Monograph. Saphris /Sycrest (asenapine) Bipolar I disorder

Transcription

1 Monograph Saphris /Sycrest (asenapine) Bipolar I disorder

2 Contents 1. Overview 1.1 Disease background Mechanism of action 2.1 Chemical structure 2.1 Receptor binding profile Efficacy in manic and mixed episodes associated with bipolar I disorder 3.1 Overview of asenapine clinical studies 3.1 Efficacy as monotherapy 3.3 Efficacy as add-on therapy 3.14 Efficacy summary Safety and tolerability in bipolar I disorder 4.1 Overview 4.1 Monotherapy studies in bipolar I disorder short-term data 4.2 Monotherapy studies in bipolar I disorder long-term data 4.3 Add-on study in bipolar I disorder long-term data 4.4 Pooled long-term clinical study data in bipolar I disorder 4.5 Adverse drug reactions 4.6 Warnings and precautions Dosing and administration 5.1 Recommended dosing 5.1 Special populations 5.1 Administration Pharmacokinetics 6.1 Absorption and distribution 6.1 Bioavailability 6.2 Metabolism and elimination 6.2 Drug drug interactions 6.2 Special populations Full summary of product characteristics References 8.1 Contents i

3 ii Contents

4 1. Overview Saphris /Sycrest (asenapine) is a second-generation antipsychotic agent that is approved in Europe for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. 1 It can be administered as monotherapy or in combination with other treatments. 1 (In the US, asenapine is indicated for the treatment of schizophrenia and for acute treatment of manic and mixed episodes associated with bipolar I disorder in adults. 2 ) Asenapine is presented as a sublingual tablet in two dosage strengths (5 mg and 10 mg) for twice-daily (BID) administration. 1 The recommended starting dose is 10 mg BID for monotherapy and 5 mg BID for combination (add-on) therapy. 1 Several short- and long-term clinical studies have demonstrated the efficacy of asenapine in the treatment of acute mania associated with bipolar disorder. 1, 3-7 The efficacy of asenapine is thought to be mediated via antagonistic activity at dopamine D 2 and serotonin 5-HT 2A receptors, although asenapine also has high affinity and antagonistic potency for other dopamine, serotonin, α-adrenergic and histamine receptors. 1,8 It has minimal affinity for muscarinic cholinergic receptors. 8,9 The safety and tolerability of asenapine is supported by a clinical trial database that includes 4,565 subjects who have received sublingual asenapine, including 3,457 patients in the Phase II/III clinical programme (for bipolar disorder and schizophrenia). 9 In the database, 1,314 patients were treated with asenapine for at least 6 months, and 785 patients were treated for at least 12 months. 9 Almost all of these patients received the approved dosages of 5 or 10 mg BID. 9 Asenapine has no contraindications (apart from hypersensitivity to the active substance and product excipients). 1 However, there are several warnings and precautions that need to be considered before prescribing asenapine. 1 For example, use of asenapine is not approved in elderly patients with dementia-related psychosis, who are at increased risk of mortality with antipsychotic treatment Overview 1.1

5 Disease background Bipolar disorder is a chronic, typically cyclic, mood disorder with a lifetime prevalence of approximately 0.8% to 1.6%. 10 The disorder is characterised by the occurrence of episodes of significantly altered mood, which may be manic, depressive (meeting criteria for major depressive episode), or mixed. 10 Bipolar I disorder is characterised by the occurrence of at least one manic or mixed episode according to the criteria of DSM-IV-TR. 10 The duration of a manic episode can extend from days to months. 10 Typical symptoms of a manic episode include abnormally and persistently elevated or irritable mood accompanied by inflated self-esteem, ideas of grandiosity, decreased need for sleep, increase in goal-directed activity, logorrhoea, or flight of ideas. 10 Manic patients are at increased risk of engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments. 10 Patients with mixed episodes experience rapidly alternating moods meeting the criteria for both a manic and major depressive episode, over a prolonged period of time of at least 1 week. 10 Individuals with bipolar I disorder have a substantially elevated risk of suicidality, with 10 15% of affected individuals eventually committing suicide. 10 Treatment of bipolar I disorders comprises an effective treatment of manic or mixed symptoms as well as treatment of bipolar depression, which differs substantially from the treatment of unipolar depression due to the increased risk of a switch into mania. 9 Moreover, an important long-term goal is mood stabilisation, ideally in the state of euthymia. 9 For the treatment of manic symptoms, a variety of drug treatment options have been used over the past decades. 9 Lithium and anticonvulsant drugs, such as valproate or carbamazepine, have demonstrated antimanic effects. 9 First-generation antipsychotics have frequently been used to control manic symptoms; their use; however, was often limited by the occurrence of extrapyramidal symptoms (EPS). 9 More recently, second-generation antipsychotics have been used with increasing success and have been approved to treat manic episodes associated with bipolar I disorder. 9 The risk of developing co-morbid metabolic conditions is a challenge for treatment, as long-term use of second-generation antipsychotics is associated with metabolic adverse events, including weight gain, hyperlipidaemia, insulin resistance, and type 2 diabetes mellitus. 11 There are a number of issues relating to the identification and management of bipolar I disorder. Diagnosis can be complex as many mental disorders have overlapping symptoms. In addition, bipolar I disorder is associated with a higher risk for co-morbid conditions, especially metabolic complications, compared to the general population Overview

6 2. Mechanism of action Chemical structure Saphris /Sycrest contains asenapine as the maleate salt as its active substance. 1 It is a white to off-white non-hygroscopic (i.e., does not absorb water from the atmosphere) powder that is slightly soluble in water. 9 Its dissociation constant, pka, is 8.6 (protonated free base). 9 The chemical name of asenapine maleate is (3aR,12bR)-rel-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-1h-dibenz[2,3:6,7]oxe pino[4,5-c]pyrrole-(2z)-2-butenedioate (1:1). 9 The molecular formula of asenapine maleate is C 17 H 16 ClNO.C 4 H 4 O 4, and its relative molecular mass is The chemical structure of asenapine (Figure 1) is unrelated to that of other antipsychotics. 8 Figure 1: Chemical structure of asenapine 9 Receptor binding profile In common with other medications for bipolar disorder, the mechanism of action of asenapine is not fully understood. 1 It is hypothesised that the antipsychotic efficacy of asenapine is mediated primarily through a combination of antagonist activity at dopamine D 2 and serotonin 5-HT 2A receptors. 1 Asenapine has a higher affinity for 5-HT 2A receptors than D 2 receptors. 8 Asenapine also has a high affinity for several other serotonin receptors, including 5-HT 2C, 5-HT 7, 5-HT 2B, and 5-HT 6, at which it exerts antagonistic effects. 8 In addition, asenapine has demonstrated a high affinity for dopamine D 3, D 4, and D 1 receptors; α 1 - and α 2 -adrenergic receptors; and histamine H 1 receptors. 8 It has moderate affinity for histamine H 2 receptors. 8 Asenapine has no appreciable affinity for muscarinic receptors M 1 to M 4. 8 Other receptors for which asenapine has demonstrated low affinity include β 1 - and β 2 -adrenergic, H 3, and 5-HT 3 receptors. 8 The receptor binding affinities of asenapine are illustrated in Figure 2. The clinical significance of these data is unknown, although the binding affinities and antagonistic properties of asenapine differ appreciably from those of other antipsychotic drugs Mechanism of action 2.1

