Asenapine review, part II: clinical efficacy, safety and tolerability.

Drug Safety Evaluation

Asenapine review, part II: clinical efficacy, safety and tolerability Leslie Citrome 1.

Introduction

New York Medical College, Valhalla, NY, USA

2.

Overview of randomized controlled clinical trials of

Introduction: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/ mixed episodes. Areas covered: The purpose of this review is to describe the clinical profile of asenapine. Expert opinion: Asenapine’s efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 -- 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine’s overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine’s effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin.

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Newcastle on 08/24/14 For personal use only.

asenapine 3.

Efficacy

4.

Safety and tolerability

5.

Regulatory affairs

6.

Conclusion

7.

Expert opinion

Keywords: antipsychotic, asenapine, bipolar disorder, dosing, efficacy, safety, schizophrenia, tolerability Expert Opin. Drug Saf. (2014) 13(6):803-830

1.

Introduction

Schizophrenia and related disorders are relatively common chronic illnesses that are challenging to treat effectively [1]. Several different antipsychotic medications are available, each with its own efficacy and tolerability profile [2]. In addition to psychotic disorders, many atypical (second-generation) antipsychotics have also received regulatory approval for the treatment of bipolar disorder, usually for manic episodes, but some have also received approval for maintenance treatment, and three for bipolar depression [3]. Three have also received approval in the USA for adjunctive use with antidepressants for the treatment of major depressive disorder [4]. Asenapine (Box 1) as a sublingual tablet was initially approved by the US FDA in August 2009 for the treatment of acute schizophrenia and acute manic or mixed episodes associated with bipolar I disorder in adults [5]. In 2011, asenapine was subsequently approved for maintenance treatment of schizophrenia and for adjunctive use with lithium or valproate in the treatment of acute manic or mixed episodes associated with bipolar I disorder [6]. In addition to the original unflavored formulation, a black cherry-flavored version of asenapine was brought to market in 2010. Part I of this review, published simultaneously in Expert Opinion on Drug Metabolism and Toxicology [7], described the chemistry, pharmacodynamics and pharmacokinetic/metabolic profile of asenapine. In Part II, the clinical efficacy and safety/ tolerability data are summarized. A PubMed search was conducted on January 19, 2014, using the search term ‘asenapine’ without any date or language restrictions. The resulting 184 publications were then specifically examined for primary sources of clinical data with emphasis on the efficacy, safety, and tolerability of asenapine in humans. In addition, a search of ClinicalTrials.Gov for the text word ‘asenapine’ was conducted on January 30, 2014, in order to identify any clinical trials that have been completed but not yet published. Uncontrolled studies, case series, and 10.1517/14740338.2014.908183 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

803

L. Citrome

Box 1. Drug summary. Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/ mechanism of action


Route of administration Chemical structure

Asenapine II-IV Schizophrenia; acute treatment of manic or mixed episodes associated with bipolar I disorder as monotherapy or adjunctive therapy with either lithium or valproate Combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors. Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors, dopamine D2, D3, D4, and D1 receptors, a1 and a2-adrenergic receptors, and histamine H1 receptors, and moderate affinity for H2 receptors. In in vitro assays, asenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors Oral (sublingual) (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1) Adapted with permission from Figure 1 in [69] 9 HOOC

10

7 O

8a

6

7a

Cl

11 HOOC

12a 12

4

12b 3a

H

5

3b H

* 3

1 N 2 CH3

Pivotal trial(s)

Approval for schizophrenia in the US was based on acute [11,12] and maintenance [13]

studies. Approval for acute manic or mixed episodes associated with bipolar I disorder, with or without psychotic features, was based on acute studies [18,19,22]

case reports were excluded, as were secondary sources (reviews) unless they contained data otherwise unpublished in a primary source. The data described here are primarily from randomized controlled trials. The US product label for asenapine [6] and the FDA’s Drug Approval Package [8] served as additional sources of information, as did the briefing documents that were initially made available to the public during the drug approval process [9,10].

Overview of randomized controlled clinical trials of asenapine 2.

Asenapine has received regulatory approval for the treatment of schizophrenia and bipolar mania/mixed episodes based on specifically designed randomized controlled studies [6]. Completed double-blind randomized controlled trials of asenapine for which results are published in peer-reviewed journals are outlined in Table 1. Asenapine’s efficacy in acute schizophrenia was tested in four pivotal 6-week, randomized, double-blind, placeboand active comparator-controlled multicenter studies [5], with two of these supportive of asenapine’s efficacy in the acute treatment of schizophrenia in adults [11,12]. Asenapine’s efficacy for the maintenance treatment of schizophrenia is 804

supported by a double-blind, placebo-controlled multicenter clinical trial where subjects stabilized on asenapine were randomized to either continue asenapine or to receive placebo [13]. Additional studies completed include a 1-year head-to-head randomized study of asenapine versus olanzapine [14], and its extension, which provides data for up to 3 years in total [15], as well as two identically designed 26-week studies and their respective 26-week extensions examining asenapine versus olanzapine for effects on the negative symptoms of schizophrenia [16,17]. Asenapine’s efficacy in the treatment of manic or mixed episodes of bipolar I disorder was supported in both of the two completed Phase III randomized, placebo- and activecomparator controlled 3-week trials [18,19], and 9-week [20] and 40-week [21] extensions. Asenapine for use as adjunctive therapy with either lithium or valproate in the acute treatment of manic or mixed episodes associated with bipolar I disorder is supported by a 12-week core study (primary outcome measured at 3 weeks) and a 40-week extension [22]. The recommended dose(s) for asenapine depends on the indication and is a consequence of the design and outcomes of the pivotal clinical trials [6]. In all instances, the maximum dose is 10 mg twice a day (b.i.d). For the acute treatment of schizophrenia in adults, the starting and recommended doses

Expert Opin. Drug Saf. (2014) 13(6)


52

26

Schoemaker et al., 2010 [14]

Buchanan et al., 2012 [17]

Adapted with permission from [46].

(Study 1 -EH)

26

6

See review [5]

Kane et al., 2011 [13]

6

See review [5]

6

6

Potkin et al., 2007 [11]

Kane et al., 2010 [12]

Duration (weeks)

Study

Schizophrenia with persistent negative symptoms

Schizophrenia or schizoaffective disorder

Schizophrenia

Schizophrenia, acute exacerbation




Disease state

481

1225

386

458

277

417

182

No. randomized

10 or 20 mg/day (241); mean dose 14.4 mg/day (15.9 mg/day in extension study)

10 or 20 mg/day (913); mean dose 13.5 mg/day

10 or 20 mg/day (194); modal dose 20 mg/day

10 mg/day (114), 20 mg/day (106)

10 or 20 mg/day (91)

10 mg/day (106), 20 mg/day (102)

10 mg/day (60)

Asenapine dose (n)

Olanzapine 10 -- 20 mg/day (240); mean dose 12.5 mg/day (12.8 mg/day in extension study)

Olanzapine 10 -- 20 mg/day (312); mean dose 13.6 mg/day

None

Haloperidol 8 mg/day (115)

Olanzapine 10 -- 20 mg/day (93)

Olanzapine 15 mg/day (103)

Risperidone 6 mg/day (60)

Active control dose (n)

None

None

192

123

93

106

62

No. placebo

Asenapine 10 mg/day statistically separated from placebo but the active control did not None of the asenapine dose arms statistically separated from placebo but the active control did Asenapine did not statistically separate from placebo. The active control also failed to statistically separate from placebo Asenapine 10 mg/day, but not 20 mg/ day, statistically separated from placebo. The active control statistically separated from placebo Incidence of relapse was significantly lower with asenapine and times to relapse or discontinuation were longer with asenapine Psychopathological rating scale scores improved with both agents; the improvement was greater with olanzapine than with asenapine using last observation carried forward but not in an observed case analysis. Completers were eligible to continue into an extension study [15] Completers were eligible to enter a 26-week extension study. Asenapine was not superior to olanzapine in change in the 16-item Negative Symptom Assessment Scale total score in either the core study or the extension study. Olanzapine was associated with modest, but significantly greater, changes in PANSS-positive subscale score at various assessment times in the core study

Comments regarding efficacy outcomes

Table 1. Completed asenapine double-blind randomized controlled trials for which results are available (outcomes based on the Brief Psychiatric Rating Scale and/or Positive and Negative Syndrome Scale for the schizophrenia studies or the Young Mania Rating Scale for the bipolar studies, unless otherwise noted).


Asenapine

805

806

26

Buchanan et al., 2012 [17]


3

12

McIntyre et al., 2010 [19]

Szegedi et al., 2012 [22]

Adapted with permission from [46].

3

McIntyre et al., 2009 [18]

(Study 2 - WH)

Duration (weeks)

Study

Manic or mixed episode, bipolar I disorder



Schizophrenia with persistent negative symptoms

Disease state

326

488

489

468

No. randomized

10 or 20 mg/day plus open label lithium or valproate (159); mean dose 11.8 mg/day

Initiated at 20 mg/day, then 10 or 20 mg/day (185); mean dose 18.4 mg/day

Initiated at 20 mg/day, then 10 or 20 mg/day (194); mean dose 18.2 mg/day

10 or 20 mg/day (244); mean dose 14.5 mg/day (16.0 mg/day in the extension study)

Asenapine dose (n)

Olanzapine initiated at 15 mg/day, then 5 -- 20 mg/day (191); mean dose 15.8 mg/day Olanzapine initiated at 15 mg/day, then 5 -- 20 mg/day (205); mean dose 15.9 mg/day None

Olanzapine 10 -- 20 mg/day (224); mean dose 14.0 mg/day (14.8 mg/day in the extension study)

Active control dose (n)

167

98

104

None

No. placebo

Asenapine and the active control statistically separated from placebo. Completers were eligible for 9-week [20] and 40-week [21] extension studies Adjunctive asenapine was statistically superior to adjunctive placebo at the 3-week primary efficacy end point. Completers were eligible for a 40-week extension study [22]

Completers were eligible to enter a 26-week extension study. Asenapine was not superior to olanzapine in change in the 16-item Negative Symptom Assessment Scale total score in the core study, but asenapine was superior to olanzapine at week 52 in the extension study. Olanzapine was associated with modest, but significantly greater, changes in PANSS-positive subscale score at various assessment times in both the core study and the extension study Asenapine and the active control statistically separated from placebo. Completers were eligible for 9-week [20] and 40-week [21] extension studies

Comments regarding efficacy outcomes

Table 1. Completed asenapine double-blind randomized controlled trials for which results are available (outcomes based on the Brief Psychiatric Rating Scale and/or Positive and Negative Syndrome Scale for the schizophrenia studies or the Young Mania Rating Scale for the bipolar studies, unless otherwise noted) (continued).


