Fanapt

Indications and Usage (

Dose and Administration (

Warnings and Precautions (

Warnings and Precautions (

Warnings and Precautions, Suicide (

FANAPT^® is indicated for:

• Treatment of schizophrenia in adults
  [see

  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 2displays the estimated cumulative proportion of patients with relapse or impending relapse based on the final data set.

  ].
• Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults
  [see

  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 aDifference (drug minus placebo) in least-squares mean change from baseline *Dose was superior to placebo
  Study Number	Treatment Group (# ITT patients)	Primary Efficacy Endpoint: Change from Baseline to Day 28 in YMRS Total Score
  		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-substracted Differencea (95% CI)
  1	FANAPT (24 mg/day)* (n=198)	29.2 (5.27)	-14.0 (0.64)	-4.0 (-5.70, -2.25)
  	Placebo (n=194)	28.8 (4.64)	-10.0 (0.63)

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

  

  ]
  .

• Administer FANAPT orally twice daily without regard to meals. (
  2.1 Recommended Dosage

  Titrate FANAPT to avoid orthostatic hypotension

  [see Warnings and Precautions (5.7)]

  .

  Administer FANAPT orally with or without food.

  Table 1includes dosage recommendations for FANAPT for the treatment of schizophrenia and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

  Table 1: Dosage Recommendations for FANAPT in Adults for the Treatment of Schizophrenia or
  
  Acute Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder

  Indication and Population	Titration schedule							Recommended Dosage
  	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
  Schizophrenia	1mg twice daily	2 mg twice daily	4 mg twice daily	6 mg twice daily	8 mg twice daily	10 mg twice daily	12 mg twice daily	6 mg to 12 mg twice daily
  Bipolar I Disorder Manic or Mixed Episodes	1 mg twice daily	3 mg twice daily	6 mg twice daily	9 mg twice daily	12 mg twice daily	Titration complete		12 mg twice daily
  )
• Titrate the dosage of FANAPT to avoid orthostatic hypotension. See Full Prescribing Information for titration schedule. (
  2.1 Recommended Dosage

  Titrate FANAPT to avoid orthostatic hypotension

  [see Warnings and Precautions (5.7)]

  .

  Administer FANAPT orally with or without food.

  Table 1includes dosage recommendations for FANAPT for the treatment of schizophrenia and the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

  Table 1: Dosage Recommendations for FANAPT in Adults for the Treatment of Schizophrenia or
  
  Acute Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder

  Indication and Population	Titration schedule							Recommended Dosage
  	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
  Schizophrenia	1mg twice daily	2 mg twice daily	4 mg twice daily	6 mg twice daily	8 mg twice daily	10 mg twice daily	12 mg twice daily	6 mg to 12 mg twice daily
  Bipolar I Disorder Manic or Mixed Episodes	1 mg twice daily	3 mg twice daily	6 mg twice daily	9 mg twice daily	12 mg twice daily	Titration complete		12 mg twice daily
  )
• Recommended Dosage:

• CYP2D6 Poor Metabolizers: See Full Prescribing Information for titration schedule and recommended dosage. (
  2.2 Dosage Recommendations for Use in Patients Who Are Known CYP2D6 Poor Metabolizers

  Reduce the dose of FANAPT by one-half for CYP2D6 poor metabolizers

  [see Clinical Pharmacology (12.3, 12.5)]

  . Table 2includes dosage recommendations for FANAPT in adults who are CYP2D6 poor metabolizers.

  Table 2: Dosage Recommendations for FANAPT in Adults with Schizophrenia or Bipolar I Disorder
  
  Who are CYP2D6 Poor Metabolizers

  Indication and Population	Titration schedule							Recommended Dosage
  	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
  Schizophrenia	1mg twice daily	2 mg twice daily	4 mg twice daily	6 mg twice daily	Titration complete			3 mg to 6 mg twice daily
  Bipolar I Disorder Manic or Mixed Episodes	1 mg twice daily	3 mg twice daily	6 mg twice daily	Titration complete				6 mg twice daily
  )

FANAPT tablets are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. The tablets are white, round, flat, beveled-edged and identified with a logo “” debossed on one side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side.

• Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FANAPT during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit

  http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/

  .

