Asenapine (Saphris) for schizophrenia or bipolar I disorder (acute mania or maintenance)
Published in NPS RADAR
Date published: About this date
Sublingual wafer must be taken correctlyKey points | Evidence snapshot | PBS listing | What is it? | Who is it for? | Where does it fit? | How does it compare? | Safety issues | Reason for PBS listing | Dosing issues | Information for patients | References
- Asenapine has a similar spectrum of benefits and harms to that of other antipsychotics
As with most newer antipsychotics, asenapine is a potent inhibitor at dopamine D2 and serotonin 5-HT2A receptors.
- Trial data demonstrate efficacy up to 52 weeks in schizophrenia and 12 weeks in bipolar mania or mixed episodes
There are limited efficacy and safety data beyond one year.
- Asenapine wafers are ineffective if swallowed
The wafers must be taken sublingually twice daily, with no food or drink for 10 minutes afterwards.
- Warn patients to expect tingling or numbing of the tongue and mouth
Asenapine wafers often have a local anaesthetic effect. Symptoms usually resolve within an hour.
- Less efficacious than olanzapine in a 52-week trial for schizophrenia and schizoaffective disorder
Of those completing the trial, 52% were rated as much or very much improved with asenapine, and 66% with olanzapine.
- Appears to cause a higher incidence of extrapyramidal symptoms (EPS) than olanzapine but a lower incidence of weight gain
In a 52-week trial, 14% of patients receiving asenapine and 7% of patients receiving olanzapine experienced treatment-related EPS; rates of weight gain (≥ 7% of baseline) were 12% and 29%.
Authority required (Streamlined)
Authority required (Streamlined)
Treating an acute episode of mania or mixed episodes associated with bipolar I disorder for up to 6 months.
Maintenance therapy of bipolar I disorder as monotherapy.
May be prescribed by nurse practitioners (shared care model)
Authorised nurse practitioners may prescribe this medicine as part of a formal care plan with a medical practitioner. See the PBS website for more information on nurse practitioner PBS prescribing.
What is it?
Asenapine is an antipsychotic with similarities to clozapine, olanzapine and quetiapine, and like these drugs is a potent antagonist at dopamine D2 and serotonin 5-HT2A receptors.1,2 Asenapine also inhibits activity at a range of other receptors. Relevant to its adverse-effect profile, it binds at alpha1-adrenergic receptors and histamine H1 receptors, but has little affinity for muscarinic acetylcholine receptors.1
Asenapine is formulated as sublingual wafers that are round and white to off-white in colour. The wafer is placed under the tongue, where the drug is absorbed through the oral mucosa with an absolute bioavailability of about 35% for asenapine 5 mg wafers. 3
Asenapine is ineffective if swallowed (bioavailability as a tablet formulation was < 2%).3
Who is it for?
Asenapine is indicated for schizophrenia in adults. Most participants in trials had previously received antipsychotic treatment, but treatment-resistant individuals were excluded. People with a history of recent alcohol or illicit drug misuse, symptoms of tardive dyskinesia, a seizure disorder or concomitant treatment with another psychotropic drug were also excluded.3,4
Bipolar I disorder
Asenapine is indicated for manic or mixed episodes associated with bipolar I disorder, and for preventing relapse of manic or mixed episodes. Efficacy has not been adequately assessed beyond 12 weeks. There are no efficacy data in bipolar depression. Exclusion criteria for the bipolar I disorder clinical trials included first moderate to severe mood episode, comorbid psychotic disorder, a history of recent alcohol or illicit drug misuse, seizure disorder or a history of rapid cycling. Unlike the schizophrenia trials, participants could have a history of unsuccessful antipsychotic treatment.3,5
Where does it fit?
The therapeutic and adverse effects of asenapine are broadly consistent with those of other antipsychotics. Asenapine's particular adverse-effect profile may make it a suitable choice for certain patients (see How does it compare?). However, data suggest it is less efficacious than olanzapine in schizophrenia.
