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Asenapine in bipolar mania

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Stephen Guy MCMHP
Immediate Past President CMHP,
Principal Pharmacist, 
Knockbracken Healthcare Park, Belfast
Email: stephen.guy@cmhp.org.uk
 
Key words: Asenapine; atypical antipsychotic; bipolar 1 disorder; sublingual; extrapyramidal side-effects
 
Date received: 23 March 2012
Date accepted: 30 April 2012
 
Declaration of interest
The author has received combinations of hospitality, speaker fees, advisory boards, and conference delegates for Lundbeck (other than asenapine), Lilly, Astra Zeneca, Novartis, BMS, Servier and Janssen-Cilag.
 
Bipolar disorder is a serious, chronic mental illness affecting approximately 1% of the population. It is a cyclical disorder, characterised by periods of depression and periods of mania or hypomania. In addition to conventional mood stabilisers such as lithium and valproate, antipsychotics are commonly used to control manic episodes. Atypical antipsychotics are now preferred over conventional antipsychotics owing to a lower incidence of extrapyramidal side-effects.(1,2) Asenapine is a new atypical antipsychotic licensed in Europe for the treatment of moderate-to-severe manic episodes associated with bipolar 1 disorder in adults.(3) It is suggested that the unique receptor binding profile of asenapine could offer advantages in the management of bipolar disorder. Although asenapine is classed as an atypical antipsychotic, it is not licensed in Europe for the treatment of schizophrenia. Schizophrenia is a licensed indication in other countries, including the USA.(4)
 
Pharmacology and mechanism of action
Asenapine is a novel agent with a unique receptor binding profile. It is an antagonist at a wide range of receptors including, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, 5-HT7, D2, D3, H1, H2, α1A, α2A, α2B and α2C receptors.(5) It displays a higher affinity for the 5-HT2A receptor than for the D2 receptor, which is characteristic of an atypical antipsychotic. It has minimal affinity for muscarinic receptors.(5) Its profile is significantly different from that of other atypical antipsychotics. The exact mechanism of action of asepanine is unknown but it is believed to involve a combination of antagonist activity at D2 and 5-HT2A receptors.(3)
 
Pharmacokinetics
Asenapine has a very low bioavailability of <2% after oral administration. When administered sublingually, asenapine is rapidly absorbed with peak plasma concentration occurring between 0.5 and 1.5 hours. Absolute sublingual bioavailability is 35%.(3) Asenapine is highly protein bound with a volume of distribution of approximately 1700l.(3) Asenapine undergoes extensive metabolism by several routes, including glucuronidation mediated by UGT1A4 and oxidation and demethylation by CYP1A2, and to a lesser degree by CYP2D6 and CYP3A4.(3)  Studies have examined the effect of fluvoxamine, paroxetine, imipramine, cimetidine, carbamazepine and valproate on the pharmacokinetics of asenapine; only fluvoxamine was found to have a major effect leading to a significant increase in asenapine plasma concentrations.(3)
 
Although asenapine is at best a weak inhibitor of CYP2D6, caution is advised when it is co-administered with drugs that are both CYP2D6 substrates and inhibitors, for example, paroxetine. Asenapine may increase the inhibitory effect of such drugs on their own metabolism.(3) Owing to its antagonism of α1A receptors, the effect of antihypertensive agents can be enhanced through its action.(3) Dosage adjustment is not necessary in renal impairment, although there is no experience of asenapine in severe (<15ml/min) renal impairment.(3) Dosage adjustment is not necessary in mild hepatic impairment but caution is required in moderate hepatic impairment (Child-Pugh B). Asenapine is not recommended in severe hepatic impairment (Child-Pugh C).(3) 
 
Dosing and administration
The recommended starting dose of asenapine as monotherapy for mania is 10mg twice daily. When used in combination with a mood stabiliser, the recommended starting dose is 5mg twice daily and may be increased according to tolerability and clinical response to 10mg twice daily.(3) Drinking water after administration has been shown to reduce bioavailability from 35% to 28% at two minutes and 32% at five minutes.(6) 
 
Asenapine is presented as sublingual tablets in peelable aluminium blisters. The tablet is removed from the blister by peeling back the coloured tab and removing the tablet using dry hands. The tablet must not be pushed through the blister. The tablet is placed under the tongue and allowed to dissolve. Eating or drinking is not recommended for at least ten minutes after administration.(3,7) When other medicines are to be administered, asenapine should be given last.(3) Owing to the low oral bioavailability, asenapine is not advised in patients who will not comply with sublingual administration.(3) 
 