7 Figure 2: The receptor binding profile of asenapine: high affinity across a broad spectrum of receptors. Adapted from Shahid et al., pk i represents the log-rank quantification of drug receptor interactions in a binding assay to estimate the affinity of antagonistic drugs for receptors; receptor-binding affinity assays were performed in vitro using cloned human serotinergic, adrenergic, dopaminergic, histaminic, and muscarinic receptors. Shahid M, Walker GB, Zorn SH, Wong EHF. Journal of Psychopharmacology 23 (1): pp , copyright 2009 by British Association for Psychopharmacology. Reprinted by permission of SAGE Mechanism of action

8 3. Efficacy in manic and mixed episodes associated with bipolar I disorder Overview of asenapine clinical studies Asenapine (Sycrest ) is indicated for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. 1 This indication is supported by data from a programme of clinical studies that investigated the efficacy and safety of asenapine as monotherapy, and as add-on therapy (to monotherapy with the mood stabilisers valproate or lithium) (Figure 3). All studies were multicentre, randomised, double-blind, active- and/or placebocontrolled investigations. An overview of the main assessment scales used to measure efficacy in these studies is given in the box overleaf. Further details of study designs and efficacy results are presented in the following sections. Figure 3: Asenapine clinical studies 3-7,9 3. Efficacy 3.1

9 Young Mania Rating Scale (YMRS) 12 An 11-item clinician-administered scale used to assess the severity of mania by assessment of individual symptoms, via patient interviews. Items: mood, energy, sexual interest, sleep, irritability, speech, language thought disorder, content, disruptive aggressive behaviour, appearance, insight. Items are scored using a precisely defined severity scale to rate manic symptoms. Seven items are rated from 0 (absent) to 4 (most severe), while four items (irritability, speech, content, and disruptive aggressive behaviour) are given double weighting and rated from 0 to 8 to compensate for poor co-operation from severely ill patients. Items are summed to give a YMRS total score of Clinical Global Impression for Bipolar Disorder (CGI-BP) severity scale 13,14 A version of the CGI scale, modified specifically for use in assessing global illness severity and improvement in patients with bipolar disorder. The severity component of the CGI-BP uses a 7-point scale to evaluate the illness from 1 (normal) to 7 (very severely ill). It consists of three subscales rating severity of mania, depression, and overall bipolar illness. Montgomery Åsberg Depression Rating Scale (MADRS) 15 A 10-item clinician-administered scale used to assess the severity of depression by assessment of individual symptoms. Items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Items are scored using a precisely defined severity scale to rate depressive symptoms from 0 (normal/no symptom) to 6 (severe symptom), and summed to give a MADRS total score of Efficacy

10 Efficacy as monotherapy Monotherapy data from the asenapine study programme in bipolar I disorder is provided by two 3-week studies, followed by a joint 9-week extension, and a subsequent (primarily safety) 40-week extension, giving a total of 52 weeks of treatment data (Table 1). These studies investigated the efficacy and safety of asenapine treatment in adult patients with bipolar I disorder who were experiencing acute manic or mixed episodes. During the studies, concomitant treatment with other antipsychotic agents, mood stabilisers, antidepressants (including St John s wort), and anti-emetics functioning as dopamine antagonists, was not permitted. 3,5 Depot neuroleptics were discontinued 1 dosing cycles before baseline. 3,5 The most common concomitant medications used were lorazepam (for agitation), zolpidem (for insomnia), paracetamol, and ibuprofen. 3-6 All studies were multicentre, randomised, double-blind, and activecontrolled, with the initial 3-week studies also including a placebocontrolled arm. Across the studies, patients allocated to asenapine received flexible-dose treatment of 5 or 10 mg BID from Day 2 onwards (10 mg BID fixed dose on Day 1). 3-6 Table 1: Clinical studies of asenapine monotherapy Study Treatment and number of patients a Duration (weeks) Primary outcome measure Asenapine (n=185) Olanzapine (n=205) Placebo (n=98) 3 YMRS total score (change from baseline to Week 3) Total: 488 patients Asenapine (n=194) Olanzapine (n=191) Placebo (n=104) 3 YMRS total score (change from baseline to Week 3) (Extension study from 004 and 005) Total: 489 patients Asenapine (n=181) [+94 patients switched to asenapine from placebo arm safety analysis only] Olanzapine (n=229) Total: 504 patients 9 (+3*) YMRS total score (change from baseline to Week 12) (Extension study from 006) Asenapine (n=79) [+32 patients switched to asenapine from placebo arm safety analysis only] Olanzapine (n=107) 40 (+3+9**) Safety and tolerability [Change in YMRS total score was a secondary endpoint] Total: 218 patients a Number of patients randomised to study treatment; *+3 = 3 weeks of treatment already completed in Studies 004 and 005; **+3+9 = 3 weeks of treatment already completed in Studies 004 and 005, plus 9 weeks already completed in Study Efficacy 3.3

11 Short-term (3-week) studies (004, 005) The two 3-week investigations of asenapine monotherapy in bipolar I disorder (Study 004 and 005) were companion studies conducted in distinct patient populations, but using similar designs, as described below. It is important to note that these studies were designed to assess the efficacy (and safety) of asenapine versus placebo. Although olanzapine was included as an active comparator, this was to assess study sensitivity (validity) only; the studies were not powered to directly compare the efficacy of asenapine and olanzapine. 3,5 Patient population A total of 977 adult patients ( 18 years of age) were randomised in these studies from multiple centres worldwide (US, Ukraine, India, Russia, Philippines, Malaysia, Romania, South Korea, Turkey [Study 005 only], and Bulgaria). 3,5 Eligible patients had a current DSM-IV primary diagnosis of bipolar I disorder, experiencing manic or mixed episodes that began 3 months before the screening visit, and a YMRS total score 20 at screening and baseline. 3,5 Patients with a diagnosis of any psychotic disorder, or a primary diagnosis other than bipolar I disorder were excluded, as were those with a history of rapid cycling, those with a current DSM-IV-TR diagnosis of substance abuse or dependence, and those who had received treatment with clozapine during the 12 weeks prior to baseline. 3,5 Treatment regimen Patients were randomised (2:2:1) to 3 weeks of double-blind treatment with: 3,5 sublingual asenapine: 10 mg BID (Day 1); 5 or 10 mg BID (Days 2 21; flexible dose) oral olanzapine: 15 mg QD, i.e., once daily, (Day 1); 5 20 mg QD (Days 2 21; flexible dose) placebo. Patients received treatment in an inpatient facility for the first 7 days, after which they could complete the study as outpatients if they were deemed suitable for discharge. 3,5 Efficacy endpoints The primary endpoint was change in YMRS total score from baseline to endpoint. 3,5 Secondary endpoints included change from baseline in CGI-BP mania severity subscale; MADRS total score; and response ( 50% decrease in YMRS total score from baseline) and remission (YMRS total score 12) rates. 3,5 Efficacy was assessed in the intent-to-treat (ITT) population, including all treated patients with 1 post-baseline YMRS assessment. 3,5 Missing data were imputed using the last observation carried forward (LOCF) approach. 3, Efficacy