L. Citrome


Asenapine

are 5 and 5 mg b.i.d., respectively. For the maintenance treatment of schizophrenia in adults, the starting and recommended doses are 5 and 10 mg b.i.d., respectively. For the acute treatment of bipolar mania/mixed episodes in adults, the starting and recommended doses for monotherapy are 10 mg b.i.d. and 5 -- 10 mg b.i.d., respectively; when asenapine is used adjunctively, the starting and recommended doses for monotherapy are 5 mg b.i.d. and 5 -- 10 mg b.i.d., respectively. Because asenapine is not approved for maintenance treatment of bipolar disorder, there are no dosing recommendations for this in product labeling. Of note, in a modeling and simulation study [23], asenapine doses of 5 -- 10 mg b.i.d. had similar efficacy in the acute treatment of schizophrenia. At present, asenapine is not approved for use in children or adolescents. 3.

Efficacy

3.1

Schizophrenia Acute short-term studies

3.1.1

As noted in Table 1, two 6-week trials were supportive for the use of asenapine in acute schizophrenia [11,12]. In one study, 182 patients were randomly assigned to asenapine 5 mg b.i.d., placebo, or an active control for assay sensitivity (risperidone 3 mg b.i.d.) [11]. The primary efficacy end point was change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score. Compared with placebo, asenapine produced significantly greater decreases in PANSS total scores from week 2 onward. Risperidone did not statistically significantly separate from placebo on the PANSS total score, but did so on the PANSS-positive subscale. In the second positive trial, 458 patients with acute schizophrenia were randomly assigned to fixed-dose treatment with asenapine 5 mg b.i.d., asenapine 10 mg b.i.d., placebo or an active control for assay sensitivity (haloperidol 4 mg b.i.d.) [12]. The primary efficacy end point was also changed from baseline in the PANSS total score, and asenapine 5 mg b.i.d. and haloperidol were both superior to placebo, with statistically significant differences seen from day 21 onward. However, asenapine 10 mg b.i.d. did not demonstrate an advantage over placebo, a finding that the authors suggested may have been due in part to the high placebo response rate in that trial. For the two other 6-week acute schizophrenia trials [5,8,9], one was considered negative and the other a failed study. In the negative study, asenapine 5 or 10 mg b.i.d. failed to separate from placebo, whereas the active control (olanzapine 15 mg/day) did demonstrate efficacy. The other trial was considered a failed trial because neither flexibly dosed asenapine 5 or 10 mg b.i.d. nor the active control (flexibly dosed olanzapine 10 -- 20 mg/day) separated from placebo. A patient-level meta-analysis of pooled patient data from all four trials was conducted and found that asenapine was superior to placebo with regard to mean change in PANSS total score, with an effect comparable to active controls from the same trials [24]. The authors also completed a network metaanalysis and found that asenapine ranked fourth among the

eight agents in this analysis; estimated differences ranged from 3.9 points greater than ziprasidone to 2.9 points less than olanzapine [24]. This ranking differs somewhat from that found by Leucht and colleagues [25], where on the basis of overall change in symptoms asenapine ranked 13 out of 15 (ranked as number 1, demonstrating the most improvement, was clozapine; ranked as number 14 was lurasidone and ranked as number 15, demonstrating the least improvement, was iloperidone). However, this should be interpreted with caution as data gathered from group comparisons can be problematic because there is a substantial amount of heterogeneity regarding medication effects among patients that prevents the reliable prediction of effects on individual persons [26]. In a post hoc analysis of pooled data from the three 6-week fixed-dose studies, early improvement, as defined by a ‡ 20% reduction of the PANSS total score at 2 weeks, successfully predicted treatment outcome with asenapine at week 6 regarding response (PANSS reduced by ‡ 50%) or remission (PANSS item score £ 3 on selected items) [27]. Relapse prevention Asenapine’s efficacy regarding the prevention of relapse was tested in a maintenance study where patients with schizophrenia were stabilized on asenapine 5 -- 10 mg b.i.d. during a 26-week open-label treatment period and then randomized to either continue asenapine 5 -- 10 mg b.i.d. or to receive placebo, double-blind, for up to an additional 26 weeks [13]. Of the 700 enrolled patients who were treated with open-label asenapine, 386 met stability criteria and entered the doubleblind phase. Time to relapse/impending relapse was significantly longer with asenapine than with placebo. The incidence of relapse/impending relapse was 12% for asenapine and 47% for placebo, yielding a number needed to treat (NNT) of 3 (95% CI 3 -- 4). Dose--response could not be determined as the study used a flexible-dose design, but the most commonly used dose of asenapine was 10 mg b.i.d. in both the open-label and the double-blind phases. 3.1.2

52-Week comparison with olanzapine Although not placebo-controlled, long-term efficacy data are available from a double-blind randomized trial comparing asenapine with olanzapine in patients with schizophrenia or schizoaffective disorder. Both asenapine and olanzapine were flexibly dosed (10 or 20 mg/day) for up to 1 year [14], with completers eligible to participate in an extension study [15] and thus providing up to 3 years of data. Rates of discontinuation because of insufficient therapeutic effect were 25.1% for asenapine and 14.5% for olanzapine, yielding a NNT advantage for olanzapine of 10 (95% CI 7 -- 18). Changes from baseline in PANSS total score were similar for asenapine and olanzapine at week 6 but showed a statistically significant difference in favor of olanzapine at end point (Last Observation Carried Forward); however, among completers changes in PANSS total scores were similar for asenapine versus 3.1.3


807

L. Citrome

olanzapine at week 6 and at week 52. In general, clinical stability was maintained in the extension study for both groups. Persistent negative symptoms In another set of double-blinded studies, asenapine was compared with olanzapine in patients with schizophrenia experiencing persistent negative symptoms [16,17]. Two identically designed 26-week studies and their respective 26-week extensions were completed. Asenapine was not superior to olanzapine in change in the 16-item Negative Symptom Assessment Scale (NSA-16) total score in either core study, but asenapine was superior to olanzapine at week 52 in one of the extension studies. Olanzapine was associated with modest, but significantly greater, changes in the PANSS-positive subscale score at various assessment times in both core studies and in one of the extension studies. In the two core studies, 26-week completion rates with asenapine were 64.7 and 49.6%, versus 80.4 and 63.8%, respectively, with olanzapine, yielding NNTs in favor of olanzapine of 7 (95% CI 5 -- 13) and 7 (95% CI 5 -- 19), respectively. In the two extension studies, completion rates were 84.3 and 66.3% with asenapine versus 89.0 and 80.9%, respectively, with olanzapine, yielding NNTs in favor of olanzapine of 22 (ns) and 7 (95% CI 4 -- 45), respectively. An analysis was also conducted where data were pooled [28]; although there were no differences between asenapine and olanzapine at week 26, asenapine showed superiority over olanzapine at week 52 on the NSA-16 total score.


3.1.4

3.2

Bipolar disorder Acute short-term studies

3.2.1

The acute treatment of bipolar mania or mixed episodes is supported by two identically designed 3-week studies where subjects were randomly assigned to receive flexibly dosed asenapine 5 -- 10 mg b.i.d. (starting dose 10 mg b.i.d.), olanzapine 5 -- 20 mg/day (starting dose 15 mg/day), or placebo [18,19]. The primary outcome measure for each of these studies was change from baseline in the Young-Mania Rating Scale (YMRS) total score and for each study. YMRS total scores were statistically significantly improved from baseline to day 21 for asenapine and olanzapine compared with placebo and statistically significant improvement in the YMRS score compared with placebo was noted for asenapine and olanzapine from day 2 onward. In the first study [18], the proportions of subjects meeting criteria for response (‡ 50% decrease from baseline YMRS total score) and remission (YMRS total score £ 12) were higher with asenapine (42.3 and 40.2%, respectively) than with placebo (25.2 and 22.3%, respectively), yielding a NNT for response of 6 (95% CI 3 -- 17) and a NNT for remission of 6 (95% CI 3 -- 14). The NNT for response for olanzapine versus placebo was 5 (95% CI 2 -- 8) and that for remission was 6 (95% CI 3 -- 16). However, in the second study [19], rates of response (42.6%) and remission (35.5%) with asenapine did not differ significantly from those with placebo (34 and 808

30.9%, respectively), yielding NNTs of 12 and 22, respectively. Olanzapine was superior to placebo in rates of response (54.7%) and remission (46.3%), with NNTs for olanzapine versus placebo of 5 (95% CI 3 -- 12) and 7 (95% 3 -- 26), respectively, and for olanzapine versus asenapine of 9 (95% CI 5 -- 47) and 10 (95% CI 5 -- 97), respectively. Several post hoc analyses have been conducted that pooled together data from these two 3-week trials. In an item analysis of the YMRS, each of the 11 individual item scores were significantly reduced with asenapine or olanzapine versus placebo at day 21 [29]. Early effects (day 2) were noted for the items of disruptive/aggressive behavior, content, irritability, elevated mood, sleep and speech. Another analysis demonstrated a potential antidepressant effect for asenapine in those subjects who had clinically relevant depressive symptoms at baseline, with less consistent effects noted for olanzapine [30]. In an evaluation of the effect of depressive features on treatment outcome, it was observed that with increasing baseline severity of depressive features, treatment outcome was poorer with olanzapine and placebo, but remained stable with asenapine [31]. Efficacy for asenapine for mixed episodes was further supported by a post hoc analysis [32] that also included the 9-week extension data [20]. An additional report is of an evaluation of the baseline impact of episode type (manic vs mixed) on health-related quality of life (HRQoL) as measured by the 36-item Short-Form Health Survey, and the possible effect of asenapine versus placebo and olanzapine on HRQoL in patients with mixed episodes [33]; patients with mixed episodes reported considerable impairments in HRQoL versus patients with manic episodes. At 3 weeks among patients with mixed episodes, asenapine was associated with significant improvements in HRQoL compared with olanzapine and placebo. Lastly, early improvement within 1 week of treatment (as measured by different thresholds of reductions of the YMRS total score by ‡ 15%, ‡ 20%, ‡ 25% or by a ‡ 1 point change on the Clinical Global Impression Bipolar Disorder severity score) was predictive of end point response or remission, and that absence of improvement within week 1 of treatment initiation strongly predicted the unlikely success of subsequent treatment [34]. Longer-term extension studies Patients in the two 3-week studies were invited to participate in a 9-week extension study [20], followed by another 40 weeks [21]. Subjects who were treated with placebo in the feeder trials were blindly allocated to receive asenapine 5 -- 10 mg b.i.d. in the extension trial. Asenapine was statistically noninferior to olanzapine as measured by the YMRS total score from baseline to day 84 for the observed case subjects who had 3 weeks of previous exposure to study medication. The proportions of participants who were YMRS responders and remitters were similar in the asenapine and olanzapine groups (response rates of 77 and 82% with asenapine and olanzapine, respectively, and remission rates of 75 and 79%, respectively). For the patients who were 3.2.2


Asenapine

Table 2. Asenapine: incidence and number needed to harm (95% CI) versus placebo for treatment emergent adverse events as reported in product labeling for events with incidence $ 5% and twofold greater than placebo in acute studies.


