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Saphris (Asenapine Maleate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

SAPHRIS is a psychotropic agent that is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1). Its molecular formula is C17H16ClNO•C4H4O4 and its molecular weight is 401.84 (free base: 285.8). The chemical structure is:

Asenapine is a white to off-white powder.

SAPHRIS is supplied for sublingual administration in tablets containing 5-mg or 10-mg asenapine; inactive ingredients include gelatin and mannitol.

SAPHRIS, black cherry flavor, is supplied for sublingual administration in tablets containing 5-mg or 10-mg asenapine; inactive ingredients include gelatin, mannitol, sucralose, and black cherry flavor.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of asenapine, as with other drugs having efficacy in schizophrenia and bipolar disorder, is unknown. It has been suggested that the efficacy of asenapine in schizophrenia is mediated through a combination of antagonist activity at D2 and 5-HT2A receptors.

Pharmacodynamics

Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors (Ki values of 2.5, 4.0, 0.06, 0.16, 0.03, 1.6, 0.25, and 0.13 nM), dopamine D2, D3, D4, and D1 receptors (Ki values of 1.3, 0.42, 1.1, and 1.4 nM), α1 and α2-adrenergic receptors (Ki values of 1.2 and 1.2 nM), and histamine H1 receptors (Ki value 1.0 nM), and moderate affinity for H2 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 M1).

Pharmacokinetics

Following a single 5-mg dose of SAPHRIS, the mean Cmax was approximately 4 ng/mL and was observed at a mean tmax of 1 hour. Elimination of asenapine is primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). Following an initial more rapid distribution phase, the mean terminal half-life is approximately 24 hrs. With multiple-dose twice-daily dosing, steady-state is attained within 3 days. Overall, steady-state asenapine pharmacokinetics are similar to single-dose pharmacokinetics.

Absorption: Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations occurring within 0.5 to 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is 35%. Increasing the dose from 5 mg to 10 mg twice daily (a two-fold increase) results in less than linear (1.7 times) increases in both the extent of exposure and maximum concentration. The absolute bioavailability of asenapine when swallowed is low (<2% with an oral tablet formulation).

The intake of water several (2 or 5) minutes after asenapine administration resulted in decreased asenapine exposure. Therefore, eating and drinking should be avoided for 10 minutes after administration [see Dosage and Administration].

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 α1-acid glycoprotein.

Metabolism and Elimination: Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) are the primary metabolic pathways for asenapine.

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. Following an initial more rapid distribution phase, the terminal half life of asenapine is approximately 24 hours. Steady-state concentrations of asenapine are reached within 3 days of twice daily dosing.

After administration of a single dose of [14C]-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. SAPHRIS activity is primarily due to the parent drug.

In vitro studies indicate that asenapine is a substrate for UGT1A4, CYP1A2 and to a lesser extent CYP3A4 and CYP2D6. Asenapine is a weak inhibitor of CYP2D6. Asenapine does not cause induction of CYP1A2 or CYP3A4 activities in cultured human hepatocytes. Coadministration of asenapine with known inhibitors, inducers or substrates of these metabolic pathways has been studied in a number of drug-drug interaction studies [see Drug Interactions (7) ].

Smoking: A population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, had no effect on the clearance of asenapine in smokers. In a crossover study in which 24 healthy male subjects (who were smokers) were administered a single 5-mg sublingual dose, concomitant smoking had no effect on the pharmacokinetics of asenapine.

Food: A crossover study in 26 healthy male subjects was performed to evaluate the effect of food on the pharmacokinetics of a single 5-mg dose of asenapine. Consumption of food immediately prior to sublingual administration decreased asenapine exposure by 20%; consumption of food 4 hours after sublingual administration decreased asenapine exposure by about 10%. These effects are probably due to increased hepatic blood flow.

In clinical trials establishing the efficacy and safety of SAPHRIS, patients were instructed to avoid eating for 10 minutes following sublingual dosing. There were no other restrictions with regard to the timing of meals in these trials [see Dosage and Administration and Patient Counseling Information].