Uncertainty about asenapine's efficacy compared with other antipsychotics and its long-term safety mean that established antipsychotics may be a better first choice for people with schizophrenia or, if an antipsychotic is indicated, in bipolar I disorder. Consider clozapine for people with treatment-resistant schizophrenia — asenapine is untested in this population.
Asenapine wafers may be unsuitable for some people because they are taken sublingually twice daily and must not be swallowed.
Consider established antipsychotics first in schizophrenia
There are many existing first-line choices for treating schizophrenia. Consider these before asenapine wafers, given the relative lack of comparative data and experience. Efficacy and safety data for asenapine beyond 52 weeks are limited, and rare adverse effects have not been well characterised. At the time of TGA evaluation, 779 people had been exposed to asenapine for at least 12 months in clinical studies.5 Asenapine was less efficacious and had a higher incidence of treatment-related serious adverse effects than olanzapine in a 52-week trial (see How does it compare?).
No data in treatment-resistant schizophrenia
Consider clozapine for all adults with schizophrenia who have not responded to two or more antipsychotic drugs.6 Asenapine has not been tested in people with treatment-resistant schizophrenia. In asenapine clinical trials, participants must have responded previously to an antipsychotic other than clozapine, or be treatment naive.4
Efficacy not adequately assessed beyond 12 weeks in bipolar disorder
Antipsychotics, lithium, antidepressants and anticonvulsants all have a place in treating bipolar disorder.6-8 Asenapine is efficacious in acute mania and mixed episodes of bipolar I disorder, but has not been adequately assessed beyond 12 weeks.3 While guidelines recommend several antipsychotics as first-line options for acute mania, olanzapine, quetiapine or risperidone depot injection are the only ones with data showing effectiveness at preventing relapse of mania or depression over 1 year.6-8 Asenapine has not been evaluated in bipolar depression. Bipolar disorder indications and PBS listings for newer antipsychotics are listed in Table 1.
Asenapine may be useful when other antipsychotics are relatively contraindicated
The choice of antipsychotic should be guided by patient risk factors, history and preferences. As with any antipsychotic, asenapine's specific adverse-effect profile may suit particular patients [see More extrapyramidal symptoms (EPS) than olanzapine but less weight gain]. However, there are limited data to inform these decisions — there have been direct comparisons of asenapine with olanzapine, risperidone or haloperidol, but none with aripiprazole, amisulpride, quetiapine or ziprasidone.1,5
Table 1. Indications and PBS listings for atypical antipsychotic drugs in bipolar I disorder
(up to 6 months)
Olanzapine (Zyprexa, Zyprexa Zydis)
Olanzapine injection (Zyprexa IM)
Quetiapine (Seroquel) and
Risperidone (Ozidal, Resdone, Rispa, Risperdal, Risperdal Quicklet, Rixadone)
Risperidone depot injection (Risperdal Consta)
* Acute mania and mixed episodes
† (P) — TGA approved indication available on private prescription only
How does it compare?
Less efficacious than olanzapine in a 52-week trial for schizophrenia and schizoaffective disorder
At 52 weeks, olanzapine reduced the Positive and Negative Syndrome Scale (PANSS) total score* more than asenapine (–27.5 vs –21.0, p < 0.0001). A difference of 6 points on the PANSS scale would not be clinically significant for an individual; however, among participants who completed the trial, 66% of those taking olanzapine were rated as much or very much improved, compared with 52% of those taking asenapine. Furthermore, 14% (45/312) of participants receiving olanzapine and 25% (228/913) receiving asenapine discontinued treatment because of a lack of response.9
People with a history of non-response or intolerable side effects with olanzapine were excluded from this trial, and this group may do relatively better with asenapine. People with schizoaffective disorder made up 13% of the trial participants. Asenapine may be less effective in schizoaffective disorder and is not registered for this indication.9
Efficacy relative to olanzapine in bipolar mania and mixed episodes is uncertain
Asenapine was efficacious and significantly reduced mania symptoms in a 12-week trial.*1,11 At week 12, the difference in Young Mania Rating Scale (YMRS) score† between asenapine and olanzapine was not statistically significant in a post hoc analysis (mixed model for repeated measures estimated difference in YMRS score 0.6, 95% confidence interval –1.3 to 2.5). 1,11-13 According to European regulators, non-inferiority to olanzapine could not be concluded.1
Asenapine was efficacious as an adjunct to lithium or valproate in a 12-week trial involving participants with an acute manic or mixed episode that had not completely responded to lithium or valproate alone. At 12 weeks, asenapine reduced the YMRS more than placebo (–12.7 vs –9.3, p = 0.0073). Response rates were 25% (39/155) for asenapine and 20% (33/163) for placebo (intention-to-treat population).1,5
* The trial was conducted as two identical 3-week trials and a single 9-week continuation trial.