Adverse Event

Schizophrenia Somnolence Akathisia Oral hypoesthesia Bipolar disorder (monotherapy) Somnolence Dizziness Extrapyramidal symptoms other than akathisia Weight increased Bipolar disorder (adjunctive) Somnolence Oral hypoesthesia

Placebo

Asenapine 5 or 10 mg b.i.d.

Asenapine 5 mg b.i.d.

Incidence (%)

Incidence (%)

NNH (95% CI)

Incidence (%)

n = 378 7 3 1 n = 203

n = 572 13 6 5 n = 379

17 (11 -- 43) 34 (18 -- 249) 25 (17 -- 52)

6 3 2

24 11 7

6 (5 -- 9) 13 (9 -- 25) 20 (13 -- 56)

10, except for somnolence for patients with bipolar disorder, for both monotherapy and adjunctive use of asenapine. In the 6-week acute schizophrenia trials, 9% of asenapinetreated patients and 10% of placebo subjects discontinued due to adverse reactions. There were no specific drug-related adverse reactions associated with discontinuation in subjects treated with asenapine at the rate of ‡ 1% and at least twice the rate for placebo. In the 3-week bipolar disorder monotherapy trials, 10% of asenapine-treated patients discontinued treatment due to an adverse reaction compared with about 6% on placebo (NNH 25, ns). The most common adverse


809

L. Citrome


reactions associated with discontinuation in subjects treated with asenapine (rate of ‡ 1% and at least twice the placebo rate) were anxiety (1.1%) and oral hypoesthesia (1.1%) compared with placebo (0%). In the asenapine bipolar disorder adjunctive trial, 16% of asenapine-treated patients discontinued treatment due to an adverse reaction compared with 11% on placebo (NNH 20, ns). The most common adverse reactions associated with discontinuation in patients treated with asenapine (rate of ‡ 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%). Somnolence Overall, somnolence is the single most common adverse event associated with asenapine treatment. The highest rates of somnolence were observed in the short-term acute manic/ mixed-episode bipolar monotherapy trials (most common dosage was 10 mg b.i.d.), where somnolence was reported in 24% of patients receiving asenapine versus 6% of patients receiving placebo. The product label describes this effect as usually transient, with the highest incidence reported during the first week of treatment [6]. In addition, somnolence/ sedation led to discontinuation in only a small proportion (0.6%) of patients treated with asenapine in the short-term, placebo-controlled trials [6]. In a post hoc analysis of 10 clinical trials [35], in the shortterm schizophrenia cohort (from the four 6-week trials, including [11,12]), the incidence of somnolence was 13.1% for asenapine, highest for olanzapine (19.1%) and lowest for haloperidol (5.2%). The differences between risperidone or haloperidol and placebo were not significant. The shortest median time to onset of somnolence was observed for asenapine and olanzapine (2 days) versus 6, 3 and 7 days for risperidone, haloperidol and placebo, respectively. Median duration of somnolence was 15 days for asenapine and olanzapine, longest for haloperidol (22.5 days) and shortest for risperidone (3 days). No patient discontinued because of somnolence/sedation in the placebo, risperidone, or haloperidol groups, but one patient (0.2%) receiving asenapine and two patients (1.0%) receiving olanzapine discontinued due to somnolence. One event of severe somnolence was reported in the asenapine group. In the long-term schizophrenia cohort (from [14]), the incidence, time to onset, and duration of somnolence with asenapine and olanzapine were similar (18.4 vs 19.6%, 9 vs 12 days and 22 vs 21 days, respectively). Nine patients (1.0%) receiving asenapine and one receiving olanzapine (0.3%) discontinued as a result of somnolence/sedation. Thirteen patients (1.43%) treated with asenapine and four (1.29%) treated with olanzapine experienced severe somnolence. In schizophrenia with persistent negative symptoms (from [17]), the incidence and median time to onset of somnolence with asenapine and olanzapine were similar (18.5 vs 21.1%, 9.0 vs 7.5 days, respectively); however, duration differed numerically (25.0 vs 41.5 days, respectively). Five 4.2

810

patients (1.0%) in the asenapine group and three patients (0.7%) in the olanzapine group discontinued as a result of somnolence/sedation. Three patients (0.62%) treated with asenapine and five patients (1.08%) treated with olanzapine experienced severe somnolence. In the bipolar disorder monotherapy cohort (from the two 3-week trials [18,19]), the incidence of somnolence with asenapine and olanzapine were similar (23.8 vs 26.4%, respectively), as were median time to onset (1 day vs 2 days, respectively), and duration of somnolence (7 vs 8.5 days, respectively). No patient in the placebo group, one (0.3%) in the asenapine group, and two (0.5%) in the olanzapine group discontinued because of somnolence/sedation. Severe somnolence was experienced by two patients (0.53%) treated with asenapine, two patients (0.51%) treated with olanzapine, and none with placebo. In the bipolar disorder adjunctive asenapine cohort (from [22]), the median time to onset and duration of somnolence with asenapine versus placebo were 1.5 versus 2 days and 12.5 versus 7 days, respectively. In another report, oral second-generation antipsychotics were compared with placebo on the outcome of somnolence in short-term acute trials of schizophrenia as reported in product labeling. There was a broad range of incidence rates, producing NNH values versus placebo as robust as 7 for olanzapine or quetiapine extended-release, to a nonstatistically significant NNH of 42 for paliperidone [36]. For the pooled data, the NNH value for asenapine was 17. In the metaanalysis conducted by Leucht and colleagues [25], asenapine ranked 9 out of 15 on sedation (ranked as number 1, demonstrating the least sedation, was amisulpride, and followed closely by paliperidone; ranked as number 15, demonstrating the most sedation, was clozapine). Dizziness and syncope The product labels for all of the oral second-generation antipsychotic medications contain a class-level warning about orthostatic hypotension and syncope [36]. Although asenapine has high affinity for the a1-adrenergic receptor, rates of spontaneously reported adverse events of dizziness appear low (in the short-term schizophrenia trials, rates were 7, 3, and 5% for asenapine 5, 10 mg b.i.d., and all doses combined, respectively, compared with 4% for placebo) [6]. Rates of dizziness for the bipolar disorder adjunctive asenapine study were also low, with 4% for asenapine 5 -- 10 mg b.i.d. versus 2% for placebo. Differences from placebo were somewhat higher in the bipolar disorder monotherapy trials, with rates of 11% for asenapine 5 -- 10 mg b.i.d. versus 3% for placebo. Overall rates of syncope were observed to be low among patients in contrast to rates observed among healthy volunteers in the clinical pharmacology trials [8,9]. In short-term schizophrenia trials, syncope was reported in 0.2% (1/572) of patients treated with asenapine 5 mg or 10 mg b.i.d. versus 0.3% (1/378) for placebo [6]. In the short-term bipolar mania trials, syncope was reported in 0.3% (1/379) of patients treated with asenapine 5 mg or 10 mg b.i.d. versus 0% (0/203) of patients 4.3


Asenapine

treated with placebo. In total, during pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with asenapine. Extra-pyramidal symptoms and akathisia Asenapine has a dose-related association with EPS and akathisia, although the frequency of these events is substantially lower with asenapine than with haloperidol [5]. In the 1-year study comparing asenapine with olanzapine [14], EPS reported as adverse events were more common with asenapine (18%) than with olanzapine (8%) (asenapine vs olanzapine, NNH = 10, 95% CI 8 -- 17). The most commonly reported type of movement disorder in the asenapine and olanzapine groups was akathisia, with treatment-emergent rates of 10% for asenapine and 4% for olanzapine (asenapine vs olanzapine, NNH = 17, 95% CI 12 -- 33). In the 2-year blinded extension study, incidence rates of EPS-related adverse events that started during the extension were lower for both asenapine (4.5%) and olanzapine (3.3%) compared with those that started during the core study [14,15]. There was little change in EPS severity, and not many new cases of akathisia were reported during the extension period [15]. In the 40-week extension to the acute bipolar trials [21], the percentage of patients shifting to above a prespecified akathisia global rating scale threshold was higher in the asenapine group compared with the placebo/asenapine and olanzapine groups. In the Leucht meta-analysis [25], asenapine ranked 9 out of 15 on EPS (ranked as number 1, demonstrating the least EPS, was clozapine; ranked as number 15, demonstrating the most EPS, was haloperidol; olanzapine was ranked as number 3).


4.4

Body weight and metabolic variables The asenapine product label [6] contains a class-level warning regarding weight gain, as well as hyperglycemia and diabetes mellitus, and monitoring is recommended. However, asenapine’s effects on weight and metabolic variables appear modest. The mean weight gain observed in the acute schizophrenia trials was 1.1 kg for asenapine versus 0.1 kg for placebo [6]. Among these patients, the proportion with a ‡ 7% increase in body weight (at end point) was 4.9% for asenapine versus 2% for placebo [6], yielding a NNH versus placebo of 35 (95% CI 20 -- 132) [5]. In the acute bipolar monotherapy trials, the mean weight gain for asenapine was 1.3 kg versus 0.2 kg for placebo [6]. Among these patients, the proportion with a ‡ 7% increase in body weight (at end point) was 5.8% for asenapine versus 0.5% for placebo [6], for a NNH of 19 (95% CI 13 -- 37) [5]. In the 52-week study comparing asenapine with olanzapine in patients with schizophrenia or schizoaffective disorder [14], the mean weight gain from baseline observed with asenapine was 0.9 kg (at end point) and 1.6 kg (observed cases) compared with 4.2 kg (at end point) and 5.6 kg (observed cases) for olanzapine; the proportion of patients with a ‡ 7% increase in body weight for asenapine was 14.7% (at end point) and 22.5% (observed cases). For

olanzapine-treated patients in that study, the proportion of patients with a ‡ 7% increase in body weight was 36.1% (at end point) and 44.4% (observed cases), yielding a NNH for olanzapine versus asenapine of 5 (95% CI 4 -- 7) for both the end point and the observed cases analyses [5]. In the 2-year blinded extension study [15], mean body weight during the extension did not change beyond the weight gain in the core study. In the 40-week extension to the acute bipolar trials [21], clinically relevant weight gain (‡ 7% increase) occurred in 21.9, 39.2, and 55.1% of patients in the placebo/asenapine, asenapine, and olanzapine groups, respectively; the NNH for clinically relevant weight gain for olanzapine versus asenapine was 7, 95% CI 3 -- 63. Overall, asenapine treatment had limited effects on clinical laboratory parameters. Table 3 summarizes the proportions of patients in the acute studies with abnormal metabolic variables at end point as noted in product labeling [6]. Long-term data regarding metabolic outcomes extending out to 12 months and beyond are consistent with the short-term data [14,15]. In a post hoc analysis of 17 clinical trials [37], the authors concluded that asenapine was associated with greater weight gain and glucose changes than placebo but not associated with a meaningful change in triglycerides or cholesterol levels. In addition, asenapine was not significantly different from olanzapine in change in glucose levels but lower than olanzapine with respect to triglycerides, weight gain and increased cholesterol. In the Leucht meta-analysis [25], asenapine ranked 6 out of 15 on weight gain (ranked as number 1, demonstrating the least weight gain, was haloperidol, and followed closely by ziprasidone and lurasidone; ranked as number 15, demonstrating the most weight gain, was olanzapine).