12 Study 004 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): Figure 4: LS mean change from baseline in YMRS total score (ITT, LOCF) 5 Baseline characteristics In Study 004, 488 patients (from 61 centres) were randomised to asenapine (n=185), olanzapine (n=205), or placebo (n=98). 5 All patients received at least one dose of treatment. 5 Baseline characteristics were comparable across the treatment arms. 5 Most patients were Caucasian (55.1%) and aged years (98.0%; mean age, 38.6 years). 5 Overall, 336 patients (68.9%) had a primary diagnosis of mania, and 152 patients (31.1%) had mixed episodes. 5 The ITT population comprised 183 asenapine-, 203 olanzapine-, and 94 placebo-treated patients. 5 Efficacy results Mean total daily doses of medication were 18.4 mg for asenapine, and 15.9 mg for olanzapine, with most asenapine patients maintained on their initial dose of 10 mg BID. 5 Study completion rates were 67%, 79%, and 58% for asenapine, olanzapine, and placebo, respectively. 5 Primary endpoint As shown in Figure 4, asenapine and olanzapine were significantly superior to placebo in reducing symptoms of mania over 3 weeks. 5 A statistically significant difference in YMRS total score versus placebo was seen as early as Day 2. 5 *p 0.05; **p 0.01; ***p vs placebo; p<0.01 vs asenapine (based on post hoc analysis at Day 21 only) Reprinted from Journal of Affective Disorders, Vol 122, McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J, Asenapine in the treatment of acute mania in bipolar I disorder: A randomized, double-blind, placebocontrolled trial, pp Copyright 2010, with permission from Elsevier. At endpoint, least squares (LS) mean (±SE) changes from baseline in YMRS total score were (±0.8) with asenapine (p<0.007 versus placebo), (±0.8) with olanzapine (p< versus placebo), and -7.8 (±1.1) with placebo. 5 Post hoc analysis showed that this effect was significantly greater for olanzapine versus asenapine Efficacy 3.5

13 Secondary endpoints CGI-BP: asenapine and olanzapine produced a significant reduction in mania severity versus placebo over 3 weeks (Figure 5). 5 Figure 5: LS mean change from baseline to endpoint in CGI-BP mania severity score (ITT, LOCF) 5 At endpoint, LS mean (±SE) changes from baseline were -1.2 (±0.10) with asenapine (p=0.012 versus placebo), -1.5 (±0.09) with olanzapine (p< versus placebo), and -0.8 (±0.13) with placebo. 5 Post hoc analysis showed that this change from baseline was significantly greater for olanzapine versus asenapine (p=0.004). 5 YMRS response and remission rates: asenapine produced no statistically significant difference in response (42.6% versus 34.0%) and remission (35.5% versus 30.9%) rates versus placebo. 5 The effect of olanzapine on response (54.7%; p<0.002) and remission (46.3%; p=0.016) rates was significant versus placebo. 5 MADRS: asenapine produced a significant reduction in depressive symptoms versus placebo at Day 7 (p=0.011), but not at endpoint. 5 At endpoint, LS mean (±SE) changes from baseline were -3.0 (±0.4) with asenapine (not significant versus placebo), -4.1 (±0.4) with olanzapine (p<0.003 versus placebo), and -1.9 (±0.6) with placebo. 5 However, post hoc analysis found that the treatment effect at endpoint was not significantly different between asenapine and olanzapine Efficacy

14 Study 005 McIntyre RS, Cohen M, Zhao J, et al. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord 2009; 11 (7): Erratum in: Bipolar Disord 2010; 12 (3): Figure 6: LS mean change from baseline in YMRS total score (ITT, LOCF) 3 Baseline characteristics A similar pattern of results emerged in a second trial, in which 489 patients from 55 centres were randomised to receive asenapine (n=194), olanzapine (n=191), or placebo (n=104); one olanzapine patient did not receive treatment. 3 Baseline demographics were comparable across the treatment arms, and were similar to those observed in Study Most patients were Caucasian (60.5%) and aged years (98.8%; mean age, 39.4 years). In total, 338 patients (69.3%) had a primary diagnosis of mania, and 150 patients (30.7%) had mixed episodes. 3 The ITT population comprised 189 asenapine-, 188 olanzapine-, and 103 placebo-treated patients. 3 Efficacy results Mean total daily doses of medication were 18.2 mg for asenapine, and 15.8 mg for olanzapine, with most asenapine patients maintained on their initial dose of 10 mg BID. 3 Study completion rates were 63%, 80%, and 62% for asenapine, olanzapine, and placebo, respectively. 3 Primary endpoint As shown in Figure 6, asenapine and olanzapine were significantly superior to placebo in reducing symptoms of mania over 3 weeks. 3 A statistically significant difference in YMRS total score versus placebo was seen as early as Day 2. 3 At endpoint, LS mean (±SE) changes from baseline in YMRS total score were (±0.8) with asenapine (p< versus placebo), (±0.8) with olanzapine (p< versus placebo), and -5.5 (±1.0) with placebo. 3 *p 0.01; **p 0.001; ***p vs placebo McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord 2009: 11: The Authors. Reprinted by permission of John Wiley & Sons, Inc. Secondary endpoints CGI-BP: asenapine and olanzapine produced a significant reduction in mania severity versus placebo (Figure 7), from Day 2 onwards. 3 At endpoint, LS mean (±SE) changes from baseline were -1.2 (±0.01) with asenapine (p<0.002 versus placebo), -1.4 (±0.01) with olanzapine (p< versus placebo), and -0.7 (±0.1) with placebo Efficacy 3.7

15 Figure 7: LS mean change from baseline to endpoint in CGI-BP mania severity score (ITT, LOCF) 3 Treatment effect versus olanzapine In these short-term studies, asenapine demonstrated significant efficacy in reducing acute mania associated with bipolar I disorder, although the magnitude of effect appeared to be smaller than that of olanzapine. However, it should be noted that olanzapine was only included as a sensitivity control in these studies, and that neither investigation was powered to directly compare the efficacy of asenapine and olanzapine. 3,5 In this regard, the European Medicine s Agency assessment report on asenapine cited the following: 9 YMRS response and remission rates: both asenapine and olanzapine produced significantly greater response and remission rates than placebo. 3 the size of the treatment effect [with asenapine] was shown to be in line with responses seen for other, approved, atypical [i.e., second-generation] antipsychotics, and the results were also comparable to those from the Phase III pivotal trials supporting the marketing authorisation applications for other atypical antipsychotics. The fact that olanzapine seemed to show greater efficacy is not a barrier to approval as olanzapine probably has greater efficacy than a number of atypical antipsychotics approved for the treatment of bipolar I disorder, but also has major safety and tolerability disadvantages. Response rates were 42.3% with asenapine (p<0.01 versus placebo), 50.0% with olanzapine (p< versus placebo), and 25.2% with placebo. 3 Remission rates were 40.2% with asenapine (p<0.01 versus placebo), 39.4% with olanzapine (p= versus placebo), and 22.3% with placebo. 3 MADRS: olanzapine, but not asenapine, produced a significant change from baseline in depression symptoms versus placebo. 3 At endpoint, LS mean (±SE) changes from baseline were -3.2 (±0.5) with asenapine, -4.2 (±0.5) with olanzapine (p<0.005 versus placebo), and -1.8 (±0.7) with placebo Efficacy

