Monotherapy

Adults: The efficacy of asenapine sublingual tablets in the treatment of acute mania was established in two similarly designed 3-week, randomized, double-blind, placebo-controlled, and active-controlled (olanzapine) trials of adult patients who met DSM-IV criteria for Bipolar I Disorder with an acute manic or mixed episode with or without psychotic features.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). Patients were also assessed on the Clinical Global Impression – Bipolar (CGI-BP) scale. In both trials, all patients randomized to asenapine sublingual tablets were initially administered 10 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. Ninety percent of patients remained on the 10 mg twice daily dose. Asenapine sublingual tablets was statistically superior to placebo on the YMRS total score and the CGI-BP Severity of Illness score (mania) in both studies (Trials 1 and 2 in Table 14).

In another 3-week, randomized, double-blind, placebo-controlled trial (n=359), comparing two fixed doses of asenapine sublingual tablets (5 mg and 10 mg twice daily) to placebo, both doses were statistically superior to placebo on the YMRS total score and CGI-BP Severity of Illness overall score. (Trial 3 in Table 14).

An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, or race.

Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. All patients were initially administered 5 or 10 mg twice daily, and the option to titrate down to 5 mg twice daily was provided based on tolerability. A total of 549 patients entered open-label treatment with asenapine sublingual tablets for a period of 12 to 16 weeks. Of these, a total of 252 patients who met pre-specified criteria for continued stability were randomized to and treated in a double-blind, placebo-controlled, randomized withdrawal phase. Asenapine sublingual tablets was statistically superior to placebo in time to relapse defined as 1) YMRS or MADRS score ≥ 16; 2) requirement or initiation of any non-study medication to treat mixed, manic, or depressive symptoms, including an antipsychotic, antidepressant, or mood-stabilizing agent; 3) requirement or initiation of psychiatric hospitalization; 4) investigator judgment to discontinue the study due to a mood event. The Kaplan-Meier curves of the time to relapse during the double-blind, placebo-controlled, randomized withdrawal phase of this trial for asenapine sublingual tablets and placebo are shown in Figure 5.

Figure 5: Kaplan-Meier Estimation of Percent Relapse for Asenapine Sublingual Tablets and Placebo

Pediatric patients: The efficacy of asenapine sublingual tablets in the treatment of acute mania was established in a single, 3-week, placebo-controlled, double-blind trial of 403 pediatric patients 10 to 17 years of age, of whom 302 patients received asenapine sublingual tablets at fixed doses of 2.5 mg, 5 mg and 10 mg twice daily. All patients were started on 2.5 mg twice daily. For those assigned to 5 mg twice daily, the dose was increased to 5 mg twice daily after 3 days. For those assigned to 10 mg twice daily, the dose was increased from 2.5 to 5 mg twice daily after 3 days, and then to 10 mg twice daily after 3 additional days.

Asenapine sublingual tablets was statistically superior to placebo in improving YMRS total score and the CGI-BP Severity of Illness overall score as measured by the change from baseline to week 3 (Trial 3 Pediatric in Table 14). An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, and race.

Adjunctive Therapy: The efficacy of asenapine sublingual tablets as an adjunctive therapy in acute mania was established in a 12-week, placebo-controlled trial with a 3-week primary efficacy endpoint involving 326 adult patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially responsive to lithium or valproate monotherapy after at least 2 weeks of treatment. All patients randomized to asenapine sublingual tablets were initially administered 5 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. Asenapine was statistically superior to placebo in the reduction of manic symptoms (measured by the YMRS total score) as an adjunctive therapy to lithium or valproate monotherapy at Week 3 (Trial 5 Adjunctive in Table 14).