4.5

ECG QTc interval Asenapine’s effect on the ECG QTc interval is relatively small and similar to that seen with quetiapine in a dedicated QT study [38,39]. Asenapine at doses up to 20 mg b.i.d. was associated with increases in the QTc interval ranging from 2 to 5 msec compared with placebo; no patients treated with asenapine experienced QTc increases ‡ 60 msec from baseline measurements, nor did any patient experience a QTc of ‡ 500 msec. Product labeling [6] notes that rates of postbaseline QT prolongations exceeding 500 msec were reported at comparable rates for asenapine versus placebo in these shortterm trials, and there were no reports of torsade de pointes or any other adverse reactions associated with delayed ventricular repolarization. However, the product label recommends that asenapine should be avoided in combination with other drugs known to prolong the QTc interval and 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. In the Leucht meta-analysis [25], asenapine ranked 8 out of 15 on QTc prolongation (ranked as number 1, demonstrating the least effect 4.6


811

L. Citrome

Table 3. Asenapine: incidence of subjects with abnormal values for metabolic variables at end point and number needed to harm (95% CI) versus placebo.


Metabolic variable

Schizophrenia Fasting serum glucose ‡ 126 mg/dl at end point Total cholesterol ‡ 240 mg/dl at end point Triglycerides ‡ 200 mg/dl at end point Bipolar disorder (monotherapy) Fasting serum glucose ‡ 126 mg/dl at end point Total cholesterol ‡ 240 mg/dl at end point Triglycerides ‡ 200 mg/dl at end point

Placebo

Asenapine (any dose)

Incidence (%)

Incidence (%)

NNH (95% CI)

6 7 10.5

7.4 8.3 13.2

72 (ns) 77 (ns) 38 (ns)

2.2 8.6 11.4

4.9 8.7 15.2

38 (ns) 1000 (ns) 27 (ns)

Data from the product label [6]; the product label did not contain the numerators and denominators necessary for the calculation of the 95% CI but a prior review [5] noted they were all ns. Adapted with permission from [46]. NNH: Number needed to harm; ns: Not statistically significant; the 95% CI encompasses infinity.

on the QTc interval, was lurasidone; ranked last, demonstrating the largest effect on the QTc interval, was sertindole). Prolactin As with all antipsychotics that are strong antagonists at the dopamine D2 receptor, asenapine would be expected to be associated with elevations in plasma prolactin; however, in general, the effects on prolactin levels in the short-term schizophrenia and bipolar mania/mixed studies revealed no clinically relevant changes [5]. In the asenapine clinical trials, the rate of adverse events related to abnormal prolactin levels was 0.4% for asenapine versus 0% for placebo [6]. In general, although mean prolactin values decreased from baseline among the patients receiving asenapine 5 -- 10 mg b.i.d. in the Phase II and III clinical program, an outlier analysis revealed higher proportions of patients on asenapine with marked increases in prolactin compared with those on placebo and comparable to what was observed for olanzapine [5]. Shifts to higher than normal levels of prolactin were observed in 19, 44, 97, 72, and 51% of subjects randomized to placebo, asenapine, risperidone, haloperidol, and olanzapine, respectively; yielding NNH versus placebo values of 4 (95% CI 4 -- 5), 2 (95% CI 2 -- 2), 2 (95% CI 2 -- 3), and 4 (95% CI 3 -- 4) for asenapine, risperidone, haloperidol, and olanzapine, respectively [5]. In the 6-week schizophrenia trials specifically, the proportion of patients with prolactin elevations ‡ 4 times the upper limit of normal were 2.6% for asenapine versus 0.6% for placebo [6], for a NNH of 50 (95% CI 29 -- 208) [5]. In the 3-week bipolar monotherapy trials, the proportion of patients with prolactin elevations ‡ 4 times the upper limit of normal were 2.3% for asenapine versus 0.7% for placebo, for a NNH of 63 (ns) [5]. In the 52-week trial of asenapine versus olanzapine in schizophrenia and schizoaffective disorder, plasma prolactin levels decreased from elevated levels at baseline in both treatment groups [15]. In the Leucht meta-analysis [25], asenapine ranked 3 out of 15 on prolactin increase (ranked as number 1,

demonstrating the least effect on prolactin, was aripiprazole; ranked last, demonstrating the largest effect on prolactin, was paliperidone).

4.7

812

Hypersensitivity reactions When asenapine was commercially released in 2009, the product label did not contain any contraindications for use [40]. There were no reported cases of anaphylaxis or serious hypersensitivity in the clinical trials program that included > 4500 subjects [41]. Subsequently, postmarketing MedWatch data became available, and on September 1, 2011, the FDA announced that the labeling was changed to include information about hypersensitivity reactions [42], and labeling now warns of hypersensitivity reactions (anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash) that have been observed in patients treated with asenapine [6]. In several cases, these reactions occurred after the first dose. Thus, asenapine is now contraindicated in patients with a known hypersensitivity to the product. 4.8

Dysgeusia and oral hypoesthesia Asenapine can cause dysgeusia (distorted, altered, or unpleasant taste) or oral hypoesthesia (numbness). Although rates of spontaneously reported dysgeusia and oral hypoesthesia were relatively low in the clinical trials, patients in clinical practice may more readily complain about these potential effects and should be forewarned in order to avoid nonadherence. A black cherry-flavored formulation is now available and may lessen or mask asenapine’s unpleasant taste [6]. In the 6-week schizophrenia trials, the rates of spontaneously reported oral hypoesthesia were 5% for those receiving asenapine versus 1% for placebo [6]. In the 3-week bipolar disorder monotherapy trials, the rates were 4% versus < 1%, respectively. Product labeling notes that oral hypoesthesia usually resolves within 1 h [6]. There were no discontinuations due to oral hypoesthesia in the short-term schizophrenia 4.9



P05786, A7501009

NCT00145509,

813

Bipolar disorder

Schizophrenia

Bipolar disorder

Bipolar disorder

Condition(s)

A Double-Blind, 9-Week Extension Study Evaluating the Safety and Maintenance of Effect of Asenapine vs. Olanzapine in the Treatment of Subjects With Acute Mania Clinical Trial Protocol A7501006 (Secondary Title: ARES) A Phase 3, Randomized, Placebo-Controlled, Double-Blinded Trial Evaluating the Safety and Efficacy of Asenapine in Subjects Continuing Lithium or Valproic Acid/Divalproex Sodium for the Treatment of an Acute Manic or Mixed Episode A Multicenter, DoubleBlind, Flexible -Dose, 6-Month Trial Comparing the Efficacy and Safety of Asenapine With Olanzapine in Stable Subjects With Predominant, Persistent Negative Symptoms of Schizophrenia. A Phase 3, PlaceboControlled, DoubleBlinded Continuation Trial Evaluating the Safety and Efficacy of Asenapine in Subjects Completing a 12-week Lead-in Trial and Continuing Lithium or Valproic Acid/Divalproex

Official title

MSD

MSD

SP

SP; Pfizer

Sponsor

III

III

III

III

Adult/ senior

Adult/ senior

Adult/ senior

Adult/ senior

Phase Age group

77

468

324

504

n

40

26

12

9

Study length (weeks)

Olanzapine 5 -- 20 mg q.d.

Placebo

5 -- 10 mg b.i.d.

Placebo

5 -- 10 mg b.i.d.

5 -- 10 mg b.i.d.

Olanzapine 5 -- 20 q.d.

Control

5 -- 10 mg b.i.d.

Asenapine dose

12/2007

12/2008

04/2007

06/2006

Yes

Yes

No

No

Completion Study date results posted?

AM: In the morning; b.i.d.: Twice a day; MSD: Merck Sharp & Dohme Corp; NA: Not applicable; q.d.: Once a day; QHS: At bedtime; SP: Schering-Plough; SSRI: Serotonin-specific reuptake inhibitor.

[22]

[17]

P05771, Aphrodite, A7501013

A7501008, P05844

A7501006

Other identifier(s)

NCT00145496,

[22]

NCT00145470,

[20]

NCT00143182,

NCT identifier, citation if available

Table 4. Clinical trials registered at www.clinicaltrials.gov as of January 30, 2014, using search term ‘asenapine’ or ‘ORG 5222’. Study completion dates are as per the registration record unless they are dated after 01/2014, in which case they are noted as ‘ongoing’; for studies with a completion date prior to 01/2014, the study may not be flagged as completed in the registration record.


Asenapine

814

41022, Hera

P05785, Hera, 41513

41512, Hera, P05784

NCT00151424

NCT00156065

NCT00156091


Schizophrenia

Schizophrenia

Schizophrenia

Schizophrenia

Condition(s)

Sodium for the Treatment of an Acute Manic or Mixed Episode A Randomized, PlaceboControlled, Double-Blind Trial of Asenapine in the Prevention of Relapse After Long-Term Treatment of Schizophrenia A Multicenter, Randomized, DoubleBlind, Flexible-Dose, 6-Week Trial of the Efficacy and Safety of Asenapine Compared With Placebo Using Olanzapine Positive Control in Subjects With an Acute Exacerbation of Schizophrenia A Multicenter, Randomized, Double-Blind, Flexible-Dose, Long-Term Extension Trial of the Safety and Maintenance of Effect of Asenapine Using Haloperidol Positive Control in Subjects Who Complete Protocol 041023 [NCT00156104] A Multicenter, Randomized, Double-Blind, Flexible-Dose, Long-Term Extension Trial of the Safety and Maintenance of Effect of Asenapine Using Olanzapine Positive

Official title

III

III

III

MSD

SP

III

Adult/ senior

Adult/ senior

Adult/ senior

Adult/ senior

Phase Age group

Organon

MSD

Sponsor

260

187

277

831

n

52

52

6

26


Placebo, olanzapine 10 --20 mg q.d.

Haloperidol 2 -- 8 mg b.i.d.


5 -- 10 mg b.i.d.

5 -- 10 mg b.i.d.

Placebo

Control

5 -- 10 mg b.i.d.

5 -- 10 mg b.i.d.