16 9-week extension study (006) McIntyre RS, Cohen M, Zhao J, et al. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009; 11 (8): Erratum in: Bipolar Disord 2010; 12 (1): Patients who completed either of the 3-week studies of asenapine versus placebo (Study 004 and 005) were eligible to enter a 9- week, double-blind extension study (Study 006). 4 The objective of the study was to assess the efficacy, safety, and tolerability of asenapine versus olanzapine in the extended treatment of bipolar manic and mixed episodes. 4 Results from the primary outcome were used to determine the non-inferiority of asenapine versus olanzapine. 4 Entry into the extension was immediate, with no breaking of study blinding or re-randomisation. 4 Treatment regimen Those patients who were receiving active treatment in the 3-week studies continued on the same treatment regimen during the extension. 4 Patients who had been receiving placebo were blindly switched to asenapine (10 mg BID on Day 1; 5 or 10 mg BID flexible dosing thereafter), and assessed for safety outcomes only. 4 Efficacy endpoints The study assessed the non-inferiority of asenapine versus olanzapine over the total 12-week period i.e., from baseline of the 3-week studies to the end of the 9-week extension. 4 The primary endpoint was change in YMRS total score from baseline to Week 12 (Day 84). 4 Secondary endpoints included change from baseline in CGI-BP subscales for severity of mania, severity of depression, and overall bipolar illness, and change from baseline in MADRS total score. 4 A key secondary efficacy assessment was the percentage of YMRS responders ( 50% decrease in YMRS total score from baseline) and remitters (YMRS total score 12). 4 Psychotic symptoms (Positive and Negative Syndrome Scale, PANSS) and overall health and well-being (Short Form 36 health survey, SF-36) were also assessed. 4 The primary efficacy outcome, and the secondary endpoints YMRS response and remission rates, were assessed in the per protocol (PP) population of treated patients without major protocol violations, using the observed cases (OC) approach. 4 The robustness of results was assessed by repeating the analyses using LOCF in the ITT population (including treated patients with 1 post-baseline YMRS assessment in the extension period). 4 Further secondary endpoints were assessed in the ITT population using OC and LOCF analyses. 4 Patient population A total of 680 patients completed the two 3-week acute mania trials (Study 004: n=342, 70.1% completion rate; Study 005: n=338, 69.1% completion rate). 4 Of these patients, 504 (181 asenapine, 229 olanzapine, 94 placebo) were enrolled in the 9- week extension study and received 1 dose of study medication. 4 A primary diagnosis of mania was present in 354 (70.2%) patients, and 150 (29.8%) patients experienced mainly mixed episodes Efficacy 3.9

17 The ITT population included 175 asenapine- and 222 olanzapinetreated patients, while the PP population included 173 asenapineand 221 olanzapine-treated patients. 4 Efficacy results The mean total daily dose of medication was 17.6 mg for asenapine and 16.1 mg for olanzapine (and 16.1 mg in the placebo/asenapine switch group). 9 Study completion rates were 62%, 64%, and 53% for asenapine, olanzapine, and placebo/asenapine, respectively. 4 Primary endpoint As shown in Figure 8, there was no significant difference between asenapine and olanzapine in YMRS total scores after 12 weeks (84 days) of treatment. 4 At Week 12, mean (SD) changes from baseline were (8.7) with asenapine, and (7.9) with olanzapine (PP, OC). 4 These OC results were confirmed by LOCF analysis in the ITT population. 4 Figure 8: Mean change from baseline in YMRS total score (PP, OC) 4 McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009: 11: The Authors. Reprinted by permission of John Wiley & Sons, Inc Efficacy

18 Secondary endpoints There were no significant differences between asenapine and olanzapine in any secondary endpoint measures at Week 12 (Table 2). 4 In the CGI-BP subscales of severity of mania and overall bipolar illness, the percentage of patients categorised as clinically worse, unchanged, or improved were similar in both treatment groups. 4 Over 80% of patients were rated as improved on these subscales. 4 YMRS response and remission rates were not significantly different between asenapine and olanzapine at any assessment during the study period. 4 At endpoint, response rates for asenapine and olanzapine were 90% and 92%, respectively, with remission rates of 88% and 91% (PP, OC). 4 These OC results were confirmed by LOCF analysis in the ITT population. 4 Table 2: Secondary efficacy measures change from baseline to Week 12 (ITT, OC) 4 Efficacy measure CGI-BP Severity of mania Severity of depression Severity of overall bipolar illness LS mean change (SE) a Asenapine -2.9 (0.11) -0.1 (0.09) -2.6 (0.12) Olanzapine -2.8 (0.09) 0.0 (0.08) -2.4 (0.10) MADRS total score -3.6 (0.69) -2.4 (0.61) PANSS total score (1.04) (0.92) SF-36 Physical component Mental component 0.38 (0.90) 3.69 (1.62) (0.75) 0.77 (1.35) a Asenapine vs olanzapine (all efficacy measures): p=not significant 3. Efficacy 3.11

19 40-week extension study (007) 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): Patients who completed 12 weeks of treatment in the 3-week studies (Study 004 and 005) followed by the 9-week extension (Study 006), were eligible to enter a further 40-week, double-blind extension study (Study 007). The main aim of this study was to assess the long-term safety and tolerability of asenapine. 6 Treatment regimen Patients were maintained on their pre-established treatment (flexible dosing with asenapine 5 or 10 mg BID, or olanzapine 5 20 mg QD). 6 Patients who had been switched from placebo to asenapine at the start of the 9-week extension study continued on this regimen, but were assessed for safety outcomes only. 6 Doubleblinding was maintained. 6 Efficacy endpoints The primary objective was to characterise the long-term safety and tolerability of asenapine in patients with manic or mixed episodes of bipolar I disorder for up to 52 weeks. 6 Efficacy endpoints were considered to be secondary, and the trial was not powered to assess non-inferiority or superiority of the active treatments. 6 Efficacy endpoints included: YMRS total score; CGI-BP mania severity; MADRS score; and response ( 50% decrease in YMRS total score from baseline) and remission (YMRS total score 12) rates. 6 Time to response failure (number of days between a patient achieving responder status and reverting to 30% reduction in baseline YMRS total score) was also examined. 6 Efficacy endpoints were assessed in the ITT population (including patients who received 1 dose of study treatment and 1 YMRS assessment in the 40-week extension period) using OC and LOCF approaches. 6 Patient population In total, 218/308 patients who completed the 3-week studies plus 9-week extension (79 asenapine, 107 olanzapine, 32 placebo/ asenapine) were enrolled in the 40-week extension study and received 1 dose of study medication. 6 Of these patients, 171 (78.4%) had a primary diagnosis of mania, and 47 (21.6%) experienced mainly mixed episodes. 6 The ITT population included 76 asenapine- and 104 olanzapinetreated patients Efficacy

20 Efficacy results The overall mean treatment duration was 44.7 weeks with asenapine, and 42.9 weeks with olanzapine (and 35.7 weeks in the placebo/asenapine group). 6 The mean total daily dose of medication was 16.3 mg for asenapine and 15.4 mg for olanzapine (and 15.7 mg in the placebo/asenapine group). 6 Study completion rates were 66% with asenapine and 64% with olanzapine (and 41% in the placebo/asenapine group. 6 Efficacy outcomes (secondary endpoints) The mean change in YMRS, CGI-BP mania severity, and MADRS scores over 52 weeks are shown in Table 3. 6 The efficacy of asenapine appeared to be maintained in the long-term, with continued decline in manic symptoms throughout the 40-week extension. 6 At Week 52, YMRS response and remission rates were the same, and did not differ significantly between the asenapine and olanzapine groups (97.8% versus 98.4%, OC) (Fisher s exact tests). 6 Due to the high proportion of responders at endpoint, time to response failure could not be calculated. 6 However, a log-rank test based on a Kaplan Meier estimate indicated that time to response failure was significantly longer with asenapine than with olanzapine (p=0.0127). 6 Table 3: Efficacy measures change from baseline to Week 52/endpoint (ITT) 6 Efficacy measure Mean change (SD) OC LOCF Asenapine Olanzapine Asenapine Olanzapine YMRS total score (8.1) (6.8) (10.3) (8.4) CGI-BP severity of mania subscore -3.6 (1.1) -3.5 (0.9) -3.2 (1.3) -3.2 (1.1) MADRS total score -4.8 (5.8) -4.4 (5.4) -4.8 (6.5) -3.2 (8.6) 3. Efficacy 3.13

