom
bas
elin
ein
YM
RS
to
tal s
core
Adjunctive Therapy Trial2
<0.05 vs placebo + lithium or valproate
Primary end point(at Day 21)
Placebo + SAPHRIS +
P<0.05
lithium or valproate
lithium or valproate
P
lithium or valproate (n=155)SAPHRIS 5 or 10 mg BID
Initially approved for the acute treatment of manic or mixed episodes associated with bipolar I disorder, with or without psycho tic features
• Evaluated in 2 similarly designed, 3-week, multicenter, randomized, double-blind, placebo- controlled, and active-controlled trials in adults receiving SAPHRIS® (asenapine) 5 or 10 mg twice daily (BID)1,3,4 (Figure 2)
• SAPHRIS demonstrated significant improvement vs placebo in the Young Mania Rating Scale (YMRS) total score at end point (Day 21)3,4
SELECTED SAFETY INFORMATION (continued)Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with administration of antipsychotic drugs, including SAPHRIS. NMS can cause hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dys-rhythmia. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.
Tardive Dyskinesia (TD): The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumulative dose increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. If signs and symptoms appear, discontinuation should be considered.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases associated with ketoacidosis, hyperos-molar coma, or death, has been reported in patients treated with atypical antipsychotics. Patients with risk factors for diabetes mellitus who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of and during treatment. Any patient treated with atypical antipsy-chotics 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 also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atyp-ical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the antipsychotic drug.
Prescribing Alert
(continued on next page)3
significAnt imProvement in Ymrs totAl score vs PlAcebo
Proven efficacy as maintenance treatment of schizophrenia • Evaluated in a placebo-controlled, double-blind, multicenter, flexible-dose trial with a
randomized withdrawal design that assessed maintenance of efficacy of SAPHRIS® (asenapine) for up to 26 weeks5
• The randomized withdrawal phase included 386 patients who meet prespecified criteria for continued stability (mean length of stabilization was 22 weeks) in a 26-week, open-label phase involving a total of 700 patients5
• Primary end point was time to relapse or an impending relapse (Figure 3)5
• In this maintenance trial, SAPHRIS was statistically superior to placebo in time to relapse or impending relapse based on this log-rank test (P<0.0001). That is, the time to relapse or impending relapse was longer in the SAPHRIS group compared with the placebo group5
• While there is no body of evidence available to answer the question of how long the schizo- phrenic patient should remain on SAPHRIS, patients should be periodically reassessed to determine the need for maintenance treatment1
SELECTED SAFETY INFORMATION (continued)Weight Gain: Patients receiving SAPHRIS should receive regular monitoring of weight. There were differences in mean weight gain between SAPHRIS-treated and placebo-treated patients in short-term schizophrenia trials (1.1 kg vs 0.1 kg) and in bipolar mania trials (1.3 kg vs 0.2 kg). In a 52-week study, the proportion of patients with a ≥7% increase in body weight was 14.7%.
Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects: SAPHRIS may induce orthostatic hypotension and syncope. SAPHRIS should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, conditions which would predispose them to hypotension, and 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 orthos-tatic 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, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including SAPHRIS. Patients with a preexisting low white blood cell count (WBC) or a history of 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 a decline in WBC in the absence of other causative factors.
Prescribing Alert
(continued on next page)4
Please click here for Prescribing Information, including Boxed Warning.
Figure 3
mAintenAnce of treAtment effect
a Time (days) in this Kaplan-Meier estimation represents the number of days from randomization (poststabilization on SAPHRIS). PANSS = Positive and Negative Syndrome Scale
Sources: SAPHRIS [package insert]1; Kane 2011.5
100
90
80
70
60
50
40
30
20
10
15 30 45 18016515060 75 90 105 120 1350
0Daysa
Per
cen
t
Placebo (n=191)SAPHRIS 5 or 10 mg BID (n=191)
Probability of non-occurrence of relapse/impending relapse Relapse/impending relapse were 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.