Asenapine dose

06/2007

10/2007

02/2006

07/2008

NA

Yes

No

Yes



[13]

P05770, A7501012

Other identifier(s)

NCT00150176,


Table 4. Clinical trials registered at www.clinicaltrials.gov as of January 30, 2014, using search term ‘asenapine’ or ‘ORG 5222’. Study completion dates are as per the registration record unless they are dated after 01/2014, in which case they are noted as ‘ongoing’; for studies with a completion date prior to 01/2014, the study may not be flagged as completed in the registration record (continued).


L. Citrome


A7501004

NCT00159744, Bipolar disorder

Schizophrenia

Schizophrenia

Condition(s)

Control in Subjects Who Complete Protocols 041021 or 041022 A Multicenter, Randomized, Double-Blind, Fixed-Dose, 6-Week Trial of the Efficacy and Safety of Asenapine Compared With Placebo Using Haloperidol Positive Control in Subjects With an Acute Exacerbation of Schizophrenia A Multicenter, Randomized, Double-Blind, Fixed-Dose, 6-Week Trial of the Efficacy and Safety of Asenapine Compared With Placebo Using Olanzapine Positive Control in Subjects With an Acute Exacerbation of Schizophrenia A Phase III, Randomized, Placebo-Controlled, Double-Blind Trial Evaluating the Safety and Efficacy of Sublingual Asenapine vs. Olanzapine and Placebo in In-Patients With an Acute Manic Episode Clinical Trial Protocol 7501004 (Secondary Title: ARES)

Official title

Organon; Pfizer

SP

Organon

Sponsor

III

III

III

Adult/ senior

Adult/ senior

Adult/ senior

Phase Age group

488

417

460

n

3

6

6


Placebo, olanzapine 15 mg q.d.

Placebo, olanzapine 5 -- 20 mg q.d.

5 -- 10 mg b.i.d.

Placebo, haloperidol 4 mg b.i.d.

Control

5, 10 mg b.i.d.

5, 10 mg b.i.d.

Asenapine dose

04/2006

05/2006

10/2006

No

No

No



[19]

41021, Hera

41023, Hera

Other identifier(s)

NCT00156117

[12]

NCT00156104,




Asenapine

815

816

A7501005

NCT00159796,


P05772, Aphrodite, A7501014

25520, P05846

NCT00212771, Schizophrenia, schizoaffective disorder

Schizophrenia

Bipolar disorder

Bipolar disorder

Condition(s)

A Double-Blind, 40-Week Continuation Study Evaluating the Safety of Asenapine and Olanzapine in the Treatment of Subjects With Acute Mania Clinical Trial Protocol A7501007 (Secondary Title: ARES) A Phase III, Randomized, Placebo-Controlled, Double-Blind Trial Evaluating the Safety and Efficacy of Sublingual Asenapine vs. Olanzapine and Placebo in In-Patients With an Acute Manic Episode Clinical Trial Protocol 7501005 (Secondary Title: ARES) A Multicenter, DoubleBlind, Flexible-Dose, 6-Month Extension Trial Comparing the Safety and Efficacy of Asenapine With Olanzapine in Subjects Who Completed Protocol A7501013 Long-Term Efficacy and Safety Evaluation of Asenapine (10-20 mg/ Day) in With Schizophrenia or Schizoaffective Disorder, in a Multicenter Trial Using [olanzapine] (10 -- 20 mg/Day) as a Control

Official title

SP

MSD

Organon; Pfizer

MSD

Sponsor

III

III

III

III

Adult/ senior

Adult/ senior

Adult/ senior

Adult/ senior

Phase Age group

440

196

489

218

n

Openended

26

3

40


Olanzapine 05/2009 5 -- 20 mg q.d.


5 -- 10 mg b.i.d.

5 -- 10 mg b.i.d.

10/2006

04/2006

Placebo, olanzapine 5 -- 20 mg q.d.

5 -- 10 mg b.i.d.

04/2007

No

Yes

No

Yes



Control

5 -- 10 mg b.i.d.

Asenapine dose


[15]

[17]

NCT00174265,

[18]

[21]

P05857, A7501007

Other identifier(s)

NCT00159783,




L. Citrome


P05777, 25544, Aphrodite

NCT00265343, Schizophrenia

Schizophrenia

Schizophrenia, schizoaffective disorder

Condition(s)

Sponsor

A Phase III, Double-Blind, SP Randomized, ActiveControlled, Two-Armed, Multicenter, Efficacy and Safety Assessment (ACTAMESA) of Org 5222 and Olanzapine in the Treatment of Patients With Schizophrenia or Schizoaffective Disorder SP A Multicenter, DoubleBlind, Flexible -Dose, 6-Month Trial Comparing the Efficacy Safety of Asenapine With Olanzapine in Stable Subjects With Predominant, Persistent Negative Symptoms of Schizophrenia MSD A Multicenter, DoubleBlind, Flexible-Dose, 6-Month Extension Trial Comparing the Safety and Efficacy of Asenapine With Olanzapine in Subjects Who Completed the Protocol 25543 (NCT 00212836; P05817)

Official title

III

III

III

Adult/ senior

Adult/ senior

Adult/ senior

Phase Age group


306

444

26

26

1225 52

n



5 -- 10 mg b.i.d.

Olanzapine 10 -- 20 mg q.d. (see [37])

Control

5 -- 10 mg b.i.d.

5 -- 10 mg b.i.d.

Asenapine dose

01/2008

06/2007

03/2006

Yes

No

No



[17]

[17]

5543, Aphrodite, P05817

25517, ACTAMESA

Other identifier(s)

NCT00212836,

[14]

NCT00212784,




Asenapine

817

818


A7501024

NCT00878462

Psychosis

MSD

MSD

Sponsor

III

III

132

174

Adult/ senior

366

122

n

Child/ adult

Adult/ senior

Adult/ senior

Phase Age group

IV Johns Hopkins University; National Institute of Mental Health (NIMH); University of Maryland; University of North Carolina, Chapel Hill; The Zucker Hillside Hospital II A Randomized, Crossover SP Study Evaluating the Acceptability of Unflavored Asenapine and Raspberry Flavored Asenapine in Stable Subjects With A Psychotic Disorder

A Randomized, Parallel Group, Multiple Dose, 6-Week Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Asenapine in Elderly Subjects With Psychosis A Phase 3b, Multicenter, Double-Blind, Fixed-Dose, Parallel-Group, Three Week Placebo Controlled Trial Evaluating the Safety and Efficacy of Asenapine in Subjects With Bipolar 1 Disorder Experiencing an Acute Manic or Mixed Episode (Protocol P05691) Improving Metabolic Parameters of Antipsychotic Child Treatment

Official title

3 days

24

3

6


White/ flavored, red/flavored, white/ unflavored

Asenapine is included as one of the eligible medications

5, 10 mg b.i.d.

Titrated to 10 mg b.i.d.

Asenapine dose

None

NA

Placebo

None

Control

10/2005

Ongoing

Ongoing

12/2008

No

NA

NA

Yes



R01 MH080270, R01MH080270, DSIR 84-CTS

NCT00806234

Psychotic disorders

P05691, Bipolar I disorder 2010-018409-13

NCT00764478

[70]

Psychosis

Condition(s)

P05717, A7501021

Other identifier(s)

NCT00281320,




L. Citrome


P05896, Schizophrenia 2009-017971-10, MK-8274-020-0

NCT01190254

A Multicenter, Randomized, Doubleblind, Fixed-dose, 6-week Trial of the Efficacy and Safety of Asenapine Compared With Placebo in Subjects With an Acute Exacerbation of Schizophrenia (Phase 3; P06124) A Single-center, Openlabel, 2-way Crossover Relative Bioavailability and Safety Trial With Two Differing Strength Tablets (3 5 mg vs 1 15 mg) of Sublingually Administered Org 5222 in Subjects With Schizophrenia or Schizoaffective Disorder Long-term Extension Trial of Asenapine in Subjects With Schizophrenia (Phase 3; Protocol No. P06125) An 8-week, Placebocontrolled, Double-blind, Randomized, Fixed-dose Efficacy and Safety Trial of Asenapine in Adolescent Subjects With Schizophrenia

Official title

III

III

MSD

II

III

Child

Adult

Adult

Adult

Phase Age group

MSD

MSD

MSD

Sponsor

306

264

8

528

n

8

52

1

6


2.5, 5 mg b.i.d.

5, 10 mg b.i.d.

3 5 mg b.i.d., 1 15 mg b.i.d.

5, 10 mg b.i.d.

Asenapine dose

Placebo

None

NA

Placebo

Control

04/2013

Ongoing

12/2002

Ongoing

No

NA

Yes

NA



Schizophrenia

P06125

NCT01142596

Schizophrenia, schizoaffective disorder

Schizophrenia

Condition(s)

P05937

P06124

Other identifier(s)

NCT01101464

NCT01098110




Asenapine

819

820


P06238, 132325 Schizophrenia

P05898

NCT01244828

NCT01349907

A 26-week, Multi-center, Open-label, Flexible Dose, Long-term Safety Trial of Asenapine in Adolescent Subjects With Schizophrenia A Sequential Groups, Open Label, Rising Multiple Dose Study to Assess the Pharmacokinetics, Safety and Tolerability of Sublingual Asenapine in a Pediatric Population With Schizophrenia or Bipolar I Disorder Efficacy and Safety of 3-Week Fixed-Dose Asenapine Treatment in Pediatric Acute Manic or Mixed Episodes Associated With Bipolar I Disorder (Protocol No. P06107) Long-term Study of Asenapine in Subjects With Residual Subtype, Receiving Multiple or/and High Dose Drugs, or Treatment Refractory Schizophrenia (Protocol P06238) A 50-Week Open-Label, Flexible-Dose Trial of Asenapine

Official title

III

III

MSD

MSD

III

I

MSD

MSD

III

Child

Adult/ senior

Child

Child

Child

Phase Age group

MSD

Sponsor

280

160

404

30

204

n

50

52

3

12 days

26


Placebo

NA

NA

5 -10 mg b.i.d.

2.5 -10 mg b.i.d.

None

None

Control

2.5, 5, 10 mg b.i.d.

2.5, 5, 10 mg b.i.d.

2.5 -- 5 mg b.i.d.

Asenapine dose

Ongoing

Ongoing

09/2013

08/2011

10/2013

NA

NA

No

Yes

No



Bipolar disorder

P06107

NCT01244815

Bipolar I disorder

Schizophrenia, bipolar I disorder

P06522

NCT01206517

Condition(s)

P05897, Schizophrenia 2009-018038-12, MK-8274-021-0

Other identifier(s)

NCT01190267




L. Citrome


Extension Treatment to P06107 in Pediatric Acute Manic or Mixed Episodes Associated With Bipolar I Disorder (Protocol No. P05898) A Multicenter, DoubleBlind, Fixed-Dose, Long-Term Extension Trial of the Safety of Asenapine in Subjects Diagnosed With Bipolar 1 Disorder Who Completed Protocol P05691 (Formerly 041044) (Phase 3B, Protocol P05692 [Formerly 041045]) A Double-Blind, PlaceboControlled Trial of Asenapine in the Prevention of Recurrence of a Mood Episode After Stabilization of an Acute Manic/Mixed Episode in Subjects With Bipolar 1 Disorder (Phase 3B, Protocol P06384) Treating Acutely Agitated Patients With Asenapine Sublingual Tablets: A Single-Dose,

Official title

St. Joseph Hospital Health Center/SP

MSD

MSD

Sponsor

IV

III

III

Adult

Adult/ senior

Adult/ senior

Phase Age group

120

550

230

n

2h

26

26


10 mg

5 -10 mg b.i.d.

