FANAPT Tablet Ref.[10297] Active ingredients: Iloperidone

Iloperidone acts as an antagonist with high (nM) affinity binding to serotonin 5-HT_2A, dopamine D₂ and D₃ receptors, and norepinephrine NE_α1 receptors (K_i values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). Iloperidone has moderate affinity for dopamine D₄, and serotonin 5-HT₆ and 5-HT₇ receptors (K_i values of 25, 43, and 22, nM respectively), and low affinity for the serotonin 5-HT_1A, dopamine D₁, and histamine H₁ receptors (K_i values of 168, 216, and 437 nM, respectively). Iloperidone has no appreciable affinity (K_i>1000 nM) for cholinergic muscarinic receptors. The affinity of iloperidone metabolite P88 is generally equal to or less than that of the parent compound, while the metabolite P95 only shows affinity for 5-HT_2A (K_i value of 3.91) and the NE_α1A, NE_α1B, NE_α1D, and NE_α2C receptors (K_i values of 4.7, 2.7, 8.8, and 4.7 nM respectively).

The pharmacokinetics of iloperidone is more than dose proportional. Steady-state concentrations are attained within 3 to 4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics.

Absorption

Iloperidone is well absorbed after administration of the tablet with time to peak plasma concentrations (T_max) occurring within 2 to 4 hours. The relative bioavailability of the tablet formulation compared to oral solution is 96%.

Effect of Food

Administration of iloperidone with a standard high-fat meal did not significantly affect the C_max or AUC of iloperidone, P88, or P95, but delayed T_max by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. FANAPT can be administered without regard to meals.

Distribution

Iloperidone has an apparent volume of distribution of 1340-2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is ~3% and of each metabolite (P88 and P95) it is ~8%.

Elimination

The observed mean elimination half-lives for iloperidone, P88, and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26, and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37, and 31 hours, respectively.

Iloperidone has an apparent clearance (clearance / bioavailability) of 47 to 102 L/h.

Metabolism

Elimination of iloperidone is mainly through hepatic metabolism. Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively.

Approximately 7% - 10% of Caucasians and 3% - 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive, or ultrarapid metabolizers.

Excretion

The bulk of the radioactive materials were recovered in the urine (mean 58.2% and 45.1% in EM and PM, respectively), with feces accounting for 19.9% (EM) to 22.1% (PM) of the dosed radioactivity.

Specific Populations

Patients with Renal Impairment

Renal impairment (creatinine clearance <30 mL/min) had minimal effect on C_max of iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 in any of the 3 analytes measured. AUC0–∞ was increased by 24%, decreased by 6%, and increased by 52% for iloperidone, P88 and P95, respectively, in subjects with renal impairment.

Patients with Hepatic Impairment

In adult subjects with mild hepatic impairment, no relevant difference in pharmacokinetics of iloperidone, P88 or P95 (total or unbound) was observed compared to healthy adult controls. In subjects with moderate hepatic impairment a higher (2-fold) and more variable free exposure to the active metabolites P88 was observed compared to healthy controls, whereas exposure to iloperidone and P95 was generally similar (less than 50% change compared to control). Studies with severe liver impaired subjects have not been conducted [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Effect of Smoking

Based on in vitro studies utilizing human liver enzymes, FANAPT is not a substrate for CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of FANAPT.

Drug Interactions Studies

CYP2D6 and CYP3A4 Inhibitors

The effects of fluoxetine and ketoconazole on the exposures of FANAPT, P88, and P95 are summarized in Figure 1.

Figure 1. Effect of CYP3A4 and CYP2D6 Inhibitors on the Pharmacokinetics of FANAPT and its Metabolites:

Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4 days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone to 19 healthy volunteers, ages 18-45 years, increased the area under the curve (AUC) of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied.

Fluoxetine: Coadministration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 healthy volunteers, ages 29-44 years, who were classified as CYP2D6 extensive metabolizers, increased the AUC of iloperidone and its metabolite P88, by about 2- to 3- fold, and decreased the AUC of its metabolite P95 by one-half.

Paroxetine: Coadministration of paroxetine (20 mg/day for 5-8 days), a potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 years resulted in increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6 fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half.

Paroxetine and Ketoconazole: Coadministration of paroxetine (20 mg once daily for 10 days), a CYP2D6 inhibitor, and ketoconazole (200 mg twice daily) with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 years resulted in a 1.4 fold increase in steady-state concentrations of iloperidone and its metabolite P88 and a 1.4 fold decrease in the P95 in the presence of paroxetine.

Dextromethorphan: A study in healthy volunteers showed that changes in the pharmacokinetics of dextromethorphan (80 mg dose) when a 3 mg dose of iloperidone was co-administered resulted in a 17% increase in total exposure and a 26% increase in the maximum plasma concentrations C_max of dextromethorphan. Thus, an interaction between iloperidone and other CYP2D6 substrates is unlikely.