Efficacy in bipolar disorder
Clinical trials
The short-term efficacy of asenapine as monotherapy for bipolar disorder has been evaluated in two flexible, dose-randomised, placebo/olanzapine controlled clinical trials of three weeks’ duration.(8,9) Olanzapine was included to assess assay sensitivity; the studies were not powered to allow reliable comparisons to be made between asenapine and olanzapine. The primary outcome measure in both studies was the change in Young Mania Rating Scale (YMRS) total score from baseline to endpoint (day 21). Secondary outcomes included changes from baseline in Clinical Global Impression Bipolar Disorder (CGI-BP), in depressive symptoms on the Montgomery–Asberg Depression Rating Scale (MADRS) and the percentage of responders (≥50 reduction in YMRS score) and the percentage of remitters (YRMS ≤ 12 at endpoint).(8,9) Across the two studies, a total of 977 patients were randomised on a 2:2:1 basis to asenapine, olanzapine or placebo. The doses on day one were fixed at asenapine 10mg twice daily and olanzapine 15mg daily but were flexible thereafter (asenapine 5–10mg twice daily and olanzapine 5–20mg daily).(8,9)
 
In both short-term studies, asenapine and olanzapine were more effective than placebo, having statistically significant mean changes from baseline YRMS scores.(8,9) Superiority of asenapine and olanzapine compared with placebo was evident as early as day two.(8,9) In one study, the YRMS response rate at day 21 for asenapine did not differ significantly from placebo (42.6% vs 34.0%, respectively; p=0.1951).(8) In the same study, response to olanzapine was superior to placebo (54.7%; p=0.002).(8) In the second study, YRMS response to asenapine at day 21 was superior to placebo (42.3% vs 25.2% respectively; p= 0.01); olanzapine was also superior to placebo (50.0%; p=0.001).(9)
 
The longer-term efficacy of asenapine in bipolar disorder has been evaluated in two extension studies of the short-term efficacy trials.(10,11) In order to assess non-inferiority of asenapine versus olanzapine, patients completing either of the two short term studies with no major protocol breaches were eligible to enter a nine-week extension study. Patients in the asenapine and olanzapine groups were maintained on their current dose whereas patients on placebo were transferred to asenapine and assessed for safety only. Blinding was maintained in all treatment arms for the duration of the study.(10) At the end of 12 weeks, the mean change from baseline in YRMS scores was similar for both asenapine and olanzapine (–24,4 and –23.9, respectively). There was no significant difference between asenapine and olanzapine according to the criteria for non-inferiority set out in the trial protocol.(10) Patients completing the nine-week extension study were eligible to continue onto a further 40-week extension study, which examined safety and tolerability issues for up to one year of treatment with asenapine.(11)
 
The efficacy of asenapine in combination with a mood stabiliser (lithium or valproate) has been investigated in a 12-week double-blind study in 326 subjects where asenapine (5 or 10mg twice daily) or placebo was added to the existing open label treatment.(12) This study (and the associated 40-week extension study) is only available as an abstract. In line with the monotherapy studies, the primary efficacy measure was the mean change from baseline YRMS scores at day 21. A significantly greater reduction in YRMS score at day 21 was observed for asenapine compared with placebo (–9.7 and –7.7; p<0.05). Patients completing the 12-week study without major protocol violations were eligible to enter a 40-week extension study that focused primarily on safety and tolerability issues.(12)
 
Efficacy in schizophrenia
Clinical trials
The efficacy of asenapine in acute schizophrenia has been evaluated in a six-week, double-blind study where patients were randomly assigned to asenapine 5mg twice daily, risperidone 3mg twice daily or placebo. A total of 174 patients were included in the intention-to-treat analysis.(13) On the primary outcome measure, that is, mean reduction in Positive and Negative Syndrome Scale (PANSS) at day 42, asenapine was superior to placebo (p=0.005); in the same study risperidone was not superior to placebo.(13) In a larger study, 458 patients were randomly assigned to asenapine 5mg twice daily, asepanine 10mg twice daily or haloperidol 4mg twice daily. Haloperidol was present to verify assay sensitivity.(14) Asenapine 5mg twice daily and haloperidol 4mg twice daily were both superior to placebo (p<0.05) on the primary outcome measures; however, asenapine 10mg twice daily failed to show superiority over placebo.(14)
 
The long-term efficacy of asenapine in schizophrenia has been evaluated in a 52-week double-blind study in 1225 patients comparing asenapine 5–10mg twice daily with olanzapine 10–20mg daily.(15) Asenapine and olanzapine demonstrated similar improvements in mean changes in PANSS scores at day 42; however, at the end of one year olanzapine was superior to asenapine on a last observation carried forward basis but not for those subjects who completed (observed cases) a full 12 months of treatment.(15) 
 