5, 10 mg b.i.d.

Asenapine dose

Placebo

Placebo

None

Control

12/2012

Ongoing

Ongoing

No

NA

NA



Agitation

P00184

NCT01400113,

[47]

P06384, Bipolar I disorder 2010-018671-20

NCT01396291

Condition(s)

P05692, Bipolar I Disorder 2010-018410-78

Other identifier(s)

NCT01395992




Asenapine

821

822


Pro00029068

NCT01549041,

Posttraumatic stress disorder

Schizophrenia

Bipolar disorder

Bipolar disorder, schizophrenia

Bipolar disorder

Condition(s)

An Observational PostAuthorization Safety Surveillance (PASS) Study of Sycrest (Asenapine) Among Patients Aged 18 and Older Diagnosed With Bipolar Disorder An Observational Drug Utilization Study of SYCREST^ (Asenapine) in the United Kingdom A Randomized Comparison of TwiceDaily Versus Once-Daily Asenapine for Schizophrenia An Open Label Pilot Study of Adjunctive Asenapine for the Treatment of Posttraumatic Stress Disorder

Randomized, DoubleBlind Placebo Controlled Trial Asenapine in the Treatment of Older Adults With Bipolar Disorder

Official title

Tuscaloosa Research & Education Advancement Corp./MSD

Duke University/ MSD

MSD

University Hospitals of Cleveland; Case Western Reserve University MSD

Sponsor

IV

IV

NA

NA

IV

Adult

Adult

Child/ adult/ senior

Adult/ senior

Adult/ senior

Phase Age group

12


20

30

12

2

3000 52

3000 52

30

n

5 mg b.i.d. adjunctive to SSRI

10 mg q.d. (evening), 5 mg b.i.d.

NA

Any

5 -10 mg b.i.d.

Asenapine dose

None

None

NA

NA

None

Control

Ongoing

07/2013

Ongoing

Ongoing

Ongoing

NA

No

NA

NA

NA



NCT01587118

00156

P08308

NCT01498770

[71]

P08307

39358

Other identifier(s)

NCT01495741

NCT01460290




L. Citrome

Condition(s)


Pro00037462

Asenapine Stuttering

NCT01670019

NCT01684657

A Multicenter, Randomized, DoubleBlind, Fixed-Dose, 6-Week Trial of the Efficacy and Safety of Asenapine Compared With Placebo Using Olanzapine as an Active Control in Subjects With an Acute Exacerbation of Schizophrenia A Multicenter, DoubleBlind, Fixed-Dose, Long-Term Extension Trial of the Safety of Asenapine Using Olanzapine as an Active Control in Subjects Diagnosed With Schizophrenia Who Completed Protocol P05688 A Randomized, Blinded, Comparison of Asenapine and Placebo as Adjunctive Treatment in Patients With Non-Psychotic Major Depressive Disorder Incompletely Responsive to Antidepressant Monotherapy Randomized, PlaceboControlled Study to Evaluate the Efficacy and

Official title

University of California, Irvine/MSD

IV

Adult

Adult

Duke IV University/MSD

Adult/ senior

Adult/ senior

III

Phase Age group

III

MSD

MSD

Sponsor

32

130

170

354

n

8 weeks [as per

6

26

6


Olanzapine 15 mg q.d.

Placebo

Placebo

5 -20 mg/day (5 mg QHS, 5 mg b.i.d., 5 mg AM & 10 mg QHS, or 10 mg b.i.d.

2.5 -10 mg/day [given

Placebo, olanzapine 15 mg q.d.

Control

2.5, 5 mg b.i.d.

2.5, 5 mg b.i.d.

Asenapine dose

12/2013 [status is ongoing

Ongoing

Ongoing

Ongoing

No

NA

NA

NA



Stuttering

Major depressive disorder without psychotic features

P05689, Schizophrenia 2010-018408-96

P05688, Schizophrenia 2010-018407-28

Other identifier(s)

NCT01617200

NCT01617187




Asenapine

823

824


NONSTOP

2012-4181

NCT01765829

NCT01807741

Official title

Tolerability of Asenapine With Flexible Dosing From 5 mg to 20 mg in Adults With Developmental Stuttering Bipolar I disorder An Observational PostAuthorisation Safety Specialist Cohort Monitoring Study (SCEM) to Monitor the Safety and Utilisation of Asenapine (Sycrest) in the Mental Health Trust Setting in England Bipolar I disorder An Observational PostAuthorization Modified Prescription-Event Monitoring Safety Study to Monitor the Safety and Utilization of Asenapine (Sycrest) in the Primary Care Setting in England Psychosis NOS/Other Randomized Multicentric Open-label Phase III Clinical Trial to Evaluate the Efficacy of Continual Treatment Versus Discontinuation Based in the Presence of Prodromes in a First Episode of Non-affective Psychosis Bipolar depression Asenapine for Bipolar Depression

Condition(s)

NA

NA

University of Cincinnati; University of Louisville/MSD

II

Adult

Adult

Child/ adult/ senior

Adult/ senior

Phase Age group

III Fundacio´n blica Pu Andaluza Progreso y Salud; Instituto de Salud Carlos III

Drug Safety Research Unit, Southampton, UK; Professor Saad Shakir/ MSD

Drug Safety Research Unit, Southampton, UK; Professor Saad Shakir/ MSD

Sponsor

86

8

52

5000 12

104

Asenapine dose

NA

Placebo

5 -10 mg b.i.d.

NA

NA

Control

Asenapine is included as one of the eligible medications

Any

Any

contact at QHS as per contact at study site] study site]


1000 12

n

Ongoing

Ongoing

Ongoing

Ongoing

as per contact at study site]

NA

NA

NA

NA



Asenapine ModPEM

OBSERVA

Other identifier(s)

NCT01765127

NCT01734278




L. Citrome


IIS - Switch Asenapine

ASN-101

Other identifier(s)

Schizophrenia and disorders with psychotic Features

Schizophrenia, bipolar disorder

Condition(s)

An Open-label, Randomized, Two Treatment, Multi-site, Multiple Dose, Steady State, Three-way, Reference-replicated Crossover, Pharmacokinetic Study to Determine the In-vivo Bioequivalence Between Asenapine 10 mg Sublingual Tablet and SAPHRIS (Asenapine) 10 mg Sublingual Tablet An Open-label Switch Study to Asenapine in the Early Stage of Psychosis

Official title

Centre de Recherche de l’Institut Universitaire en Sante´ Mentale de Que´bec

IV

Adult/ senior

Adult/ senior

Phase Age group

bioRASI, LLC; I Sun Pharmaceutical Industries Ltd

Sponsor

12

66

n

12

21


5 mg b.i.d.

10 mg b.i.d.

Asenapine dose

None

Branded 10 mg b.i.d.

Control

Ongoing

09/2013 [flagged as ongoing]

NA

No



NCT01968161

NCT01948024




Asenapine

825


L. Citrome

trials [6]. In the 3-week bipolar asenapine monotherapy trials, the rate of study discontinuation because of oral hypoesthesia was 1.1% for asenapine versus 0 for placebo. Across the shortterm schizophrenia (n = 572) and bipolar mania (n = 379) trials and the 52-week schizophrenia trial (n = 908) with asenapine 5 or 10 mg b.i.d., the rate of discontinuation due to oral hypoesthesia was 0.27% [43]. Directly asking patients about oral hypoesthesia may yield higher rates of this adverse effect. In a study that examined the effect of absorption site on the pharmacokinetics of asenapine in healthy male subjects, reported rates of oral paresthesias were 75.8, 55.9, and 45.7% for the sublingual, supralingual, and buccal absorption sites, respectively [44]. The mechanism of action for the effect of oral hypoesthesia is via local anesthetic activity, as determined by a preclinical study of isolated, partially desheathed sciatic nerves of female clawed toads, where the local anesthetic effect of asenapine was evaluated utilizing lidocaine as a reference compound [43].

with schizophrenia with a dose lower than 5 mg twice b.i.d. (e.g., 2.5 mg b.i.d.). As per query of www.clinicaltrials.gov, several pediatric studies have been completed (NCT01206517, NCT01190254, NCT01244815, NCT011 90267), a fixeddose study in bipolar mania that includes asenapine 5 mg b.i.d. is underway (NCT00764478, NCT0139 5992), as is a fixed-dose study in schizophrenia that includes asenapine 2.5 mg b.i.d. (NCT01617187), as well as a bipolar disorder maintenance study (NCT01396291), and a study in schizophrenia likely intended for the approval process in Japan (NCT01098110). Table 4 provides a table of all currently registered trials. At the present time, in contrast to approved indications elsewhere, asenapine’s approval in the EU is solely for the treatment of moderate-to-severe manic episodes associated with bipolar I disorder in adults [45].

6. 4.10

Similar to other antipsychotics, the asenapine product label [6] also contains a class-level boxed warning regarding increased mortality in elderly patients with dementia-related psychosis, and class-level warnings and precautions related to cerebrovascular adverse events in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs, neuroleptic malignant syndrome, tardive dyskinesia, leukopenia/neutropenia/agranulocytosis, seizures, potential for cognitive and motor impairment, and suicide [36]. The product label includes additional information regarding transient elevations in serum transaminases observed in treated patients but adds that the mean changes were not clinically relevant [6]. Elevations in creatine kinase were also reported, and may be dose related (proportion of patients with CK elevations > 3 times upper limit of normal at any time were 6.4 and 11.1% for patients treated with asenapine 5 and 10 mg b.i.d., respectively, versus 6.7% for placebo-treated patients in short-term, fixed-dose trials in schizophrenia and bipolar mania) [6]. Asenapine is categorized as pregnancy category C [6]. 5.