21 Efficacy as add-on therapy In addition to the monotherapy studies described above, the clinical study programme included two studies of asenapine as add-on therapy in acute manic or mixed episodes in adults with bipolar I disorder and incomplete response to lithium or valproate monotherapy (Table 4). 7 In the 12-week study, concomitant medication use was 80.4% in the asenapine group and 81.9% in the placebo group. 16 Concomitant medications used by 10% of patients in either treatment group were lorazepam, zolpidem, paracetamol, ibuprofen, and temazepam. 16 These comprised a multicentre, randomised, double-blind, placebocontrolled, 12-week study, followed by a double-blind, placebocontrolled 40-week extension. 7 In both studies, asenapine was administered at a flexible dose of 5 or 10 mg BID from Day 2 onwards (5 mg BID fixed dose on Day 1). 7 Table 4: Clinical studies of asenapine add-on therapy Study Treatment and no. of patients a Duration (weeks) Primary outcome measure Asenapine (n=159) Placebo (n=167) 12 YMRS total score (change from baseline to Week 3) 009 7,16 (Extension from Study 008) Total: 326 patients Asenapine (n=41) Placebo (n=36) Total: 77 patients 40 (+12)* Safety and tolerability [Efficacy analyses were included as secondary endpoints] a Number of patients randomised to study treatment; *+12 = 12 weeks of treatment already completed in Study Efficacy

22 12-week study (008) Calabrese JR, Stet L, Kothari H, et al. Asenapine as adjunctive treatment for bipolar mania: results of a placebo-controlled 12- week study and 40-week extension. Poster presented at the 62 nd Institute on Psychiatric Services of the American Psychiatric Association (APA); October 14 17, 2010; Boston, USA. 7 This 12-week study was designed to assess the efficacy (and safety) of asenapine versus placebo as add-on therapy in acute manic or mixed episodes in patients with bipolar I disorder who were not adequately responding to continuing treatment with lithium or valproate monotherapy. 7 Patient population Adult patients ( 18 years of age) were enrolled from multiple centres worldwide (US, Russia, Thailand, India, Korea, Australia, Taiwan, Czech Republic). 7 Eligible patients were required to have a primary diagnosis of bipolar I disorder, a current manic or mixed episode of 3 months duration, a YMRS total score 20 at screening and baseline, and a documented moderate-to-severe mood episode within the last 5 years. 7 The manic/mixed episode must have been treated continuously with lithium or valproate for 2 weeks immediately prior to screening. 7 Patients with a primary diagnosis other than bipolar I disorder, those who had been hospitalised for 3 weeks for current manic or mixed episodes, and those with rapid cycling were excluded from the study. 16 Those patients with a seizure disorder, current substance abuse or dependence, or use of clozapine within 12 weeks or monoamine oxidase inhibitor within 2 weeks of baseline were also excluded. 16 Treatment regimen Patients were randomised (1:1) to 12 weeks of double-blind treatment with: 7 sublingual asenapine: 5 mg BID (Day 1); 5 or 10 mg BID (Days 2 84; flexible dose) placebo. All patients continued their existing open-label treatment with lithium or valproate for the duration of the study. 7 Dose adjustments could be made as necessary, but switching between the two mood stabilisers was not permitted. 9 Efficacy endpoints The primary endpoint was change in YMRS total score from baseline to Week 3. 7 Main secondary endpoints were: change from baseline in YMRS total score (all time points); CGI-BP subscales; MADRS score; and response ( 50% decrease in YMRS total score from baseline) and remission (YMRS total score 12) rates. 7 Efficacy analysis was performed in the ITT population, including all treated patients with 1 post-baseline YMRS assessment, and using the LOCF approach. 7 Baseline characteristics Overall, 326 patients were randomised to treatment with asenapine (n=159) or placebo (n=167); one patient from each group did not receive treatment. 7 Baseline characteristics were comparable between groups. 7 Most patients in the ITT population were aged years (99.1%; mean age, 39.3 years); 61.1% of patients had a primary diagnosis of mania, and 38.9% of patients had mixed episodes. 9 The ITT population comprised 155 asenapine- and 163 placebotreated patients. 7 Efficacy results The mean total daily dose of asenapine was 11.8 mg for asenapine, 9 reflecting the fact that most patients were maintained on their initial dose of 5 mg BID. 7 As in the monotherapy studies, the most frequently used concomitant medications (excluding lithium and valproate) were lorazepam, zolpidem, paracetamol, and ibuprofen. 9 A total of 116 patients completed the study, with completion rates of 38% and 33% for asenapine and placebo, respectively Efficacy 3.15

23 Primary endpoint Asenapine add-on therapy was significantly superior to placebo in reducing YMRS total score at Week 3. 7 This significant difference emerged as early as Week 2 and was maintained to Week 12 (Figure 9). 7 Figure 9: Mean change from baseline in YMRS total score (ITT, LOCF) 7 At Week 3, the mean (±SD) change from baseline was -9.7 (±10.1) with asenapine and -7.7 (±9.6) with placebo (p<0.05). 7 At Week 12 (secondary endpoint), the mean (±SD) change from baseline was (±11.4) with asenapine and -9.1 (±11.6) with placebo (p<0.05). 7 Secondary endpoints At Weeks 3 and 12, asenapine produced significant advantages over placebo in the severity of mania and overall illness (CGI-BP subscores) (Table 5). 7 Changes in the CGI-BP depression subscore and MADRS total score were not significant versus placebo. 7 Add-on treatment with asenapine produced significantly superior response (47.7% versus 34.4%; p=0.0152) and remission (43.2% versus 30.1%; p=0.0148) rates versus placebo at Week 12 (Pearson chi-square test). 7 *p<0.05 vs placebo Table 5: Secondary efficacy measures change from baseline (ITT, LOCF) 7 Efficacy measure Mean change (SD) Week 3 Week 12 Asenapine Placebo Asenapine Placebo CGI-BP subscores Severity of mania Severity of depression Severity of overall bipolar illness -1.0 (1.2)** -0.2 (1.1) -0.9 (1.2)** -0.7 (1.2) -0.1 (1.0) -0.6 (1.1) -1.4 (1.5)*** -0.1 (1.2) -1.1 (1.5)* -0.9 (1.4) -0.1 (1.2) -0.8 (1.3) MADRS total score -2.8 (7.2) -2.2 (6.8) -1.8 (8.6) -1.8 (8.2) P-values are based on LS mean difference *p<0.05; **p<0.01; ***p<0.001 vs placebo Efficacy

24 40-week extension study (009) Calabrese JR, Stet L, Kothari H, et al. Asenapine as adjunctive treatment for bipolar mania: results of a placebo-controlled 12- week study and 40-week extension. Poster presented at the 62 nd Institute on Psychiatric Services of the American Psychiatric Association (APA); October 14 17, 2010; Boston, USA. 7 Patients completing the 12-week add-on study (Study 008) without major protocol violation were eligible for enrolment in a double-blind, 40-week extension study (Study 009). The main aim of this study was to assess the long-term safety and tolerability of asenapine versus placebo. 7 Treatment regimen Patients continued on the same treatment as allocated in the 12-week study, with dose adjustment permitted at any time. 7 Open-label treatment with mood stabilisers (lithium and valproate) also continued. 7 Double-blinding was maintained. 7 Efficacy endpoints The study primarily investigated safety and tolerability, but efficacy endpoints included: change (from baseline of the 12-week study to Week 52) in YMRS total score; CGI-BP subscales; MADRS total score; and response ( 50% decrease in YMRS total score from baseline) and remission (YMRS total score 12) rates. 7 Efficacy analysis was performed in the ITT population (all treated patients with 1 post-baseline YMRS assessment). 7 Outcomes were assessed descriptively, except for response and remission rates which were compared between groups using the Pearson chisquare test. 7 Patient population In total, 77/116 patients who completed the 12-week add-on study (41 asenapine, 36 placebo) were enrolled in the 40-week extension study and received 1 dose of study medication. 7 The ITT population comprised 38 asenapine- and 33 placebotreated patients Efficacy 3.17

