Asenapine (Page 7 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: In a lifetime carcinogenicity study in CD-1 mice asenapine was administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD of 10 mg twice daily. The incidence of malignant lymphomas was increased in female mice, with a no-effect dose resulting in plasma levels estimated to be 1.5 times those in humans receiving the MRHD. The mouse strain used has a high and variable incidence of malignant lymphomas, and the significance of these results to humans is unknown. There were no increases in other tumor types in female mice. In male mice, there were no increases in any tumor type.

In a lifetime carcinogenicity study in Sprague-Dawley rats, asenapine did not cause any increases in tumors when administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD.

Mutagenesis: No evidence for genotoxic potential of asenapine was found in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assays in human lymphocytes, the in vitro sister chromatid exchange assay in rabbit lymphocytes, or the in vivo micronucleus assay in rats.

Impairment of Fertility: Asenapine did not impair fertility in rats when tested at doses up to 11 mg/kg twice daily given orally. This dose is 10 times the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/m2 basis.

14 CLINICAL STUDIES

Efficacy of asenapine sublingual tablets was established in the following trials:

  • Two fixed-dose, short-term trials and one flexible-dose, maintenance trial in adult patients with schizophrenia as monotherapy [see Clinical Studies (14.1)]
  • One fixed-dose and two flexible-dose, short-term trials of monotherapy in adults with manic or mixed episodes associated with bipolar I disorder [see Clinical Studies (14.2)]
  • One flexible-dose, maintenance trial of monotherapy in adults with bipolar I disorder [see Clinical Studies (14.2)]
  • One fixed-dose, short term trial of monotherapy in children (10 to 17 years) with manic or mixed episodes associated with bipolar I disorder [see Clinical Studies (14.2) ]
  • One flexible-dose, short-term trial in adult patients with manic or mixed episode associated with bipolar I disorder as adjunctive treatment to lithium or valproate [see Clinical Studies (14.2) ]

14.1 Schizophrenia

The efficacy of asenapine sublingual tablets in the treatment of schizophrenia in adults was evaluated in three fixed-dose, short-term (6 week), randomized, double-blind, placebo-controlled, and active-controlled (haloperidol, risperidone, and olanzapine) trials of adult patients who met DSM-IV criteria for schizophrenia and were having an acute exacerbation of their schizophrenic illness. In two of the three trials asenapine sublingual tablets demonstrated superior efficacy to placebo. In a third trial, asenapine sublingual tablets could not be distinguished from placebo; however, an active control in that trial was superior to placebo.

In the two positive trials for asenapine sublingual tablets, the primary efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The primary endpoint was change from baseline to endpoint on the PANSS total score. The results of the asenapine sublingual tablets trials in schizophrenia follow:

In trial 1, a 6-week trial (n=174), comparing asenapine sublingual tablets (5 mg twice daily) to placebo, asenapine sublingual tablets 5 mg twice daily was statistically superior to placebo on the PANSS total score (Trial 1 in Table 13).

In trial 2, a 6-week trial (n=448), comparing two fixed doses of asenapine sublingual tablets (5 mg and 10 mg twice daily) to placebo, asenapine sublingual tablets 5 mg twice daily was statistically superior to placebo on the PANSS total score. Asenapine sublingual tablets 10 mg twice daily showed no added benefit compared to 5 mg twice daily and was not significantly different from placebo (Trial 2 in Table 13).

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

Table 13: Short-Term Schizophrenia Trials Establishing Efficacy in Adults
Trial NumberTreatment GroupPrimary Efficacy Measure: PANSS Total Score
Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Difference * (95% CI)
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons.
*
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses that are demonstrated to be effective.
Trial 1Asenapine Sublingual Tablets 5 mg twice daily96.5 (16.4)-14.4 (2.6)-9.7 (-17.6, -1.8)
Placebo92.4 (14.9)-4.6 (2.5)
Trial 2Asenapine Sublingual Tablets 5 mg twice daily89.2 (12.0)-16.2 (1.7)-5.5 (-10.7, -0.2)
Asenapine Sublingual Tablets 10 mg twice daily89.1 (12.9)-14.9 (1.7)-4.1 (-9.4, 1.2)
Placebo88.9 (11.7)-10.7 (1.6)

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 mg twice daily for 1 week and then titrated up to 10 mg twice daily. A total of 700 patients entered open-label treatment with asenapine sublingual tablets for a period of 26 weeks. Of these, a total of 386 patients who met pre-specified criteria for continued stability (mean length of stabilization was 22 weeks) were randomized to a double-blind, placebo-controlled, randomized withdrawal phase. Asenapine sublingual tablets was statistically superior to placebo in time to relapse or impending relapse defined as increase in PANSS ≥20% from baseline and a Clinical Global Impression–Severity of Illness (CGI-S) score ≥4 (at least 2 days within 1 week) or PANSS score ≥5 on “hostility” or “uncooperativeness” items and CGI-S score ≥4 (≥2 days within a week), or PANSS score ≥5 on any two of the following items: “unusual thought content,” “conceptual disorganization,” or “hallucinatory behavior” items, and CGI-S score ≥4 (≥2 days within 1 week) or investigator judgment of worsening symptoms or increased risk of violence to self (including suicide) or other persons. The Kaplan-Meier curves of the time to relapse or impending relapse during the double-blind, placebo-controlled, randomized withdrawal phase of this trial for asenapine sublingual tablets and placebo are shown in Figure 4.

Figure 4: Kaplan-Meier Estimation of Percent Relapse/Impending Relapse for Asenapine Sublingual Tablets and placebo

Figure 4
(click image for full-size original)

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