Regulatory affairs

Several postmarketing study commitments are extant. As outlined in asenapine’s initial approval [8], these include studies in pediatric patients for schizophrenia (ages 13 -- 17 years) and for acute manic or mixed episodes associated with Bipolar I Disorder (ages 10 -- 17 years), a long-term maintenance study to evaluate the efficacy and safety of asenapine in the treatment of adults with acute manic or mixed episodes associated with bipolar I disorder, a study to further characterize the utilization of asenapine in the treatment of adults with acute manic or mixed episodes associated with bipolar I disorder with a dose lower than 10 mg b.i.d. (e.g., 5 mg b.i.d.), and a study to characterize the utilization of asenapine in the treatment of adults 826

Conclusion

Other warnings and precautions

Asenapine is a second-generation antipsychotic approved in the US for the treatment of schizophrenia and the acute treatment of bipolar manic or mixed episodes. Asenapine’s efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes (as a monotherapy or adjunctive to valproate or lithium) is evidenced by several randomized, double-blind, placebocontrolled trials, including trials with an active control, as well as head-to-head randomized clinical trials, notably versus olanzapine. Asenapine’s overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, EPS/akathisia, dizziness, and oral hypoesthesia. The dysgeusia that can be encountered with asenapine has resulted in the development of a black cherry-flavored version. Asenapine’s effects on weight and metabolic variables appear modest. Asenapine’s effect on the ECG QTc interval is relatively small, and similar to that seen with quetiapine. Effects of asenapine on prolactin are also small and similar to that observed with olanzapine. Hypersensitivity reactions were not observed in the pre-approval clinical development program, but emerged once asenapine was commercialized. Underway are fixed-dose studies examining the potential of asenapine 2.5 mg b.i.d. for the treatment of schizophrenia and 5 mg b.i.d. for the treatment of bipolar mania. Also awaiting completion is a study of asenapine for the prevention of recurrence of a mood episode after stabilization of an acute manic/ mixed episode in patients with bipolar I disorder. Several efficacy studies in the pediatric age group have been completed, but their results are not yet publically available. Limitations to this review include the restriction of the search to reports indexed on PubMed, excluding from further consideration any oral or poster presentations of primary data that may have been presented at national or international congresses, unless known to the author and/or registered at www. clinicaltrials.gov. For clinical trials completed prior to drug


Asenapine

approval, this limitation is mitigated in part by the inclusion of data from publically available regulatory documents.


7.

Expert opinion

Choosing among all the different antipsychotics for an individual patient is complex, requiring consideration of the patient’s prior history of therapeutic response, prior history of tolerability with other agents, and individual patient values and preferences. Perfection is not the goal, but rather finding a medicine that works ‘well enough’, is tolerated ‘wellenough’ and that the patient is willing to take. Ultimately, heterogeneity in individual response in the clinic or office trumps differences found between groups of patients in clinical trials. Patients may also have specific sensitivities to certain adverse effects of medication, such as akathisia, sedation or weight gain, and it can be often challenging to find a ‘best fit’. Having different options in order to optimize efficacy and tolerability for the individual patient is immensely desirable. When making choices, asenapine will likely be measured against other ‘metabolically friendly’ second-generation antipsychotics such as ziprasidone, aripiprazole, iloperidone and lurasidone [46]. However, there is some variation among these antipsychotics in terms of effects on body weight and some of the metabolic variables. Moreover, they can vary in terms of other potential adverse effects (e.g., somnolence, akathisia, effects on the ECG QT interval, effects on prolactin), as well as how they may be administered (differing requirements for initial titration, ‘on-label’ dosing frequency of q.d. vs b.i.d., administration with/without food), their route of metabolism, and drug--drug interactions. As described in Part I of this review [7], asenapine is the only commercially available antipsychotic that is absorbed primarily in the oral mucosa. This is in direct contrast to orally disintegrating tablets of olanzapine, risperidone and aripiprazole, all of which must be swallowed in order to be effective. Thus, patients started on asenapine for the first time need to be informed that the medication differs from others that may have been prescribed for them in the past and that asenapine will not work if swallowed; this makes it easier for the patient to understand the recommendation that food or liquids be avoided for 10 min postadministration (although, reassuringly, substantial bioavailabilty is present after only a 2 min wait). Dysgeusia and hypoesthesia should be proactively mentioned so that patients are not surprised and adherence can be maintained. Overall, asenapine appears to have a relatively benign weight and metabolic profile, with a desirable NNH versus placebo for weight gain. No initial dose titration is required, potentially simplifying treatment. As already noted in Part I of this review [7], but worth repeating, is that an advantage of sublingual asenapine’s unique mode of antipsychotic drug delivery is that surreptitious ‘cheeking’ is not possible, potentially decreasing the

amount of time and effort required to monitor medication administration in persons who are covertly nonadherent. Asenapine’s rapid pharmacokinetics are also favorable when considering using asenapine as an antiagitation agent (an ‘off-label’ or unapproved use); this is supported by a doubleblind trial where 120 agitated adults (any diagnosis) were randomized to receive either a single dose of sublingual 10 mg tablet of asenapine or placebo [47]. Change in the PANSS-Excited Component score at 2 h was statistically significantly greater for the asenapine-treated subjects compared with the placebo-treated subjects. NNT for response versus placebo was 3 (95% CI 2 -- 4), an effect size comparable to that observed with intramuscular antipsychotics [48]. Unfortunately, there is no prospective switch study to inform us about optimal strategies when changing a patient’s antipsychotic to asenapine. However, a post hoc analysis [49] of the switching process in the 26-week trials comparing asenapine with olanzapine in patients with persistent negative symptoms [17] is available. In these studies, subjects were required to have been stable for at least 5 months prior to screening and for one additional month before randomization, and were tapered off existing antipsychotic(s) at variable rates within 28 days. Prior to randomization, most patients were treated with second-generation antipsychotics. Median time to taper off previous antipsychotics was 7 days, with approximately 40% of patients abruptly discontinuing their previous medication. The three most frequently reported adverse events within 28 days for asenapine were insomnia, somnolence and headache, and the overall rate of reported adverse events was similar irrespective of whether patients were pretreated with a secondgeneration antipsychotic, a first-generation antipsychotic, or a long-acting injectable antipsychotic. Upon the switch, minimal variation was observed in mean changes of positive symptoms, and thus for a majority of patients the previously achieved symptom control over positive symptoms continued after the switch. Other reviews of the clinical use of asenapine are also available, including those focused on the use of asenapine in patients with schizophrenia [50-54], bipolar disorder [55-63] and both schizophrenia and bipolar disorder [64-68]. In summary, asenapine’s place in the treatment of schizophrenia and bipolar manic or mixed episodes is likely to be in patients for whom metabolic concerns are of concern, and in patients who would prefer a sublingual preparation. Potential obstacles to the use of asenapine include the recommendation for b.i.d. rather than q.d. dosing (although the latter practice is common), and the recommendation to avoid food or liquids for 10 min after dosing (if taking other medicines, the asenapine tablet must be administered last). Cost may be a further impediment, given the availability of inexpensive generic versions of ziprasidone, risperidone, quetiapine and olanzapine in the US, as well as other generic second-generation antipsychotics in other countries.


827

L. Citrome

Declaration of interest No external writing assistance or financial support was utilized in the production of this article. In the past 36 months, L Citrome has engaged in collaborative research with, or received consulting or speaking fees, from Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Bibliography


Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

4.

5.

6.

7.

828

American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV-TR, Fourth edition (Text Revision). American Psychiatric Publishing, Inc., Arlington, Virginia; 2000 Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother 2009;10(12):1917-28 Citrome L, Ketter TA, Cucchiaro J, Loebel A. Clinical assessment of lurasidone benefit and risk in the treatment of bipolar I depression using number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Affect Disord 2014;155:20-7

8.

..

9.

10.

Citrome L. Adjunctive aripiprazole, olanzapine, or quetiapine for major depressive disorder: an analysis of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad Med 2010;122(4):39-48 Citrome L. Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed secondgeneration antipsychotic. Int J Clin Pract 2009;63(12):1762-84 Merck & Co., Inc. Sahphris (asenapine) sublingual tablets. Prescribing information, revised March 2013. Available from: http://www.merck. com/product/usa/pi_circulars/s/saphris/ saphris_pi.pdf [Accessed 19 January 2014] Citrome L. Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol 2014;10(6):893-903

11.

.

12.

.

13.

Lilly, Envivo, Forest, Genetech, Janssen, Lundbeck, Merck, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda and Valeant. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

US Food and Drug Administration. Asenapine Drug Approval Package. October 2, 2009, updated December 18, 2009. Available from: http://www. accessdata.fda.gov/drugsatfda_docs/nda/ 2009/022117s000TOC.cfm [Accessed 20 January 2014] Key resource that includes over 2000 pages of information used by the US Food and Drug Administration when evaluating asenapine for regulatory approval. US Food and Drug Administration. Saphris (Asenapine) Sublingual Tablets. Briefing Book. July 30, 2009. Available from: http://www.fda.gov/downloads/ AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ PsychopharmacologicDrugsAdvisory Committee/UCM173877.pdf [Accessed 26 January 2014] Schering-Plough Research Institute. Saphris (Asenapine) Sublingual Tablets. Briefing Document (Background Package). July 30, 2009. Available from: http://www.fda.gov/downloads/ AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ PsychopharmacologicDrugsAdvisory Committee/UCM173876.pdf [Accessed 26 January 2014] 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):1492-500 Pivotal randomized controlled trial. 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):106-15 Pivotal randomized controlled trial. Kane JM, Mackle M, Snow-Adami L, et al. A randomized placebo-controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term Expert Opin. Drug Saf. (2014) 13(6)

.

treatment. J Clin Psychiatry 2011;72(3):349-55 Pivotal randomized controlled trial.

14.

Schoemaker J, Naber D, Vrijland P, et al. Long-term assessment of Asenapine vs. Olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry 2010;43(4):138-46

15.

Schoemaker J, Stet L, Vrijland P, et al. Long-term efficacy and safety of asenapine or olanzapine in patients with schizophrenia or schizoaffective disorder: an extension study. Pharmacopsychiatry 2012;45(5):196-203

16.

Alphs L, Panagides J, Lancaster S. Asenapine in the treatment of negative symptoms of schizophrenia: clinical trial design and rationale. Psychopharmacol Bull 2007;40(2):41-53

17.

Buchanan RW, Panagides J, Zhao J, et al. Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia. J Clin Psychopharmacol 2012;32(1):36-45

18.

McIntyre RS, Cohen M, Zhao J, et al. A 3-week, randomized, placebocontrolled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord 2009;11(7):673-86 Pivotal randomized controlled trial.

.

19.

.

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 Pivotal randomized controlled trial.

20.

McIntyre RS, Cohen M, Zhao J, et al. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009;11(8):815-26

21.

McIntyre RS, Cohen M, Zhao J, et al. Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord 2010;126(3):358-65

Asenapine

22.

.


23.

24.

Szegedi A, Calabrese JR, Stet L, et al. Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension. J Clin Psychopharmacol 2012;32(1):46-55 Pivotal randomized controlled trial. Friberg LE, de Greef R, Kerbusch T, Karlsson MO. Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia. Clin Pharmacol Ther 2009;86(1):84-91

31.

McIntyre RS, Tohen M, Berk M, et al. DSM-5 mixed specifier for manic episodes: evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data. J Affect Disord 2013;150(2):378-83

40.

