Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Saphris (Schering-Plough)
5 mg and 10 mg sublingual wafers
Approved indication: schizophrenia, bipolar disorder I
Australian Medicines Handbook section 18.2

Asenapine is an atypical antipsychotic drug. Like other drugs in the class it is an antagonist at dopamine D2 and serotonin 5HT2 receptors. It has little affinity for muscarinic receptors.

As asenapine has low oral bioavailability it has to be taken under the tongue. Sublingual administration increases the bioavailability to 35%. Patients will need to be instructed how to take asenapine. It is important that they do not chew or swallow the wafer. They should not eat or drink for 10 minutes after taking the sublingual wafer. Patients may complain of a dry mouth or oral hypoaesthesia (asenapine has some anaesthetic effect).

As the drug is metabolised partly by the cytochrome P450 system (mainly 1A2) there is a potential for drug interactions. Apart from an interaction with fluvoxamine, few clinically significant interactions have been recognised. Most of the dose is metabolised with the metabolites appearing in urine or faeces. Asenapine is not recommended for patients with severe liver impairment.

Several short-term studies have shown that asenapine is more effective than a placebo for patients with schizophrenia. In one study 458 patients were randomised to take asenapine, 5 mg or 10 mg, haloperidol 4 mg or a placebo twice daily for six weeks. The total score on the Positive and Negative Syndrome Scale (PANSS) improved with haloperidol and asenapine 5 mg, but asenapine 10 mg had no advantage over placebo.1Another trial randomised 182 patients to take twice-daily doses of asenapine 5 mg, risperidone 3 mg or placebo. After six weeks the mean PANSS score with asenapine was significantly better than with placebo. Although there was improvement with risperidone it did not reach statistical significance.2

There are longer-term studies of asenapine in schizophrenia, but some are currently unpublished. In a 52-week study 1225 patients were randomised to take asenapine or olanzapine and 528 completed the trial. The change in PANSS score was significantly greater with olanzapine.3However, asenapine and olanzapine were not significantly different from each other in a 26-week study of 481 patients with predominantly negative symptoms.

Asenapine has also been evaluated in bipolar I disorder. It was studied with olanzapine and placebo in a trial of 489 patients experiencing mania or mixed episodes. The mean total daily doses used to control the patients' symptoms were asenapine 18 mg and olanzapine 16 mg. After three weeks the patients taking the active drugs had significantly better scores on the Young Mania Rating Scale (YMRS), than those taking placebo. This superiority was seen from the second day of treatment.4A similar trial involving 488 patients also found that both asenapine and olanzapine reduced the scores on the YMRS rating scale compared to placebo. Post hoc analysis suggested an advantage for olanzapine. The response and remission rates for asenapine were not significantly greater than with placebo after three weeks.5

Patients who completed the three-week trials could continue treatment for a further nine weeks. Those who had taken a placebo were switched to asenapine. After 12 weeks asenapine and olanzapine had produced similar changes in the YMRS. The response and remission rates were 77% and 75% with asenapine and 82% and 79% with olanzapine.6

Following the extension study, 218 patients continued treatment in a study primarily aimed to collect safety data. After another 40 weeks, efficacy appeared to be maintained with asenapine and olanzapine.7

Asenapine has also been studied as an adjunct to treatment with lithium or valproate for patients with a manic or mixed bipolar I episode. A total of 326 patients were randomised to add asenapine or a placebo. After three weeks there was a small difference in the YMRS rating scale, and the response and remission rates with asenapine (34% and 34%) were higher than with placebo (27% and 22%). In the intention to treat population, 25% of the asenapine group and 20% of the placebo group had responded by 12 weeks.

Several thousand patients have taken asenapine in clinical trials, but some of the exposures were short-term. Many patients dropped out of the trials, for example because of an inadequate response, but only 9% of the patients taking asenapine in the schizophrenia trials and 10% in the bipolar trials withdrew because of adverse reactions. This was similar to the discontinuation rates in the placebo groups. Asenapine has adverse effects similar to those of other antipsychotic drugs, for example somnolence, akathisia and extrapyramidal symptoms. In the schizophrenia trials, extrapyramidal symptoms were less frequent with asenapine than with haloperidol.1In six weeks patients taking asenapine put on an average of 0.47 kg, but this was less than the average gain of 1.6 kg with risperidone.2

As asenapine has some antagonist activity at adrenergic receptors it can cause orthostatic hypotension. This may also explain some of the complaints of dizziness.

Like other antipsychotic drugs, asenapine has the potential to cause neuroleptic malignant syndrome, tardive dyskinesia, hyperprolactinaemia and seizures. The drug should not be used in elderly patients with dementia-related psychosis because of an increased risk of death. Patients will need to be monitored for possible metabolic adverse effects.

Successful treatment of schizophrenia requires the efficacy of an antipsychotic drug to be balanced against its adverse effects. While some adverse effects may be less frequent with asenapine than with other antipsychotic drugs, there are questions about its efficacy. The indication for schizophrenia was not approved in Europe as the balance of risk and benefit was considered to be negative.

Asenapine can be used for the treatment of manic or mixed episodes in patients with bipolar I disorder. Its long-term efficacy in preventing relapse is uncertain. While atypical antipsychotic drugs have a role in bipolar I disorder, it is unclear whether asenapine will be as effective as other drugs.

manufacturer declined to supply data

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.