† A commonly used rating scale for mania symptoms in bipolar disorder clinical trials. Scores range from 0 to 60, with higher scores for worse symptoms.14
More extrapyramidal symptoms (EPS) than olanzapine but less weight gain
In the 52-week schizophrenia and schizoaffective disorder trial, rates of treatment-related adverse events were similar for asenapine (548/908, 60%) and olanzapine (190/311, 61%), as were the rates of discontinuation because of adverse events not related to worsening of disease or inadequate response to treatment (6% vs 7%). However, rates of treatment-related serious adverse events were higher for asenapine (6% vs 2%).9
Rates of treatment-related extrapyramidal symptoms (mostly akathisia) were higher with asenapine (14% vs 7%), while rates of weight gain (≥ 7% of baseline) were lower (12% vs 29%), and rates of sedation were similar (8% vs 10%). Rates of discontinuation due to extrapyramidal symptoms were similar (1% vs 1%). Adverse event rates were not compared statistically, with the exception of a post hoc analysis that found that weight gain was less with asenapine than with olanzapine (p < 0.0001).9
In pooled short- and long-term safety data, asenapine increased prolactin levels less often than olanzapine or risperidone. Asenapine caused a higher incidence of extrapyramidal symptoms than olanzapine or risperidone, but a lower incidence than haloperidol. The incidence of weight increase by ≥ 7% was less than that of olanzapine and similar to that of haloperidol. The statistical significance of these comparisons was not reported.5
Asenapine causes the typical range of antipsychotic adverse effects, including sedation and dose-dependent extrapyramidal symptoms [see More extrapyramidal symptoms (EPS) than olanzapine but less weight gain].* It caused small increases in QTc interval in a dedicated QT study, but not increased rates of clinically relevant QT prolongation in clinical trials. It may cause orthostatic hypotension in some people, particularly early in treatment, and there have been cases of neuroleptic malignant syndrome.3
Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.
* Review the product information for a complete list of known adverse effects and precautions.
Not recommended in pregnancy or during breastfeeding
Asenapine is an Australian pregnancy category C drug. It should be used in pregnancy only if the anticipated benefits outweigh the risks. As a class, antipsychotics are associated with neurological disturbances or withdrawal symptoms in neonates exposed during the third trimester of pregnancy.3
Women receiving asenapine should avoid breastfeeding, as it is not known whether the drug or its metabolites are excreted in human milk.3
Effects on the cardiovascular system
Consider the risk of QT prolongation for people with known cardiovascular disease, a family history of QT prolongation or who are also using other medicines that prolong the QT interval. In a dedicated QT study, asenapine caused a small increase in QTc interval that was considered unlikely to be of clinical relevance under ordinary circumstances.4,15 Clinically relevant QT prolongation (i.e. ≥ 500 milliseconds) has not been observed at increased rates in clinical trials.3 The European regulator concluded that asenapine seemed to be benign in terms of QT prolongation, which is an advantage over sertindole and ziprasidone.1
Asenapine may cause orthostatic hypotension, dizziness and fainting, especially early in treatment. People at particular risk include elderly patients and people with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions that contribute to hypotension (dehydration, hypovolaemia or use of antihypertensives).3
Monitor effect on weight and metabolic parameters
Monitor weight at the start of treatment, regularly for the first 3 months and once to twice yearly thereafter. Consider a change in antipsychotic for people whose weight increases in the first 3 months of treatment.6 In trials, the incidence of weight increase by ≥ 7% with asenapine was less than that for olanzapine and appeared similar to that for haloperidol [see More extrapyramidal symptoms (EPS) than olanzapine but less weight gain].