Fluoxetine: A single 3 mg dose of iloperidone had no effect on the pharmacokinetics of fluoxetine (20 mg twice daily).

Midazolam (a sensitive CYP 3A4 substrate): A study in patients with schizophrenia showed a less than 50% increase in midazolam total exposure at iloperidone steady state (14 days of oral dosing at up to 10 mg iloperidone twice daily) and no effect on midazolam C_max. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.

In Vitro Studies

Based on the in vitro data, iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.

In vitro studies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs metabolized by the following cytochrome P450 isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, or CYP2E1. Furthermore, in vitro studies in human liver microsomes showed that iloperidone does not have enzyme inducing properties, specifically for the following cytochrome P450 isozymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.

Transporter Interaction: Iloperidone and P88 are not substrates of P-gp and iloperidone is a weak P-gp inhibitor.

CYP2D6 Poor Metabolizer (PM)

The gene encoding CYP2D6 has polymorphisms that impact protein function. CYP2D6 poor metabolizers are individuals with two non-functioning alleles, resulting in no enzyme activity. P harmacokinetic data from CYP2D6 poor metabolizers (n=8) treated with iloperidone demonstrated an increase in the AUC of iloperidone and its metabolite P88 by 47% and 85%, respectively and decrease the AUC of metabolite P95 by 85% compared to normal metabolizers (n=18) [see Dosage and Administration (2.2)].

Approximately 7% of White populations, 2% of Asian populations, and 2% of African-American populations are poor metabolizers.

Carcinogenesis

Lifetime carcinogenicity studies were conducted in CD-1 mice and Sprague Dawley rats. Iloperidone was administered orally at doses of 2.5, 5.0, and 10 mg/kg/day to CD-1 mice and 4, 8, and 16 mg/kg/day to Sprague Dawley rats (0.5, 1.0, and 2.0 times and 1.6, 3.2, and 6.5 times, respectively, the MRHD of 24 mg/day on a mg/m² basis). There was an increased incidence of malignant mammary gland tumors in female mice treated with the lowest dose (2.5 mg/kg/day) only. There were no treatment-related increases in neoplasia in rats.

The carcinogenic potential of the iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present at significant amounts in mice or rats, was assessed in a lifetime carcinogenicity study in Wistar rats at oral doses of 25, 75, and 200 mg/kg/day in males and 50, 150, and 250 (reduced from 400) mg/kg/day in females. Drug-related neoplastic changes occurred in males, in the pituitary gland (pars distalis adenoma) at all doses and in the pancreas (islet cell adenoma) at the high dose. Plasma levels of P95 (AUC) in males at the tested doses (25, 75, and 200 mg/kg/day) were approximately 0.4, 3, and 23 times, respectively, the human exposure to P95 at the MRHD of iloperidone.

Mutagenesis

Iloperidone was negative in the Ames test and in the in vivo mouse bone marrow and rat liver micronucleus tests. Iloperidone induced chromosomal aberrations in Chinese Hamster Ovary (CHO) cells in vitro at concentrations which also caused some cytotoxicity.

The iloperidone metabolite P95 was negative in the Ames test, the V79 chromosome aberration test, and an in vivo mouse bone marrow micronucleus test.

Impairment of Fertility

Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. The no-effect dose was 4 mg/kg, which is 1.6 times the MRHD of 24 mg/day on a mg/m² basis.

14.1 Schizophrenia

The efficacy of FANAPT in the treatment of schizophrenia was supported by 2 placebo- and active-controlled short-term (4- and 6-week) trials and one long-term placebo-controlled randomized withdrawal trial. All trials enrolled patients who met the DSM-III/IV criteria for schizophrenia.

Three instruments were used for assessing psychiatric signs and symptoms in these studies. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) are both multi-item inventories of general psychopathology usually used to evaluate the effects of drug treatment in schizophrenia. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

Study 1, a 6-week, placebo-controlled trial (n=706), involved 2 flexible dose ranges of FANAPT (12 mg to 16 mg/day or 20 mg to 24 mg/day) compared to placebo and an active control (risperidone). For the 12 mg to 16 mg/day group, the titration schedule of FANAPT was 1 mg twice daily on Days 1 and 2, 2 mg twice daily on Days 3 and 4, 4 mg twice daily on Days 5 and 6, and 6 mg twice daily on Day 7. For the 20 mg to 24 mg/day group, the titration schedule of FANAPT was 1 mg twice daily on Day 1, 2 mg twice daily on Day 2, 4 mg twice daily on Day 3, 6 mg twice daily on Days 4 and 5, 8 mg twice daily on Day 6, and 10 mg twice daily on Day 7. The primary endpoint was change from baseline on the BPRS total score at the end of treatment (Day 42). Both the 12 mg to 16 mg/day and the 20 mg to 24 mg/day dose ranges of FANAPT were superior to placebo on the BPRS total score. The active control antipsychotic drug appeared to be superior to FANAPT in this trial within the first 2 weeks, a finding that may in part be explained by the more rapid titration that was possible for that drug. In patients in this study who remained on treatment for at least 2 weeks, iloperidone appeared to have had comparable efficacy to the active control.