  Risk Summary

  Neonates whose mothers are exposed to antipsychotic drugs, including FANAPT, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery

  [see Clinical Considerations]

  . The limited available data with FANAPT in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Iloperidone was not teratogenic when administered orally to pregnant rats during organogenesis at doses up to 26 times the maximum recommended human dose of 24 mg/day on mg/m²basis. However, it prolonged the duration of pregnancy and parturition, increased still births, early intrauterine deaths, increased incidence of developmental delays, and decreased post-partum pup survival. Iloperidone was not teratogenic when administered orally to pregnant rabbits during organogenesis at doses up to 20-times the MRHD on mg/m²basis. However, it increased early intrauterine deaths and decreased fetal viability at term at the highest dose which was also a maternally toxic dose

  [see Data]

  .

  The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

  Data

  Animal Data

  In an embryo-fetal development study, pregnant rats were given 4, 16, or 64 mg/kg/day (1.6, 6.5, and 26 times the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m²basis) of iloperidone orally during the period of organogenesis. The highest dose caused increased early intrauterine deaths, decreased fetal weight and length, decreased fetal skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and variations; this dose also caused decreased maternal food consumption and weight gain.

  In an embryo-fetal development study, pregnant rabbits were given 4, 10, or 25 mg/kg/day (3, 8, and 20 times the MRHD on a mg/m²basis) of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity.

  In additional studies in which rats were given iloperidone at doses similar to the above beginning from either pre-conception or from day 17 of gestation and continuing through weaning, adverse reproductive effects included prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased post-partum pup survival. There were no drug effects on the neurobehavioral or reproductive development of the surviving pups. No-effect doses ranged from 4 to 12 mg/kg except for the increase in stillbirth rates which occurred at the lowest dose tested of 4 mg/kg, which is 1.6 times the MRHD on a mg/m²basis. Maternal toxicity was seen at the higher doses in these studies.

  The iloperidone metabolite P95, which is a major circulating metabolite of iloperidone in humans but is not present in significant amounts in rats, was given to pregnant rats during the period of organogenesis at oral doses of 20, 80, or 200 mg/kg/day. No teratogenic effects were seen. Delayed skeletal ossification occurred at all doses. No significant maternal toxicity was produced. Plasma levels of P95 (AUC) at the highest dose tested were 2 times those in humans receiving the MRHD of iloperidone.
  )
  
  
• Lactation: Advise not to breast feed. (
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of iloperidone or its metabolites in human milk, the effects of iloperidone on a breastfed child, nor the effects of iloperidone on human milk production. Iloperidone is present in rat milk [see

  Data

  ]. Because of the potential for serious adverse reactions in breastfed infants, advise a woman not to breastfeed during treatment with FANAPT.

  Data

  The transfer of radioactivity into the milk of lactating rats was investigated following a single dose of [14C] iloperidone at 5 mg/kg. The concentration of radioactivity in milk at 4 hours post-dose was near 10-fold greater than that in plasma at the same time. However, by 24 hours after dosing, concentrations of radioactivity in milk had fallen to values slightly lower than plasma. The metabolic profile in milk was qualitatively similar to that in plasma.
  )
  
  
• Pediatric Use: Safety and effectiveness not established in children and adolescents. (
  8.4 Pediatric Use

  Safety and effectiveness of FANAPT have not been established in pediatric patients.
  )
  
  
• Hepatic Impairment: FANAPT is not recommended for patients with severe hepatic impairment. (
  2.3 Dosage Recommendations in Patients with Hepatic Impairment

  No dose adjustment for FANAPT is needed in patients with mild hepatic impairment. Patients with moderate hepatic impairment may require dose reduction, if clinically indicated. FANAPT is not recommended for patients with severe hepatic impairment

  [see Use in Specific Populations (8.6)]

  .
  ,
  8.6 Hepatic Impairment

  No dose adjustment to FANAPT is needed in patients with mild hepatic impairment (Child-Pugh class A). Patients with moderate hepatic impairment (Child-Pugh class B) may require dose reduction. FANAPT is not recommended for patients with severe hepatic impairment (Child-Pugh class C)

  [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]

  .
  )