Water: In clinical trials establishing the efficacy and safety of SAPHRIS, patients were instructed to avoid drinking for 10 minutes following sublingual dosing. The effect of water administration following 10-mg sublingual SAPHRIS dosing was studied at different time points of 2, 5, 10, and 30 minutes in 15 healthy male subjects. The exposure of asenapine following administration of water 10 minutes after sublingual dosing was equivalent to that when water was administered 30 minutes after dosing. Reduced exposure to asenapine was observed following water administration at 2 minutes (19% decrease) and 5 minutes (10% decrease) [see Dosage and Administration and Patient Counseling Information] .

Special Populations:

Hepatic Impairment: The effect of decreased hepatic function on the pharmacokinetics of asenapine, administered as a single 5-mg sublingual dose, was studied in 30 subjects (8 each in those with normal hepatic function and Child-Pugh A and B groups, and 6 in the Child-Pugh C group). In subjects with mild or moderate hepatic impairment (Child-Pugh A or B), asenapine exposure was 12% higher than that in subjects with normal hepatic function, indicating that dosage adjustment is not required for these subjects. In subjects with severe hepatic impairment, asenapine exposures were on average 7 times higher than the exposures of those in subjects with normal hepatic function. Thus, SAPHRIS is not recommended in patients with severe hepatic impairment (Child-Pugh C) [see Dosage in Specific Populations and Use in Specific Populations and Warnings and Precautions].

Renal Impairment: The effect of decreased renal function on the pharmacokinetics of asenapine was studied in subjects with mildly (creatinine clearance (CrCl) 51 to 80 mL/min; N=8), moderately (CrCl 30 to 50 mL/min; N=8), and severely (CrCl less than 30 mL/min but not on dialysis; N=8) impaired renal function and compared to normal subjects (CrCl greater than 80 mL/min; N=8). The exposure of asenapine following a single dose of 5 mg was similar among subjects with varying degrees of renal impairment and subjects with normal renal function. Dosage adjustment based upon degree of renal impairment is not required. The effect of renal function on the excretion of other metabolites and the effect of dialysis on the pharmacokinetics of asenapine has not been studied [see Use in Specific Populations].

Geriatric Patients: In elderly patients (N=96) with psychosis (65-85 years of age), asenapine exposure (AUC) was on average 40% higher compared to younger adult patients. No dosage adjustment is necessary. In a population pharmacokinetic analysis, a decrease in clearance with increasing age was observed, implying a 30% higher exposure in elderly as compared to adult patients [see Use in Specific Populations].

Gender: The potential difference in asenapine pharmacokinetics between males and females was not studied in a dedicated trial. In a population pharmacokinetic analysis, no significant differences between genders were observed.

Race: In a population pharmacokinetic analysis, no effect of race on asenapine concentrations was observed. In a dedicated study, the pharmacokinetics of SAPHRIS were similar in Caucasian and Japanese subjects.

NONCLINICAL TOXICOLOGY

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.

CLINICAL STUDIES

Schizophrenia

The efficacy of SAPHRIS 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 SAPHRIS demonstrated superior efficacy to placebo. In a third trial, SAPHRIS could not be distinguished from placebo; however, an active control in that trial was superior to placebo.

In the two positive trials for SAPHRIS, the primary efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS), which assesses the symptoms of schizophrenia. The primary endpoint was change from baseline to endpoint on the PANSS total score. The results of the SAPHRIS trials in schizophrenia follow:

In trial 1, a 6-week trial (n=174), comparing SAPHRIS (5 mg twice daily) to placebo, SAPHRIS 5 mg twice daily was statistically superior to placebo on the PANSS total score.

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

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender 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. A total of 700 patients entered open-label treatment with SAPHRIS 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. SAPHRIS 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 SAPHRIS and placebo are shown in Figure 1.

Bipolar Disorder

Monotherapy: The efficacy of SAPHRIS 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). Patients were also assessed on the Clinical Global Impression – Bipolar (CGI-BP) scale. In both trials, all patients randomized to SAPHRIS 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. SAPHRIS was statistically superior to placebo on the YMRS total score and the CGI-BP Severity of Illness score (mania) in both studies.

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

Adjunctive Therapy: The efficacy of SAPHRIS 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 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. SAPHRIS 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.

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