Test fasting blood glucose at the start of treatment and annually thereafter.6 There have been cases of hyperglycaemia or exacerbated pre-existing diabetes among people receiving asenapine. In addition, people taking asenapine in trials experienced a small increase in fasting insulin levels.3
Interacts with some SSRI antidepressants
Asenapine interacts with fluvoxamine, paroxetine and possibly fluoxetine. Consider an alternative antidepressant or coadminister these with caution. Fluvoxamine (a strong CYP1A2 inhibitor) can increase blood concentrations of asenapine, while asenapine can increase blood concentrations of paroxetine (a strong inhibitor of CYP2D6 and also a CYP2D6 substrate).3 As fluoxetine is also a strong inhibitor of CYP2D6 and a CYP2D6 substrate, an effect of asenapine on fluoxetine blood concentrations is theoretically possible.16
Hypersensitivity reactions have been reported
Counsel patients who are receiving asenapine about how to recognise the signs and symptoms of a serious allergic reaction (see Information for patients). Asenapine is contraindicated for people with a known hypersensitivity to the drug.3
Between the US approval of asenapine in August 2009 and September 2010, there were 52 cases that reported type I hypersensitivity reactions associated with asenapine. Eight cases involved hypersensitivity on initial exposure to asenapine. Reported signs and symptoms included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnoea, wheezing and rash.17
Reason for PBS listing
The Pharmaceutical Benefits Advisory Committee (PBAC) recommended listing asenapine for schizophrenia on the basis of similar cost and efficacy to that of risperidone (i.e. cost minimisation). The PBAC recommended listing asenapine for bipolar I disorder on a cost-minimisation basis with quetiapine.18
The PBAC was also concerned that health professionals should be informed about the correct use of the sublingual formulation, in light of the low bioavailability if asenapine is not taken correctly.18
Asenapine wafers must be taken sublingually. For schizophrenia the starting dose is asenapine 5 mg twice daily. For monotherapy in bipolar disorder the starting dose is asenapine 10 mg twice daily, and for combination therapy with lithium or valproate the starting dose is asenapine 5 mg twice daily. The dose can be adjusted in the range 5 mg to 10 mg twice daily after clinical assessment. The safety and efficacy of doses above 10 mg twice daily have not been evaluated.3
Asenapine wafers must not be chewed or swallowed
Asenapine has low bioavailability when swallowed (it was < 2% as a tablet formulation), while the recommended sublingual route has an absolute bioavailability of about 35% for asenapine 5 mg wafers. People taking asenapine must also avoid eating or drinking for at least 10 minutes afterwards because this can reduce the amount absorbed by 10% or more. Wafers can be taken after a meal.3
Give detailed instructions about the sublingual dosing technique
Evaluate each patient's ability to follow the instructions for sublingual dosing (see Information for patients). It may be necessary to review dosing technique regularly. Inform patients that the wafers often have an anaesthetic effect on the mouth and tongue and that these symptoms usually resolve within an hour.3 In one trial, 76% of participants experienced oral paraesthesia.19
Knowledge about dose response is limited
There is no evidence that asenapine 10 mg twice daily is more effective than asenapine 5 mg twice daily for schizophrenia, but the higher dose increases the likelihood of certain adverse reactions (notably akathisia).3
Dose response in bipolar disorder is unknown because all clinical trials allowed dose adjustment. However, most participants in monotherapy trials for bipolar I disorder continued on asenapine 10 mg twice daily.1
The safety and efficacy of doses above 10 mg twice daily has not been evaluated, and the efficacy of doses below 5 mg twice daily was not demonstrated for either condition.3,5
Not recommended for people with severe liver impairment
No dose adjustment is required for people who have mild to moderate hepatic impairment (Child–Pugh A or B). On the other hand, people with severe liver impairment (Child–Pugh C) experienced a large increase in the proportion of asenapine reaching the systemic circulation. Asenapine is extensively metabolised by liver enzymes CYP1A2 and UGT1A4 (glucuronidation).3
No dose adjustment for renal impairment
Asenapine is highly bound to plasma protein, and a study in healthy volunteers found no detectable renal elimination of unmetabolised asenapine.3,20 The single-dose pharmacokinetics of asenapine 5 mg were similar in people with different degrees of renal impairment.3
Information for patients
Advise patients that:
- asenapine must be taken twice a day, once in the morning and once in the evening, e.g. after breakfast and dinner
- asenapine must be taken after all other medicines that are taken by mouth
- asenapine can cause tingling or numbing of the tongue and mouth for up to an hour after each dose.