Schering-Plough. Saphris (asenapine) sublingual tablets. Prescribing information, as approved. 2009. Available from: http://www. accessdata.fda.gov/drugsatfda_docs/label/ 2009/022117s000lbl.pdf [Accessed 30 January 2014]

32.

Azorin JM, Sapin C, Weiller E. Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: results from post hoc analyses. J Affect Disord 2013;145(1):62-9

41.

Potkin SG. Dr Potkin Replies. J Clin Psychiatry 2012;73(5):720-1

42.

US Food and Drug Administration. FDA drug safety communication: serious allergic reactions reported with the use of Saphris (asenapine maleate). September 1, 2011. Available from: http://www.fda.gov/Drugs/DrugSafety/ ucm270243.htm [Accessed 30 January 2014]

43.

Schering-Plough. Written response to medical query. File number 2009-34490. October 1, 2009

44.

Gerrits M, de Greef R, Peeters P. Effect of absorption site on the pharmacokinetics of sublingual asenapine in healthy male subjects. Biopharm Drug Dispos 2010;31(5-6):351-7

45.

Lundbeck. Sycrest 5mg and 10mg sublingual tablets. Summary of Product Characteristics. Last updated April 18, 2013. Available from: http://www. medicines.org.uk/emc/medicine/25632/ SPC/Sycrest+5mg+and+10mg+sublingual +tablets/ [Accessed 2 February 2014]

46.

Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs 2013;27(11):879-911 Extended review of iloperidone, asenapine and lurasidone, as well as new antipsychotic medications in development.

33.

Szegedi A, Verweij P, van Duijnhoven W, et al. Meta-analyses of the efficacy of asenapine for acute schizophrenia: comparisons with placebo and other antipsychotics. J Clin Psychiatry 2012;73(12):1533-40 Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382(9896):951-62 The latest in a series of meta-analyses conducted by Leucht and colleagues.

34.

26.

Citrome L, Volavka J. Review: 15 antipsychotic drugs are more effective than placebo for the treatment of schizophrenia, but vary in their tolerability. Evid Based Ment Health 2014;17(1):9

35.

27.

Leucht S, Zhao J. Early improvement as a predictor of treatment response and remission in patients with Schizophrenia: a pooled, post-hoc analysis from the asenapine development program. J Psychopharmacol 2014;28(4):387-94

25.

..

28.

29.

30.

Potkin SG, Phiri P, Szegedi A, et al. Long-term effects of asenapine or olanzapine in patients with persistent negative symptoms of schizophrenia: a pooled analysis. Schizophr Res 2013;150(2-3):442-9 Cazorla P, Zhao J, Mackle M, Szegedi A. Asenapine effects on individual Young Mania Rating Scale items in bipolar disorder patients with acute manic or mixed episodes: a pooled analysis. Neuropsychiatr Dis Treat 2013;9:409-13 Szegedi A, Zhao J, van Willigenburg A, et al. Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials. BMC Psychiatry 2011;11:101

36.

37.

38.

39.

Michalak EE, Guiraud-Diawara A, Sapin C. Asenapine treatment and health-related quality of life in patients experiencing bipolar I disorder with mixed episodes: post-hoc analyses of pivotal trials. Curr Med Res Opin 2014;30(4):711-18 Szegedi A, Zhao J, McIntyre RS. Early improvement as a predictor of acute treatment outcome in manic or mixed episodes in bipolar-1 disorder: a pooled, post hoc analysis from the asenapine development program. J Affect Disord 2013;150(3):745-52 Gao K, Mackle M, Cazorla P, et al. Comparison of somnolence associated with asenapine, olanzapine, risperidone, and haloperidol relative to placebo in patients with schizophrenia or bipolar disorder. Neuropsychiatr Dis Treat 2013;9:1145-57 Citrome L, Nasrallah HA. On-label on the table: what the package insert informs us about the tolerability profile of oral atypical antipsychotics, and what it does not. Expert Opin Pharmacother 2012;13(11):1599-613

..

Kemp DE, Zhao J, Cazorla P, et al. Weight change and metabolic effects of asenapine in patients with schizophrenia and bipolar disorder. J Clin Psychiatry 2014;75(3):238-45

47.

Chapel S, Hutmacher MM, Haig G, et al. Exposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongation. J Clin Pharmacol 2009;49(11):1297-308

Pratts M, Citrome L, Grant W, et al. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand 2014; In press

48.

Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry 2007;68(12):1876-85

49.

Cazorla P, Mackle M, Zhao J, et al. Safety and tolerability of switching to asenapine from other antipsychotic agents: pooled results from two randomized multicenter trials in stable patients with persistent negative

Chapel S, Hutmacher MM, Bockbrader H, et al. Comparison of QTc data analysis methods recommended by the ICH E14 guidance and exposure-response analysis: case study of a thorough QT study of asenapine. Clin Pharmacol Ther 2011;89(1):75-80


829

L. Citrome


50.

Minassian A, Young JW. Evaluation of the clinical efficacy of asenapine in schizophrenia. Expert Opin Pharmacother 2010;11(12):2107-15

51.

Citrome L. Role of sublingual asenapine in treatment of schizophrenia. Neuropsychiatr Dis Treat 2011;7:325-39

52.

Potkin SG. Asenapine: a clinical overview. J Clin Psychiatry 2011;72(Suppl 1):14-18

53.

Pompili M, Serafini G, Innamorati M, et al. Unmet treatment needs in schizophrenia patients: is asenapine a potential therapeutic option? Expert Rev Neurother 2011;11(7):989-1006

54.

55.

56.

57.

58.

830

Cortese L, Bressan RA, Castle DJ, Mosolov SN. Management of schizophrenia: clinical experience with asenapine. J Psychopharmacol 2013;27(4 Suppl):14-22

67.

59.

Chwieduk CM, Scott LJ. Asenapine: a review of its use in the management of mania in adults with bipolar I disorder. CNS Drugs 2011;25(3):251-67

Stoner SC, Pace HA. Asenapine: a clinical review of a second-generation antipsychotic. Clin Ther 2012;34(5):1023-40

68.

60.

Young AH, Altamura AC, Gonza´lez-Pinto AM, et al. Use of asenapine in clinical practice for the management of bipolar mania. J Psychopharmacol 2013;27(4 Suppl):3-13

McIntyre RS, Wong R. Asenapine: a synthesis of efficacy data in bipolar mania and schizophrenia. Clin Schizophr Relat Psychoses 2012;5(4):217-20

69.

van de Wetering-Krebbers SF, Jacobs PL, Kemperman GJ, et al. Metabolism and excretion of asenapine in healthy male subjects. Drug Metab Dispos 2011;39(4):580-90

70.

Dubovsky SL, Frobose C, Phiri P, et al. Short-term safety and pharmacokinetic profile of asenapine in older patients with psychosis. Int J Geriatr Psychiatry 2012;27(5):472-82

71.

Sun X, Hamer R, McEvoy J. Once daily dosing improves asenapine effectiveness, patient acceptance and adherence as compared to twice daily dosing. Poster presentation II-87. NCDEU; 28 -- 31 May 2013; Hollywood, Florida

61.

62.

63.

McIntyre RS. Pharmacology and efficacy of asenapine for manic and mixed states in adults with bipolar disorder. Expert Rev Neurother 2010;10(5):645-9 Pompili M, Venturini P, Innamorati M, et al. The role of asenapine in the treatment of manic or mixed states associated with bipolar I disorder. Neuropsychiatr Dis Treat 2011;7:259-65 McIntyre RS. Asenapine: a review of acute and extension phase data in bipolar disorder. CNS Neurosci Ther 2011;17(6):645-8 Gonzalez JM, Thompson PM, Moore TA. Review of the safety, efficacy,

schizophrenia and bipolar mania. Drugs Today (Barc) 2009;45(12):865-76

and side effect profile of asenapine in the treatment of bipolar 1 disorder. Patient Prefer Adherence 2011;5:333-41

symptoms in schizophrenia. Neuropsychiatr Dis Treat 2012;8:247-57

Warren CG, Dubovsky SL. New approaches for the management of bipolar disorder: role of sublingual asenapine in the treatment of mania. Neuropsychiatr Dis Treat 2013;9:753-8 Samalin L, Charpeaud T, Llorca PM. Asenapine in bipolar I disorder: evidence and place in patient management. Ther Adv Chronic Dis 2013;4(1):5-14 Fagiolini A, Forgione RN, Morana B, et al. Asenapine for the treatment of manic and mixed episodes associated with bipolar I disorder: from clinical research to clinical practice. Expert Opin Pharmacother 2013;14(4):489-504

64.

Bishara D, Taylor D. Asenapine monotherapy in the acute treatment of both schizophrenia and bipolar I disorder. Neuropsychiatr Dis Treat 2009;5:483-90

65.

Weber J, McCormack PL. Asenapine. CNS Drugs 2009;23(9):781-92

66.

Tarazi FI, Shahid M. Asenapine maleate: a new drug for the treatment of


Affiliation Leslie Citrome MD MPH Clinical Professor of Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY, USA Address all correspondence to: 11 Medical Park Drive, Suite 106, Pomona, NY 10970, USA Tel: +1 845 362 2081; Fax: +1 845 362 8745; E-mail: [email protected]

Cancer Immunotherapy, Part 2: Efficacy, Safety, and Other Clinical Considerations.

Efficacy, tolerability, and safety of hypnosis in adult irritable bowel syndrome: systematic review and meta-analysis.

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability.

Assessment of linezolid efficacy, safety and tolerability in the treatment of tuberculosis: A retrospective case review.

Clinical efficacy, safety, and tolerability of fingolimod for the treatment of relapsing-remitting multiple sclerosis.

Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania.

Efficacy and safety of sertindole in schizophrenia: a clinical review.

Safety and tolerability of 5-grass pollen tablet sublingual immunotherapy: pooled analysis and clinical review.

Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism.

Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data.

Mefloquine safety and tolerability in pregnancy: a systematic literature review.

refractory mantle cell lymphoma: efficacy, tolerability, and safety findings.

Mexazolam: clinical efficacy and tolerability in the treatment of anxiety.

Electrosurgery: part II. Technology, applications, and safety of electrosurgical devices.

A Review of the Long-Term Efficacy, Tolerability, and Safety of Exenatide Once Weekly for Type 2 Diabetes.

Dapagliflozin efficacy and safety: a perspective review.

Food additive carrageenan: Part II: A critical review of carrageenan in vivo safety studies.

Sertindole: safety and tolerability profile.

Photoprotection: part II. Sunscreen: development, efficacy, and controversies.

Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety.

Safety and efficacy of clinical waste incineration.

Venom immunotherapy: clinical efficacy, safety and contraindications.

Alogliptin: safety, efficacy, and clinical implications.

Clinical safety and efficacy of celiprolol.