Secuado Asenapine 7.6 mg/d Film, Extended Release, 7 pouches — NDC 68968-0174-7 (Billing 68968-0174-07)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of action of asenapine in schizophrenia is unclear. However, it’s efficacy in schizophrenia could be mediated through a combination of antagonist activity at D 2 and 5-HT 2A receptors.

12.2Pharmacodynamics Asenapine exhibits high affinity for serotonin 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5A , 5-H T6 and 5-HT 7 receptors (Ki values of 2.5, 2.7, 0.07, 0.18, 0.03, 1.6, 0.25, and 0.11nM, respectively), dopamine D 2A , D 2B , D 3 , D 4 , and D 1 receptors (Ki values of 1.3, 1.4, 0.42, 1.1, and 1.4 nM, respectively), adrenergic α 1A , α 2A , α 2B , and α 2C receptors (Ki values of 1.2, 1.2, 0.33 and 1.2 nM, respectively), and histamine H 1 receptors (Ki value 1.0 nM), and moderate affinity for H 2 receptors (Ki value of 6.2 nM).

In in vitro assays asenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors (e.g., Ki value of 8128 nM for M 1 ).

12.3Pharmacokinetics SECUADO has a different pharmacokinetic profile compared to sublingual asenapine. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during wear time (24 hours). Following SECUADO removal, the apparent elimination half-life is approximately 30 hours.

Absorption On average, approximately 60% of the asenapine is released from the transdermal system over 24 hours. Inter-individual variability for SECUADO as coefficient of variation (%CV) for the steady-state asenapine C max,ss , C min,ss , and AUC 0-tau,ss was generally about 20% to 30%. Asenapine PK at steady-state is dose-proportional in the dose range of 3.8 mg/24 hours to 7.6 mg/24 hours following application of SECUADO.

Steady-state plasma concentrations are achieved in about 72 hours after the first application of SECUADO. Peak to trough ratio is 1.5. Based on relative bioavailability and established dose proportionality, AUC for 3.8 mg/24 hours and 7.6 mg/24 hours was considered to be similar to that for sublingual asenapine 5 mg twice daily and 10 mg twice daily, respectively.

There is no effect on asenapine PK with regards to the application site (upper arm, upper back, abdomen, and hip area). Application of a heating pad on SECUADO for 8 hours led to a faster absorption rate (median t max about 8 hours) as compared with SECUADO without a heating pad (median t max about 16 hours). Mean asenapine exposure, calculated as partial AUC 0-8 , following SECUADO application, was about 3.9 times greater than that without a heating pad, indicating the apparent heat effect in absorption during the time period of heating pad application.

Distribution Asenapine is rapidly distributed and has a large volume of distribution (approximately 20-25 L/kg), indicating extensive extravascular distribution. Asenapine is highly bound (95%) to plasma proteins, including albumin and α 1 -acid glycoprotein. Elimination Asenapine is a high clearance drug with a clearance after intravenous administration of 52 L/h.

In this circumstance, hepatic clearance is influenced primarily by changes in liver blood flow rather than by changes in the intrinsic clearance, i.e., the metabolizing enzymatic activity Metabolism Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) are the primary metabolic pathways for asenapine. Excretion After administration of a single dose of [ 14 C]-labeled asenapine, about 90% of the dose was recovered; approximately 50% was recovered in urine, and 40% recovered in feces.

About 50% of the circulating species in plasma have been identified. The predominant species was asenapine N -glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. Pharmacological activity is primarily due to the parent drug.

Special Populations Exposures of asenapine in special populations for sublingual as… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism of action of asenapine in schizophrenia is unclear. However, it’s efficacy in schizophrenia could be mediated through a combination of antagonist activity at D 2 and 5-HT 2A receptors.

12.3Pharmacokinetics SECUADO has a different pharmacokinetic profile compared to sublingual asenapine. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during wear time (24 hours). Following SECUADO removal, the apparent elimination half-life is approximately 30 hours.

Absorption On average, approximately 60% of the asenapine is released from the transdermal system over 24 hours. Inter-individual variability for SECUADO as coefficient of variation (%CV) for the steady-state asenapine C max,ss , C min,ss , and AUC 0-tau,ss was generally about 20% to 30%. Asenapine PK at steady-state is dose-proportional in the dose range of 3.8 mg/24 hours to 7.6 mg/24 hours following application of SECUADO.

Steady-state plasma concentrations are achieved in about 72 hours after the first application of SECUADO. Peak to trough ratio is 1.5. Based on relative bioavailability and established dose proportionality, AUC for 3.8 mg/24 hours and 7.6 mg/24 hours was considered to be similar to that for sublingual asenapine 5 mg twice daily and 10 mg twice daily, respectively.

There is no effect on asenapine PK with regards to the application site (upper arm, upper back, abdomen, and hip area). Application of a heating pad on SECUADO for 8 hours led to a faster absorption rate (median t max about 8 hours) as compared with SECUADO without a heating pad (median t max about 16 hours). Mean asenapine exposure, calculated as partial AUC 0-8 , following SECUADO application, was about 3.9 times greater than that without a heating pad, indicating the apparent heat effect in absorption during the time period of heating pad application.

Distribution Asenapine is rapidly distributed and has a large volume of distribution (approximately 20-25 L/kg), indicating extensive extravascular distribution. Asenapine is highly bound (95%) to plasma proteins, including albumin and α 1 -acid glycoprotein. Elimination Asenapine is a high clearance drug with a clearance after intravenous administration of 52 L/h.