Explain the correct way to take asenapine:
- Make sure you have dry hands.
- Peel back the coloured tab and gently remove the wafer.
- Place the wafer under your tongue and it will disintegrate by itself in a few seconds.
- Do not chew or swallow the wafer, and do not eat or drink for 10 minutes after taking the wafer — otherwise the medicine will not be absorbed completely and may not work properly.
Advise patients and carers of common adverse effects (see Safety issues) and also rare but serious adverse effects. Ask them to seek medical help if they experience:
- uncontrolled movements of the tongue, face, mouth or jaw
- a significant rise in body temperature
- stiff muscles, fast breathing, abnormal sweating or decreased mental alertness
- sudden signs of allergy such as skin rash, itching or hives, swelling of the face, lips or tongue, or difficulty breathing.
Discuss the Saphris consumer medicine information (CMI) leaflet with the patient or carer. It contains detailed, illustrated instructions for taking asenapine wafers.
NPS Medicine Update articles on asenapine for schizophrenia and asenapine for bipolar disorder are available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with those of other medicines.
- European Medicines Agency. European Public Assessment report for Sycrest. EMEA/H/C/001177. 1 September 2010. Scientific Discussion., 2010. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001177/WC500096898.pdf (accessed 31 August 2011).
- Meltzer HY, Massey BW. The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 2011;11:59–67. [PubMed]
- Schering-Plough Pty Ltd. Saphris product information. 21 March 2011
- US Food and Drug Administration. Saphris (Asenapine) sublingual tablets. Briefing book. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM173877.pdf (accessed 6 September 2011).
- Australian Government Department of Health and Ageing Therapeutic Goods Administration. Australian Public Assessment Report for asenapine (Saphris). Submission No: PM-2009-03233-3-1, 2011. http://www.tga.gov.au/pdf/auspar/auspar-saphris.pdf (accessed 31 August 2011).
- Psychotropic Expert Group. Therapeutic Guidelines: Psychotropic. Version 6. Melbourne: Therapeutic Guidelines Limited, 2008.
- National Institute for Health and Clinical Excellence. Bipolar disorder. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. Clinical Guideline No. 38. 2006. http://guidance.nice.org.uk/CG38/Guidance/pdf/English (accessed 9 June 2011).
- Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar disorders 2009;11:225–55. [PubMed]
- Schoemaker J, Naber D, Vrijland P, et al. Long-term assessment of Asenapine vs. Olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry 2010;43:138–46. [PubMed]
- Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–76. [PubMed]
- McIntyre RS, Cohen M, Zhao J, et al. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009;11:815–26. [PubMed]
- 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;11:673–86. [PubMed]
- 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;122:27–38. [PubMed]
- Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;133:429–35. [PubMed]
- 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;49:1297–308. [PubMed]
- Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine. 2011. http://medicine.iupui.edu/clinpharm/ddis/table.aspx (accessed 31 August 2011).
- US Food and Drug Administration. FDA Drug Safety Communication: Serious allergic reactions reported with the use of Saphris (asenapine maleate). 2011. http://www.fda.gov/Drugs/DrugSafety/ucm270243.htm (accessed 6 September 2011).
- Australian Government Department of Health and Ageing. Public summary document for asenapine, Saphris July 2011. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-mtg-july-2011 (accessed 28 October 2011).
- 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;31:351–7. [PubMed]
- Van de Wetering-Krebbers SF, Jacobs PL, Kemperman GJ, et al. Metabolism and excretion of asenapine in healthy male subjects. Drug Metab Dispos 2011;39:580–90. [PubMed]