Safety and tolerability
Short-term bipolar studies
Data from the two three-week bipolar efficacy studies show that treatment-emergent adverse events were reported by 74.7% of subjects treated with asenapine and 68.8% of subjects treated with olanzapine compared with 58.6% of subjects treated with placebo.(8,9) The combined rates of discontinuation as a result of adverse events in the two studies were 9.7% for asenapine and 3.8% for olanzapine, compared with 5.4% for placebo. The adverse events occurring at an incidence of ≥5% in either study were sedation, dizziness, somnolence, fatigue, weight increase, oral hypoaesthesia, vomiting and akathisia.(8,9) 
 
Schizophrenia and bipolar studies
The safety and tolerability data from the pre-license clinical trials for both schizophrenia and bipolar disorder are summarised in the Committee for Medicinal Products for Human Use (CHMP) Asenapine Assessment report. In total, 4565 subjects were exposed to asenapine, including 3457 subjects in the phase II and phase III clinical programs. In the clinical programs, the majority of subjects (91.4%) received the therapeutic dose of 5 or 10mg twice daily. A total of 1314 subjects were exposed to asenapine for at least six months and 785 subjects were exposed to asenapine for at least one year. A total of 2826 subjects received asenapine for schizophrenia compared with 631 subjects for bipolar disorder.(16) 
 
The most common adverse events with an incidence ≥10% were anxiety and somnolence. Other adverse events reported at a rate ≥1% but <10% include weight gain, increased appetite, dysgeusia, extrapyramidal effects, sedation, dizziness, oral hypoaesthesia, muscle rigidity, increased alanine aminotranferase levels and fatigue.(3)
 
The FDA has received 52 adverse reports of type I hypersensitivity reactions associated with the use of asenapine. Eight of the cases occurred after just one dose of asenapine. Symptoms of type I reactions can include anaphylaxis, angioedema, low blood pressure, tachycardia, swollen tongue, difficulty breathing, wheezing or rash.(17) 
 
Extrapyramidal side-effects
In the two short-term bipolar efficacy studies, the combined incidence of any extrapyramidal side-effects (EPS) were asenapine 10%, olanzapine 9.4% compared with 4% for placebo. The only individual EPS with an incidence > 5% was akathisia (asenapine 5.1% vs placebo 3.1%).(8) In the pooled safety data from the long-term bipolar studies, the incidence of akathisia for asenapine (5.5%) was comparable to placebo (5.4%).(16) In a one-year, double-blind study in schizophrenia and schizoaffective disorder, the incidence of EPS was 18% for asenapine compared with 8% for olanzapine.(15)
 
QTc prolongation
The effects of asenapine on QTc were investigated using an exposure–response analysis with a dose-escalation design, using a placebo control and quetiapine 375mg for assay sensitivity. The maximum dose of asenapine was 20mg twice daily. The model predicted a mean increase in QTcF (Fridericia’s correction) of <5msec at all asenapine doses,(18) which is below the International Conference on Harmonisation threshold of concern. In one of the three-week efficacy studies on asenapine, clinically relevant QTc prolongation was reported in one subject.(8)
 
Effect on prolactin
There were no clinically significant increases in prolactin levels observed during the three-week efficacy studies.(8,9) The combined safety data from all phase II /III bipolar and schizophrenia studies show that the incidence of prolactin-related disorders, for example, menstrual abnormalities and uterine bleeding disorders was comparable across treatment groups.(16) 
 
Weight gain
In short-term bipolar efficacy studies the mean±SD change in weight from baseline was asenapine 0.9±3kg, placebo 0.1±2.0kg and olanzapine 2.6±3.6kg in one study and asenapine 1.6±2.9kg, placebo 0.3±2.0kg and olanzapine 1.9±3.2kg in another study.(8,9) The proportion of subjects with clinically significant weight gain (≥7% increase from baseline) was asenapine 7.2%, placebo 1.2% and olanzapine 19.0% in one study and asenapine 6.0%, placebo 0.0% and olanzapine 12.9% in another study.(8,9) The proportion of subjects with weight gain in the combined safety data from all phase II /III bipolar and schizophrenia studies asenapine 8.4%, placebo 1.0%, haloperidol 2.6%, risperidone 5% and olanzapine 19.5%.(16) The mean increase in weight for asenapine was 0.8kg compared with 3.5kg for olanzapine and minimal change for placebo.(16)
 
Discussion
Asenapine is an atypical antipsychotic and yet it is not approved in Europe for the treatment of schizophrenia. The European Medicines Agency’s Committee for Medicinal Products for Human Use reviewed the evidence submitted for a license application for asenapine for bipolar disorder and schizophrenia. The Committee found sufficient evidence to approve asenapine for the management of acute manic episodes associated with bipolar 1 disorder.(16) With regard to schizophrenia, the Committee found that the evidence of efficacy from phase III studies was weak, inconsistent and of questionable clinical significance. A clear benefit of the proposed 10mg twice-daily dose over 5mg twice daily was not demonstrated.(16) Given these uncertainties, approval for use in schizophrenia was not granted. 
 