Study 2 (NCT00254202), a 4-week, placebo-controlled trial (n=604), involved one fixed-dose of FANAPT (24 mg/day) compared to placebo and an active control (ziprasidone). The titration schedule for this study was similar to that for the 6-week study. This study involved titration of FANAPT starting at 1 mg twice daily on Day 1 and increasing to 2, 4, 6, 8, 10, and 12 mg twice daily on Days 2, 3, 4, 5, 6, and 7. The primary endpoint was change from baseline on the PANSS total score at the end of treatment (Day 28). The 24 mg/day FANAPT dose was superior to placebo in the PANSS total score. FANAPT appeared to have similar efficacy to the active control drug which also needed a slow titration to the target dose.

In a longer-term trial (Study 3; NCT01291511), clinically stable adult outpatients (n=303) meeting DSM-IV criteria for schizophrenia who remained stable following 12 weeks of open-label treatment with flexible doses of FANAPT (8 mg to 24 mg/day administered as twice daily doses) were randomized to placebo or to continue on their current FANAPT dose (8 mg to 24 mg/day administered as twice daily doses) for observation for possible relapse during the double-blind relapse prevention phase. Stabilization during the open-label phase was defined as being on an established dose of FANAPT that was unchanged due to efficacy in the 4 weeks prior to randomization, having CGI-Severity score of ≤4 and PANSS total score ≤70, a score of ≤4 on each of the following individual PANSS items (P1-delusions, P2-conceptual disorganization, P3-hallucinatory behavior, P6-suspiciousness/persecution, P7-hostility, or G8-uncooperativeness), and no hospitalization or increase in level of care to treat exacerbations. Relapse or impending relapse during the double-blind relapse prevention phase was defined as any of the following: hospitalization due to worsening of schizophrenia, increase (worsening) of the PANSS total score ≥30%, CGI-Improvement score ≥6, patient had suicidal, homicidal, or aggressive behavior, or need for any other antipsychotic medication.

Figure 2. Kaplan Meier Estimation of Percent Relapse/Impending Relapse (Study 3):

Based on the interim analysis, an independent data monitoring committee decided the study should be discontinued early due to evidence of efficacy. Based on results from the interim analysis, which were confirmed by the final analysis dataset, patients treated with FANAPT experienced a statistically significant longer time to relapse or impending relapse than patients who received placebo. Figure 2 displays the estimated cumulative proportion of patients with relapse or impending relapse based on the final data set.

14.2 Manic or Mixed Episodes Associated with Bipolar I Disorder

The efficacy of FANAPT in the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults was supported by one multicenter, randomized, double-blind, placebo-controlled study that enrolled patients who met the DSM-5 criteria for bipolar I disorder, manic or mixed type (Study 1; NCT04819776). Demographic and baseline characteristics were similar for the FANAPT and placebo groups. Median age was 46 (range 18 to 65). 45% were female, 64% were White, and 28% were Black or African-American.

Manic symptoms were assessed with the Young Mania Rating Scale (YMRS). The YMRS is an 11-item clinician rated scale traditionally used to assess the degree of manic symptomatology. YMRS total scores may range from 0 to 60 with a higher score reflecting greater severity.

A 4-week, placebo-controlled trial (n=392) involved one fixed-dose of FANAPT (24 mg/day) compared to placebo. The primary endpoint was change in YMRS total score from baseline to Day 28. The 24 mg/day dose of FANAPT was superior to placebo on the primary endpoint. Examination of subgroups did not reveal clear evidence of differential responsiveness on the basis of age, sex, or race.

The results of the study are shown in Table 8. The LS mean changes from baseline in YMRS total score are shown in Figure 3.

Table 8. Primary Efficacy Results for Change from Baseline in YMRS Total Score in the Acute Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder in Adults (Study 1):

ITT = intent-to-treat, YMRS = Young Mania Rating Scale, LS mean = least Squares mean, SD = standard deviation, SE = standard error a Difference (drug minus placebo) in least-squares mean change from baseline
^* Dose was superior to placebo

Figure 3. Change from Baseline in YMRS Total Score by Study Visit (Study 1):