25 Efficacy results Overall, 34 patients completed the full 52 weeks of treatment, with completion rates of 46% and 42% for asenapine and placebo, respectively. 7 Efficacy outcomes (secondary endpoints) Mean YMRS total score (Figure 10), CGI-BP subscores and MADRS total score decreased in both treatment groups by Week 52 (Table 6). Changes in CGI-BP subscales were similar between treatment groups at Week Although slightly higher with placebo, response and remission rates did not differ significantly between asenapine and placebo groups at Week 52 (response: 68.4% versus 78.8%; remission: 65.8% versus 78.8%). 7 Table 6: Efficacy measures change from baseline to Week 52 (ITT) 7 Efficacy measure Mean change (SD) Asenapine Placebo YMRS total score (13.7) (11.8) CGI-BP subscores Severity of mania Severity of depression Severity of overall bipolar illness -2.1 (1.7) -0.2 (1.4) -1.9 (1.7) -2.3 (1.5) -0.2 (1.2) -2.1 (1.4) MADRS total score -3.3 (9.8) -3.9 (7.7) Figure 10: Mean change from baseline in YMRS total score (ITT) Efficacy

26 Efficacy summary As monotherapy for the treatment of acute mania in patients with bipolar I disorder, asenapine: was fast acting and efficacious in reducing manic symptoms over 3 weeks maintained efficacy, and showed noninferiority to olanzapine, over 12 weeks of treatment showed maintenance of effect beyond 12 weeks of treatment (52-week data) produced improvements across several measures of mania including YMRS scores, CGI-BP scores, and YMRS response and remission rates. As add-on therapy for the treatment of acute mania in patients with bipolar I disorder who show incomplete response to lithium or valproate, asenapine: demonstrated superior efficacy to lithium or valproate monotherapy as early as after 2 weeks of treatment maintained efficacy for up to 12 weeks of treatment produced improvements across several measures of mania including YMRS scores, CGI-BP scores, and YMRS response and remission rates. 3. Efficacy 3.19

27 Efficacy

28 4. Safety and tolerability in bipolar I disorder Overview Clinical safety programme The asenapine safety database contains data from 4,565 patients who received sublingual asenapine. 9 This includes 3,457 subjects from the Phase II/III clinical programme, 3,159 of whom (91.4%) received the recommended therapeutic doses of asenapine (5 or 10 mg BID). 9 A total of 1,314 patients were treated with asenapine for at least 6 months, and 785 patients for at least 12 months. 9 Overall, 2,826 patients from the Phase II/III programme received asenapine treatment for schizophrenia, and 631 patients were treated for bipolar disorder. 9 The overall conclusion from the European Medicines Agency (EPAR assessment), based upon these combined safety data, was that the safety profile of asenapine appeared to be favourable. 9 Assessment of safety in bipolar I disorder clinical studies In the short- and long-term clinical studies of asenapine monotherapy/add-on therapy in acute bipolar manic or mixed episodes, safety and tolerability monitoring included assessments of treatment-emergent adverse events (AEs; evaluated throughout the study), clinical laboratory analysis, metabolic indices analysis, physical examination, vital signs, anthropometric measurements (including waist circumference, body weight, and body mass index, BMI), extrapyramidal symptoms (EPS; assessed using the Simpson- Angus Scale (SAS), the Barnes Akathisia Rating Scale (BARS), and the Abnormal Involuntary Movement Scale (AIMS)), and study discontinuations Safety and tolerability 4.1

29 Monotherapy studies in bipolar I disorder short-term data Adverse events The safety population from the two 3-week studies of asenapine monotherapy included a total of 976 patients, 379 of whom received treatment with asenapine 5 10 mg BID. 3,5 Overall, treatment-emergent AEs were reported by 74.7% of asenapinetreated patients compared with 58.6% of placebo-treated patients. 3,5 The most common AEs with asenapine treatment, occurring at an incidence of 5% (and at least twice that of placebo) in one or both studies, were sedation, dizziness, somnolence, fatigue, oral hypoaesthesia, vomiting, and increased weight. 3,5 Combining data from both studies, the frequencies of the most common AEs with asenapine treatment (versus placebo) were: sedation 13.7% versus 3.9%; dizziness 11.1% versus 3.0%; and somnolence 10.3% versus 2.5%. 3,5 Clinically significant increases in weight gain ( 7%) occurred in 6.5% of asenapine-treated patients, compared with 0.6% of placebo-treated patients. 1 Absolute mean increases (±SD) in weight in the asenapine groups in the two studies were 0.9±3.0 kg and 1.6±2.9 kg. 3,5 The only individual EPS-related AE that was reported by >5% of patients treated with asenapine was akathisia (5.4% of asenapineand 3.1% of placebo-treated patients in Study 004). 3,5 However, EPS rating scales did not indicate any significant worsening from baseline in EPS with asenapine treatment versus placebo. 17 There were no clinically significant changes in metabolic parameters, laboratory values or vital signs. 3,5 The incidence of treatment-emergent serious AEs (SAEs) was low and comparable between treatment groups (5.3% asenapine, 6.9% placebo). 3,5,17 Tolerability Combining data from both studies, the overall study discontinuation rate was slightly lower in the asenapine-treated group (133/379 patients; 35.1%) compared with placebo (81/202 patients; 40.1%). 3,5 The main reasons for discontinuing treatment were withdrawal of consent, AEs (asenapine 9.8% versus placebo 5.4%), and lack of efficacy (asenapine 7.9% versus placebo 15.3%). 3, Safety and tolerability

30 Monotherapy studies in bipolar I disorder long-term data Adverse events 9-week extension study In the 9-week extension study (Study 006; n=504) of the asenapine monotherapy trial reports safety and tolerability data from 12 weeks of therapy (i.e., from the start of the 3-week study). 4 The incidence of treatment-emergent AEs (including SAEs) was 76.6%, 76.8%, and 77.7% in the placebo/asenapine, asenapine, and olanzapine groups, respectively. 4 The incidence of treatment-related AEs was 55.3%, 64.6%, and 63.8%, respectively. 4 The most commonly reported AEs in the placebo/asenapine-treated group were headache, somnolence, nausea, and constipation. 4 The most common treatment-emergent AEs in the asenapine-treated group were sedation, dizziness, insomnia, headache, and somnolence. 4 Treatment-related SAEs were reported by four patients in the placebo/asenapine treatment group, five patients in the asenapine treatment group, and eight patients in the olanzapine treatment group. 4 The percentage of patients with clinically significant weight gain at 12 weeks of treatment was lower with asenapine (18.8%) than with olanzapine (30.6%). 4 Headache, somnolence, insomnia, nausea, parkinsonism, tremor, and constipation were the most commonly reported AEs in the placebo/asenapine-treated group. 6 Insomnia, depression, headache, somnolence, increased weight, dizziness, nausea, and akathisia were the most common treatment-emergent AEs with asenapine. 6 Reports of weight gain, insomnia, depression, and akathisia as AEs were increased compared with the rates observed in the 3- and 9- week monotherapy studies. 3-6 Clinically significant increases in weight gain ( 7%) occurred in 39.2% of asenapine patients (mean increase ±SD, 3.5±6.7 kg) and 55.1% of olanzapine patients (mean increase, 6.0±6.6 kg). 6 According to the EPS rating scales, changes from baseline in EPS were minimal and similar between groups. 6 Treatment-related SAEs were reported by three patients in each of the asenapine and olanzapine groups. 6 There were no clinically relevant changes in metabolic or laboratory values. 6 Tolerability Discontinuation due to AEs occurred in seven asenapine patients (8.9%), and nine olanzapine patients (8.4%) week extension study The 40-week extension study (Study 007; n=218) of the asenapine monotherapy trial reports safety and tolerability data from the full 52 weeks of therapy (i.e., from the start of the 3-week study). 6 The incidence of treatment-emergent AEs (including SAEs) was 71.9%, 86.1%, and 79.4% in the placebo/asenapine, asenapine, and olanzapine groups, respectively. 6 The incidence of treatmentrelated AEs was 53.1%, 70.9%, and 61.7%, respectively Safety and tolerability 4.3