The evidence demonstrates efficacy in acute mania with continued preventative benefit for up to 12 weeks of treatment. In the management of bipolar disorder, tolerability is central to achieving good adherence to treatment. Asenapine could offer some advantages over other agents in this respect.
 
Although the overall incidence or EPS with asenapine is relatively low, there is some uncertainty as to how it compares to other atypical antipsychotics. In the short-term bipolar studies, it is comparable to olanzapine but in one long-term schizophrenia study it showed a higher incidence of EPS compared with olanzapine. A minor concern is that the majority of safety data on asenapine are derived from schizophrenia studies rather than studies in bipolar disorder. There is some evidence that the incidence of EPS might be higher in people treated with atypical antipsychotics for bipolar disorder compared with those treated for schizophrenia.(19) 
 
Asenapine demonstrates minimal risk for elevated prolactin and comparatively lower weight gain compared with olanzapine. 
There are no pharmacoeconomic studies published for asenapine as yet, so it is not possible to determine its cost effectiveness at this stage. In addition, there are no adequately powered comparative studies with other atypical antipsychotics licensed for bipolar mania. Until this additional information is available, asenapine might offer an alternative where tolerability has been an issue with other atypical antipsychotics in the management of bipolar mania.
 
Key points
  • Asenapine (Sycrest®; Lundbeck) is licensed in the European Union for the treatment of moderate to severe manic episodes associated with bipolar 1 disorder in adults.
  • Studies have demonstrated short-term efficacy in mania, with evidence of protective effect for up to 12 weeks of treatment.
  • Asenapine has a low potential for raised prolactin and lower weight gain risk compared with olanzapine and is unlikely to cause clinically significant weight gain.
  • Asenapine is unlikely to lead to clinically significant QTc prolongation
  • The most common adverse effects are somnolence and anxiety.
  • Asenapine must be administered sublingually owing to very low oral bioavailability.
  • When other medicines are to be taken, asenapine should be taken last.
  • Patient counselling will be required in order to ensure asenapine is taken correctly.
 
 
References
  1. National Institute for Health and Clinical Excellence. Bipolar disorder. CG38. National Institute for Health and Clinical Excellence;2006. http://guidance.nice.org.uk/CG38 (accessed 8 June 2012).
  2. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: Recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2003;17:149–73. 
  3. Asenapine. Summary of Product Characteristics. N V Organon. Last update 24 October 2011. www.sycrest.co.uk/siteuploads/SmPC.pdf (accessed 8 June 2012).
  4. Asenapine. Structured Product Labelling. Organon USA Inc. Last update 10 October 2011. www.accessdata.fda.gov/drugsatfda_docs/label/2011/022117s009lbl.pdf (accessed 8 June 2012).
  5. Shahid M et al. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol 2009;23(1):65–73.
  6. Hulskotte E et al. Effects of water intake and smoking on absorption of sublingually administered asenapine. Poster presented at the 110th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT);18–21 March 2009.
  7. Patient Information Leaflet. Sycrest sublingual tablets, NV Organon. Last update October 2011. www.sycrest.co.uk/siteuploads/PIL.pdf (accessed 8 June 2012).
  8. McIntyre RS 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.
  9. McIntyre RS et al. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord 2009;11(7):673–86. Erratum in Bipolar Disord 2010;12(3):350.
  10. McIntyre RS et al. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009 Dec;11(8):815–26. Erratum in: Bipolar Disord 2010;12(1):112.
  11. McIntyre RS 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.
  12. Calabrese JR 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 62nd Institute on Psychiatric Service of the American Psychiatric Association;14–17 October 2010.
  13. 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.
  14. Kane JM 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.
  15. Schoemaker J. Long-term assessment of asenapine vs. olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry 2010;43(4):138–46. Erratum in: Pharmacopsychiatry 2011;44(7):343.
  16. Committee for Medicinal Products for Human Use (CHMP). Asenapine assessment. 2010 European Medicines Agency.
  17. FDA Drug Safety Communication: Serious allergic reactions reported with the use of Saphris (asenapine maleate), September 2011. www.fda.gov/Drugs/DrugSafety/ucm270243.htm (accessed 8 June 2012).
  18. Chapel S 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.
  19. Gao K et al. Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review. J Clin Psychopharmacol 2008;28(2):203–9.
 

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