In this circumstance, hepatic clearance is influenced primarily by changes in liver blood flow rather than by changes in the intrinsic clearance, i.e., the metabolizing enzymatic activity Metabolism Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) are the primary metabolic pathways for asenapine. Excretion After administration of a single dose of [ 14 C]-labeled asenapine, about 90% of the dose was recovered; approximately 50% was recovered in urine, and 40% recovered in feces.

About 50% of the circulating species in plasma have been identified. The predominant species was asenapine N -glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. Pharmacological activity is primarily due to the parent drug.

Special Populations Exposures of asenapine in special populations for sublingual asenapine are summarized in Figure 1 . Based on population pharmacokinetic analysis for sublingual asenapine, no effects of sex, race, ethnicity (Japanese versus Caucasian), BMI, and smoking status on asenapine exposure were observed. Exposure in elderly patients is 30-40% higher as compared to adults.

Figure 1: Effect of Intrinsic Factors on Sublingual Asenapine Pharmacokinetics Drug Interaction Studies Effects of other drugs on the exposure of asenapine are summarized in Figure 2 . Marginal increase of asenapine exposure was observed when sublingual asenapine is used with fluvoxamine at 25 mg administered twice daily. However, the tested fluvoxamine dose was suboptimal.

Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure. Figure 2: Effect of Other Drugs on Asenapine Pharmacokinetics The effects of asenapine on the pharmacokinetics of other co-administered drugs are summarized in Figure 3 . Figure 3: Effect of Asenapine on Other Drug Pharmac… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Asenapine exhibits high affinity for serotonin 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5A , 5-H T6 and 5-HT 7 receptors (Ki values of 2.5, 2.7, 0.07, 0.18, 0.03, 1.6, 0.25, and 0.11nM, respectively), dopamine D 2A , D 2B , D 3 , D 4 , and D 1 receptors (Ki values of 1.3, 1.4, 0.42, 1.1, and 1.4 nM, respectively), adrenergic α 1A , α 2A , α 2B , and α 2C receptors (Ki values of 1.2, 1.2, 0.33 and 1.2 nM, respectively), and histamine H 1 receptors (Ki value 1.0 nM), and moderate affinity for H 2 receptors (Ki value of 6.2 nM).

In in vitro assays asenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors (e.g., Ki value of 8128 nM for M 1 ).

14 CLINICAL STUDIES The efficacy of SECUADO in the treatment of adult patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the sublingual formulation of asenapine. In addition, the efficacy of SECUADO was evaluated in a 6-week, fixed-dose, randomized, double-blind, and placebo-controlled trial (Study 1; NCT 02876900) of adult patients who met DSM-IV criteria for schizophrenia. In Study 1, the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) rating scales were used as the primary and key secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: 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.

CGI-S is a validated clinician-rated scale that measures the patient’s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale, based on the rater’s total clinical experience with this population. The primary endpoint was change from baseline in PANSS total score to Week 6. The change from baseline for SECUADO was compared to that for placebo.

The results of the trial are shown in Table 8 . The time course of efficacy is shown in Figure 4 . In the 6-week trial (n=607) comparing two fixed doses of SECUADO (3.8 mg/24 hours and 7.6 mg/24 hours) to placebo, both doses were statistically superior to placebo for both PANSS total score and CGI-S.

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex or race. Table 8: Primary Efficacy Results for Change from Baseline in PANSS Total Score Week 6 (Study 1) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. A negative value for the placebo subtracted difference represents improvement. *: Statistically significant after multiplicity adjustments.

Treatment Group Primary Efficacy Measure: PANSS Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) to Week 6 Placebo-subtracted Difference a (95% CI) SECUADO 3.8 mg/24 hours* 97.0 (9.78) -22.1 (1.2) -6.6 (-9.81, -3.40) SECUADO 7.6 mg/24 hours* 95.6 (8.68) -20.4 (1.2) -4.8 (-8.06, -1.64) Placebo 97.4 (10.07) -15.5 (1.2) -- Figure 4: Change from Baseline in PANSS Total Score Over Time (Weeks) in Patients with Schizophrenia (Study 1) Maintenance of Efficacy with Sublingual Asenapine Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose with sublingual asenapine (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 sublingual asenapine 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.

Sublingual asenapine 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 v… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 10.0 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.

In a 39-week study in minipigs, the asenapine transdermal system was administered at doses of 0.43 to 3.84 mg/kg asenapine, once every 24 hours. No significant dermal findings occurred at doses up to 17 times the MRHD of 12.8 mg transdermal asenapine daily for schizophrenia. 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 MRHD of 10 mg twice daily asenapine given sublingually on a mg/m 2 basis and 16.6 times the MRHD of 12.8 mg daily asenapine given transdermally on a mg/m 2 basis.

13.2Animal Toxicology and/or Pharmacology Transdermal administration of asenapine to rats, dogs and minipigs did not demonstrate any significant dermal findings when applied daily for 24 hours. Rats were treated for 26-weeks with percutaneous doses of asenapine (as free base) up to 1.42 mg/kg (1.3 times the MRHD of 12.8 mg transdermal asenapine as free base daily on a mg/kg basis), dogs were treated for 13-weeks with percutaneous doses of asenapine (as free base) up to 5.6 mg/kg (14.2 times the MRHD of 12.8 mg transdermal asenapine daily on mg/m 2 basis) and minipigs were treated for 39-weeks with percutaneous doses of asenapine (as free base) up to 3.84 mg/kg (17 times the MRHD of 12.8 mg transdermal asenapine [as free base] daily on mg/m 2 basis).