The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.
Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.
In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.
Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.10
Tolerability in clinical trials
Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:11
- 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
- 486 subjects were treated for at least 24 weeks
- 293 subjects were treated for at least 52 weeks.
Overall, asenapine was well tolerated (Table 3).11 The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.
Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.
Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.
In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.3 Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.
In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.3 In both groups, the greatest weight increase occurred in subjects with body mass index <23.
There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.
Table 3
Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo
| Schizophrenia | Bipolar disorder (mania/mixed) | |||||
|---|---|---|---|---|---|---|
| Adverse effect | Placebo (n=378) | Asenapine, 5 mg bid (n=274) | Asenapine, 10 mg bid (n=208) | Asenapine, 5 or 10 mg bid (n=572) | Placebo (n=203) | Asenapine, 5 or 10 mg bid (n=379) |
| Oral hypoesthesia | 1 | 6 | 7 | 5 | <1 | 4 |
| Weight gain | <1 | 2 | 2 | 3 | <1 | 5 |
| Increased appetite | <1 | 3 | 0 | 2 | 1 | 4 |
| Anxiety | 2 | 4 | ||||
| Akathisia | 3 | 4 | 11 | 6 | 2 | 4 |
| Other EPS (excluding akathisia) | 7 | 9 | 12 | 10 | 2 | 7 |
| Insomnia | 13 | 16 | 15 | 15 | 5 | 6 |
| Somnolence | 7 | 15 | 13 | 13 | 6 | 24 |
| Dizziness | 4 | 7 | 3 | 5 | 3 | 11 |
| EPS: extrapyramidal symptoms | ||||||
| Source: Reference 11 | ||||||
Contraindications
There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:
- women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
- breast-feeding mothers
- patients with severe hepatic impairment (Child-Pugh C).
Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.