31 Add-on study in bipolar I disorder long-term data Adverse events The 40-week extension study (Study 009; n=77) of the asenapine add-on trial, in which asenapine was administered on top of existing therapy with lithium or valproate, reports safety and tolerability data from the full 52 weeks of therapy. 7 The incidence of treatment-emergent AEs was 78.0% with asenapine and 69.4% with placebo. 7 The incidence of treatment-related AEs was 51.2% and 36.1%, respectively. 7 In the asenapine-treated group, the most common AEs were headache, sedation, insomnia, and somnolence. 7 Clinically significant increases in weight gain ( 7%) occurred in 36.6% of asenapine-treated patients and 19.4% of placebo-treated patients. 7 The mean (±SD) weight increase from baseline was 3.5±5.2 kg with asenapine and 1.7±4.4 kg with placebo. 7 According to the EPS rating scales, changes from baseline in EPS were similar between treatment groups. 7 Changes in laboratory variables were not clinically relevant. 7 Tolerability Discontinuation due to AEs occurred in ten asenapine patients (24.4%), and three placebo patients (8.3%) Safety and tolerability

32 Pooled long-term clinical study data in bipolar I disorder The most common AEs (incidence 5%) observed in clinical studies of long-term treatment with asenapine monotherapy or add-on treatment (up to 52 weeks; Studies 006, 007, 008 and 009) are shown in Table 7. 9 The most frequently reported AEs were sedation, insomnia, headache and somnolence. 9 Table 7: Most common adverse events with asenapine ( 5% incidence) in long-term studies in bipolar mania 9 Adverse event Number of patients (%) Asenapine 5 or 10 mg BID flexible dose (n=433) Placebo (n=166) Olanzapine 5 20 mg QD flexible dose (n=229) Any adverse event 337 (77.8) 119 (71.7) 189 (82.5) Sedation 58 (13.4) 10 (6.0) 42 (18.3) Insomnia 57 (13.2) 18 (10.8) 27 (11.8) Headache 53 (12.2) 23 (13.9) 36 (15.7) Somnolence 53 (12.2) 8 (4.8) 36 (15.7) Dizziness 40 (9.2) 6 (3.6) 17 (7.4) Depression 37 (8.5) 7 (4.2) 19 (8.3) Weight increase 31 (7.2) 1 (0.6) 39 (17.0) Mania 30 (6.9) 19 (11.4) 11 (4.8) Nausea 28 (6.5) 11 (6.6) 8 (3.5) Akathisia 25 (5.8) 9 (5.4) 21 (9.2) Tremor 24 (5.5) 9 (5.4) 8 (3.5) Anxiety 22 (5.1) 10 (6.0) 8 (3.5) 4. Safety and tolerability 4.5

33 Adverse drug reactions Overall adverse drug reaction profile The incidence of adverse drug reactions (ADRs) associated with asenapine therapy, based on reporting from Phase II/III bipolar mania and schizophrenia clinical studies, is shown in Table 8. 1 The most frequently reported ADRs ( 10% incidence) were somnolence and anxiety. 1 Table 8: Adverse drug reactions with asenapine 1 Body system Frequency* Event Blood and lymphatic disorders Rare Neutropenia Metabolism and nutrition disorders Common Weight increased, increased appetite Uncommon Hyperglycaemia Psychiatric disorders Very common Anxiety Nervous system disorders Very common Somnolence Common Uncommon Rare Dystonia, akathisia, dyskinesia, parkinsonism, sedation, dizziness, dysgeusia Syncope, seizure, extrapyramidal disorder, dysarthria Neuroleptic malignant syndrome Eye disorders Rare Accommodation disorder Cardiac disorders Uncommon Sinus bradycardia, bundle branch block, electrocardiogram QT prolonged Vascular disorders Uncommon Orthostatic hypotension, hypotension Respiratory, thoracic and mediastinal disorders Rare Pulmonary embolism Gastrointestinal disorders Common Oral hypoaesthesia Uncommon Swollen tongue, dysphagia, glossodynia, oral paraesthesia Hepatobiliary disorders Common Alanine aminotransferase increased Musculoskeletal and connective tissue disorders Reproductive system and breast disorders Common Rare Uncommon Rare Muscle rigidity Rhabdomyolysis Sexual dysfunction, amenorrhoea Gynaecomastia, galactorrhoea General disorders Common Fatigue *Very common ( 10%), common ( 1%, <10%), uncommon ( 0.1%, <1%), rare ( 0.01%, <0.1%) Safety and tolerability

34 In addition, the following ADRs are singled out for special mention in the asenapine summary of product characteristics. Extrapyramidal symptoms: in combined (bipolar mania and schizophrenia) clinical trials, the incidence of EPS in asenapinetreated patients was higher than placebo (15.4% versus 11.0%). 1 Weight increase: in the combined study populations, the mean change in body weight for asenapine was 0.8 kg. 1 In the shortterm bipolar mania trials, the proportion of subjects with clinically significant weight gain ( 7% increase from baseline at endpoint) was 6.5% for asenapine compared to 0.6% for placebo. 1 Hepatic enzymes: transient, asymptomatic elevations of hepatic transaminases, alanine transferase (ALT), and aspartate transferase (AST) have been seen commonly, especially in early asenapine treatment. 1 Cerebrovascular events have been reported in patients treated with asenapine, but there is no evidence of any excess incidence over what is expected in adults between 18 and 65 years of age. 1 Asenapine has anaesthetic properties. 1 Oral hypoaesthesia and oral paraesthesia may occur directly after administration and usually resolves within 1 hour. 1 Orthostatic hypotension: the incidence of orthostatic hypotension in elderly subjects was 4.1% compared to 0.3% in the combined asenapine Phase II/III study population Safety and tolerability 4.7

35 Warnings and precautions The use of asenapine is associated with several specific warnings and precautions relating to safety, as listed below. Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics, including asenapine. 1 Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. 1 If a patient develops signs and symptoms indicative of NMS, asenapine must be discontinued. 1 Seizures In clinical trials, cases of seizure were occasionally reported during treatment with asenapine. 1 Therefore, asenapine should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures. 1 Suicide The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany treatment. 1 Orthostatic hypotension Asenapine may induce orthostatic hypotension and syncope, especially early in treatment, probably reflecting its α 1 -adrenergic antagonist properties. 1 Elderly patients are particularly at risk for experiencing orthostatic hypotension. 1 In clinical trials, cases of syncope were occasionally reported during treatment with asenapine. 1 Asenapine should be used with caution in elderly patients and in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolaemia). 1 Tardive dyskinesia Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia, and cases of tardive dyskinesia were occasionally reported in clinical studies of asenapine. 1 The onset of EPS is a risk factor for tardive dyskinesia. 1 If signs and symptoms of tardive dyskinesia appear in a patient on asenapine, discontinuation of treatment should be considered. 1 Hyperprolactinaemia Increases in prolactin levels were observed in some patients receiving treatment with asenapine. 1 However, in clinical studies, few ADRs related to abnormal prolactin levels were reported. 1 QT-interval prolongation Clinically relevant QT-interval prolongation does not appear to be associated with asenapine. 1 However, caution should be exercised when asenapine is prescribed in patients with known cardiovascular disease or family history of QT-interval prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval Safety and tolerability