Initially approved for the acute treatment of schizophrenia in adults • In 2 short-term (6-week), multicenter, randomized, double-blind, placebo-controlled, and active-
controlled trials in adults, SAPHRIS® (asenapine) showed significant improvement in Positive and Negative Syndrome Scale (PANSS) total score at end point (Day 42)1,6,7 (Figure 4)
• Trial 2 included a 10-mg twice-daily (BID) arm that showed no added benefit when compared to 5 mg twice daily (BID) and was not significantly different from placebo1
• A third, short-term (6-week) multicenter, randomized, double-blind, placebo-controlled and active-controlled trial in adults included both 5-mg and 10-mg twice-daily SAPHRIS arms. SAPHRIS could not be statistically distinguished from placebo; however, the active control in the trial was superior to placebo2
SELECTED SAFETY INFORMATION (continued)QT Prolongation: SAPHRIS was associated with increases in QTc interval ranging from 2 to 5 msec com-pared to placebo. No patients treated with SAPHRIS experienced QTc increases ≥60 msec from baseline measurements, nor did any experience a QTc of ≥500 msec. SAPHRIS should be avoided in combination with other drugs known to prolong QTc interval, in patients with congenital prolongation of QT interval or a his-tory of cardiac arrhythmias, and in circumstances that may increase the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.
Hyperprolactinemia: Like other drugs that antagonize dopamine D2 receptors, SAPHRIS can elevate prolactin levels, and the elevation can persist during chronic administration. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.
Prescribing Alert
(continued on next page)5
Please click here for Prescribing Information, including Boxed Warning.
significAnt imProvement in PAnss totAl score At end Point (dAY 42)
SELECTED SAFETY INFORMATION (continued)Seizures: SAPHRIS® (asenapine) should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold (eg, Alzheimer’s dementia).
Potential for Cognitive and Motor Impairment: Somnolence was reported in patients treated with SAPHRIS. 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: Appropriate care is advised when prescribing SAPHRIS for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
Suicide: The possibility of suicide attempt is inherent in psychotic illnesses and bipolar disorder. Close super-vision of high-risk patients should accompany drug therapy. Prescriptions for SAPHRIS should be written for the smallest quantity of tablets in order to reduce the risk of overdose.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspira-tion 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.
Hepatic Impairment: SAPHRIS is not recommended in patients with severe hepatic impairment.
Drug Interactions: The risks of using SAPHRIS in combination with other drugs have not been extensively evaluated. Given the primary CNS effects of SAPHRIS, caution should be used when it is taken in combina-tion with other centrally-acting drugs or alcohol. Co-administration of SAPHRIS with strong CYP1A2 inhibitors (fluvoxamine) or compounds which are both CYP2D6 substrates and inhibitors (paroxetine) should be done with caution.
Commonly Observed Adverse Reactions (≥5% and at least twice that for placebo): • In short-term schizophrenia trials with SAPHRIS 5 or 10 mg BID vs placebo: akathisia (6% vs 3%), oral
hypoesthesia (numbing of the tongue [5% vs 1%]), and somnolence (13% vs 7%). The safety profile of SAPHRIS in the maintenance treatment of schizophrenia was similar to that seen with acute treatment
• In short-term bipolar mania (monotherapy) trials with SAPHRIS 5 or 10 mg BID vs placebo: somnolence (24% vs 6%), dizziness (11% vs 3%), extrapyramidal symptoms other than akathisia (7% vs 2%) and weight increase (5% vs less than 1%)
• In the bipolar mania (adjunctive) therapy trial with SAPHRIS 5 or 10 mg BID vs placebo at 3 weeks: somnolence (22% vs 10%) and oral hypoesthesia (5% vs 0%)
Prescribing Alert
6
Please click here for Prescribing Information, including Boxed Warning.
RefeRences1. SAPHRIS [package insert]. Kenilworth, NJ: Schering Corporation, a subsidiary of Merck & Co., Inc.; 2011.2. Data on file, Schering Corporation, a subsidiary of Merck & Co., Inc.3. McIntyre RS, Cohen M, Zhao J, et al. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute
mania in bipolar mania and mixed states. Bipolar Disord. 2009;11(7):673-686.4. McIntyre RS, Cohen M, Zhao J, et al. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-
blind, placebo-controlled trial. J Affect Disord. 2010;122(1-2):27-38.5. Kane JM, Mackle M, Snow-Adami L, Zhao J, Szegedi A, Panagides J. A randomized placebo-controlled trial of asenapine for
the prevention of relapse of schizophrenia after long-term treatment. J Clin Psychiatry 2011;72(3):349–355.6. Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-
controlled trial. J Clin Psychiatry. 2007;68(10):1492-1500.7. Kane JM, Cohen M, Zhao J, et al. Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients
with acute exacerbation of schizophrenia. J Clin Psychopharmacol. 2010;30(2):106-115.