36 Hyperglycaemia and diabetes mellitus Hyperglycaemia or exacerbation of pre-existing diabetes has occasionally been reported during treatment with asenapine. 1 Assessment of the relationship between second-generation antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia or bipolar disorder, and the increasing incidence of diabetes mellitus in the general population. 1 Appropriate clinical monitoring is advisable in diabetic patients, and in patients with risk factors for the development of diabetes mellitus. 1 Dysphagia Oesophageal dysmotility and aspiration have been associated with antipsychotic treatment. 1 Cases of dysphagia were occasionally reported in patients treated with asenapine. 1 Body temperature regulation Disruption of the body s ability to reduce core body temperature has been attributed to antipsychotic medicines, but clinical studies have indicated that clinically relevant body temperature dysregulation is not associated with asenapine. 1 Appropriate care is advised when prescribing asenapine for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medicinal products with anticholinergic activity or being subject to dehydration. 1 Special patient populations Elderly patients with dementia-related psychosis Elderly patients with dementia-related psychosis who are treated with antipsychotic substances are at an increased risk of death. 1 Asenapine is not approved for the treatment of patients with dementia-related psychosis and is not recommended for use in this particular group of patients. 1 Parkinson s disease and dementia with Lewy bodies Patients with Parkinson s disease or dementia with Lewy bodies (DLB) may be at increased risk of NMS as well as having an increased sensitivity to antipsychotics. 1 Therefore, physicians should consider the risks versus the benefits when prescribing antipsychotic medicinal products, including asenapine, to these patients. 1 Manifestations of increased sensitivity to antipsychotics can include confusion, obtundation, postural instability with frequent falls, in addition to EPS. 1 Patients with severe hepatic impairment Asenapine exposure is increased 7-fold in patients with severe hepatic impairment (Child-Pugh Class C). 1 Therefore, asenapine is not recommended in such patients Safety and tolerability 4.9

37 Safety and tolerability

38 5. Dosing and administration Recommended dosing At approved doses (5 or 10 mg BID), asenapine sublingual tablets provide effective symptom control and documented safety and tolerability in the treatment of acute manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. As monotherapy, the recommended starting dose of asenapine is 10 mg BID, with one dose taken in the morning and one in the evening. 1 The dose can be reduced to 5 mg BID according to clinical assessment. 1 In controlled 3-week trials in bipolar I disorder in which patients had the option to lower the dose from 10 mg BID to 5 mg BID based on tolerability, 90% of patients remained on the 10 mg BID dose. 3,5 As combination (add-on) therapy, the recommended starting dose of asenapine is 5 mg BID, which can be increased to 10 mg BID, depending on the clinical response and tolerability in the individual patient. 1 Although there is no body of evidence available to address the question of how long patients should remain on asenapine, it is generally recommended that responding patients be continued beyond the acute response. 2 The physician who elects to use asenapine for extended periods in bipolar I disorder should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. 2 Special populations Patients with renal or hepatic impairment Elderly patients Asenapine should be used with care in the elderly; limited efficacy data are available in this population. 1 Asenapine is not recommended for use in elderly patients with dementia-related psychosis due to increased risk of death with antipsychotic treatment in this patient population. 1 Paediatric patients The safety and efficacy of asenapine in children (<18 years) have not been established. 1 Limited data are available in adolescents, but no dosing recommendation can be made. 1 Administration Asenapine sublingual tablets are packaged in blister cards. The tablet should be taken from the card immediately prior to administration by peeling back the coloured tab and removing the tablet gently using dry hands (the tablet will dissolve on contact with moisture). 1 The tablet should not be removed by pushing through, tearing or cutting the pack. 1 To ensure optimal absorption, the asenapine sublingual tablet should be placed under the tongue and allowed to dissolve completely. 1 Asenapine sublingual tablets should not be chewed or swallowed, and eating and drinking should be avoided for 10 minutes after administration (see Bioavailability, page 6.2). 1 When taken in combination with other medications, asenapine should be taken last. 1 No dosage adjustments are required for those with renal impairment or mild hepatic impairment (Child-Pugh Class A). 1 Due to the possibility of elevated drug levels in the plasma, asenapine should be used with caution in patients with moderate hepatic impairment (Child-Pugh Class B), and is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) Dosing and administration 5.1

39 Dosing and administration

40 6. Pharmacokinetics Absorption and distribution Following sublingual administration, the asenapine tablet dissolves in the saliva within seconds and is rapidly absorbed through the oral mucosa. 1 Peak plasma concentrations occur within 0.5 to 1.5 hours. 1 Asenapine is rapidly distributed and has a large volume of distribution (approximately 1,700 litres), indicating extensive extravascular distribution. 1 Asenapine is highly bound (95%) to plasma proteins, including albumin and α 1 -acid glycoprotein. 1 Following a single 5 mg dose of asenapine, the mean C max was approximately 4 ng/ml and was observed at a mean T max of 1 hour. 18 Mean steady-state plasma concentration versus time profiles for asenapine 5 mg and 10 mg BID are depicted in Figure These data support the twice-daily dosing recommendation for asenapine. Increasing the dose from 5 to 10 mg BID results in a less than linear (1.7-fold) increase in both extent of exposure (i.e., area under the curve, AUC) and C max, which may be related to limitations in the absorption capacity of the oral mucosa. 1 Steadystate concentrations of asenapine are reached within 3 days of BID dosing. 1 Figure 11: Steady-state concentration versus time profile for asenapine 5 mg and 10 mg BID 16 Arithmetic mean steady-state plots after 9 consecutive days of morning and evening dosing. 6. Pharmacokinetics 6.1

41 Bioavailability The absolute bioavailability of sublingual asenapine 5 mg is 35%. 1 The tablet should not be chewed or swallowed because the oral bioavailability of asenapine is low (<2%) owing to extensive firstpass metabolism. 1,9 Patients are advised to wait 10 minutes after administration before eating and drinking. 1 The intake of water within 10 minutes has been shown to decrease the bioavailability of asenapine by up to approximately 20% (Figure 12), 1 and food intake can produce an immediate decrease of 21 22% in bioavailability. 9,19 In clinical studies of asenapine there were no other restrictions in place with regard to the timing of food or water intake. Figure 12: The effects of water on the bioavailability of asenapine 10 mg (n=15 healthy male subjects) 20 Metabolism and elimination Asenapine is extensively metabolised. 1 It undergoes direct glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 1A4, and oxidation and demethylation by cytochrome P450 isoenzymes (primarily CYP1A2, but also CYP2D6 and 3A4). 1 Asenapine is a weak inhibitor of CYP2D6. 1 In vivo data indicated that the major metabolite of asenapine is asenapine N + -glucuronide, with other metabolites including N- desmethylasenapine. 1 Asenapine s therapeutic activity is primarily due to the parent compound. 1 In a mass balance study, the majority of the radioactive dose was recovered in urine (about 50%) and faeces (about 40%). 1 Following an initial more rapid distribution phase, the terminal elimination half-life is approximately 24 hours. 1 Drug drug interactions Given the primary effects of asenapine on the central nervous system, caution should be used when it is taken in combination with other centrally acting drugs or alcohol. 1 Potential for other medications to affect asenapine Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). 1 The potential effects of inhibitors and inducers of these enzyme pathways on asenapine pharmacokinetics have been studied (specifically fluvoxamine, paroxetine, imipramine, cimetidine, carbamazepine, and valproate). 1 The pharmacokinetics of asenapine were not altered in any clinically meaningful way by co-administration with most of the drugs studied. 1 An exception is fluvoxamine, which may result in clinically important increases in asenapine concentrations through inhibition of CYP1A2, and therefore co-administration should be approached with caution Pharmacokinetics