Fanapt Drug Information

FANAPT ® is indicated for: Treatment of schizophrenia in adults. Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Recommended Dosage Titrate FANAPT to avoid orthostatic hypotension. Administer FANAPT orally with or without food. Table 1 includes 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.

Dosage Recommendations for Use in Patients Who Are Known CYP2D6 Poor Metabolizers Reduce the dose of FANAPT by one-half for CYP2D6 poor metabolizers. Table 2 includes dosage recommendations for FANAPT in adults who are CYP2D6 poor metabolizers.

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.

Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inhibitors Coadministration with Strong CYP2D6 Inhibitors Reduce the dose of FANAPT one-half when administered concomitantly with strong CYP2D6 inhibitors such as fluoxetine or paroxetine. When the CYP2D6 inhibitor is withdrawn from the combination therapy, increase the dose of FANAPT to where it was before. Coadministration with Strong CYP3A4 Inhibitors Reduce the dose of FANAPT by one-half when administered concomitantly with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin.

Coadministration with Strong CYP2D6 and Strong CYP3A4 Inhibitors Reduce the dose of FANAPT by about one-half if administered concomitantly with inhibitors of CYP2D6 and CYP3A4. When both CYP2D6 and CYP3A4 inhibitors are withdrawn from the combination therapy, increase the dose of FANAPT to where it was before.

Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that the initiation titration schedule be followed whenever patients have had an interval off FANAPT of more than 3 days.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The information below is derived from a clinical trial database for FANAPT consisting of 3,229 patients exposed to FANAPT at doses of 10 mg/day or greater, for the treatment of schizophrenia and from a clinical trial database for FANAPT consisting of 312 patients exposed to FANAPT at doses of 24 mg/day, for the treatment of bipolar mania. All of these patients who received FANAPT were participating in multiple-dose clinical trials.

The conditions and duration of treatment with FANAPT varied greatly and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure. Schizophrenia The information presented in this section was derived from pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients who received FANAPT at daily doses within a range of 10 to 24 mg (n=874). Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT-Treated Patients and More Frequent than Placebo Table 3 enumerates the pooled incidences of adverse reactions that were spontaneously reported in four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, listing those reactions that occurred in 2% or more of patients treated with FANAPT in any of the dose groups, and for which the incidence in FANAPT- treated patients in any dose group was greater than the incidence in patients treated with placebo.

Table 3: Percentage of Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo- Controlled Schizophrenia Trials in Adult Patients* 3 Bipolar Mania Table 4 enumerates the adverse reactions that occurred at an incidence of ≥2% and greater than placebo in a placebo-controlled, 4-week bipolar mania trial with FANAPT. Table 4: Adverse Reactions Occurring in ≥2% of Adult Patients Treated with FANAPT and > Placebo in a Short-Term, Fixed-Dose, Placebo-Controlled Bipolar Mania Trial 1 3 Dose-Related Adverse Reactions in Clinical Trials Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, adverse reactions in patients with schizophrenia that occurred with a greater than 2% incidence in the patients treated with FANAPT, and for which the incidence in patients treated with FANAPT 20-24 mg/day were twice than the incidence in patients treated with FANAPT 10-16 mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased. Common and Drug-Related Adverse Reactions in Clinical Trials Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies of patients with schizophrenia, the following adverse reactions occurred in ≥5% incidence in the patients treated with FANAPT and at least twice the placebo rate for at least 1 dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased.

Dizziness, tachycardia, and weight increased were at least twice as common on 20-24 mg/day as on 10-16 mg/day. In a short-term, placebo-controlled trial in patients with bipolar mania the following adverse reactions occurred in ≥5% incidence in the patients treated with FANAPT and at least twice the placebo rate: tachycardia, dizziness, dry mouth, hepatic enzymes increased, nasal congestion, weight increased, hypotension, and somnolence. Extrapyramidal Symptoms (EPS) in Clinical Trials Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies of patients with schizophrenia provided information regarding EPS.

Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 5. Table 5: Percentage of EPS Compared to Placebo in 4- or 6-week Schizophrenia Trials Table 6 shows the rates of EPS-related events in a 4-week bipolar mania trial. Table 6: Percentage of EPS Compared to Placebo in a 4-week Bipolar Mania Trial Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients with schizophrenia, there was no difference in the incidence of discontinuation due to adverse reactions between FANAPT-treated (5%) and placebo-treated (5%) patients.

The types of adverse reactions that led to discontinuation were similar for the FANAPT- and placebo-treated patients. In a 4-week, placebo-controlled study in patients with bipolar mania, the incidence of discontinuation due to adverse reactions was higher in FANAPT-treated (8.7%) patients than placebo-treated (5.3%) patients. Adverse reactions that led to discontinuation in more than one FANAPT-treated subject were liver enzyme elevations, nausea and vomiting, dizziness and hypotension.

Demographic Differences in Adverse Reactions in Clinical Trials An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies of patients with schizophrenia did not reveal any evidence of differences in safety on the basis of age, sex or race. Laboratory Test Abnormalities in Clinical Trials There were no differences between FANAPT and placebo in the incidence of discontinuation due to changes in hematology, or urinalysis. Serum Transaminases In a short-term placebo-controlled trial, asymptomatic alanine aminotransferase (ALT) elevations ≥3x ULN occurred in 9.2% of FANAPT-treated patients with acute mania compared to 1.5% of placebo treated subjects.

AST elevations were less common. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial. Analysis of clinical laboratory data following administration of FANAPT suggested the mechanism of hemodilution based on consistent decreases in hematocrit, hemoglobin, white blood cells, total protein, and albumin.

Decreases in hematocrit and total protein have been observed with other alpha receptor antagonists and are attributed to hemodilution Serum Urate Levels In a 4-week placebo-controlled trial in patients with bipolar mania, treatment with FANAPT 12 mg twice a day resulted in an increase of serum urate levels of approximately 27.2 umol/L (0.457 mg/dL) compared to 0.1 umol/L (0.002 mg/dL) in placebo group. Other Reactions During the Pre-marketing Evaluation of FANAPT Patients with Schizophrenia The following is a list of MedDRA terms that reflect adverse reactions in patients treated with FANAPT at multiple doses ≥ 4 mg/day during any phase of a trial with the database of 3,210 FANAPT-treated patients with schizophrenia. All reported reactions are included except those already listed in Table 3, or other parts of the Adverse Reactions, those considered in the Warnings and Precautions, those reaction terms which were so general as to be uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions that are otherwise common as background reactions, and reactions considered unlikely to be drug related.

Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not listed in Table 3 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Blood and Lymphatic Disorders: Infrequent – anemia, iron deficiency anemia; Rare – leukopenia Cardiac Disorders: Frequent – palpitations; Rare – arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute) Ear and Labyrinth Disorders: Infrequent – vertigo, tinnitus Endocrine Disorders: Infrequent – hypothyroidism Eye Disorders: Frequent – conjunctivitis (including allergic); Infrequent – dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival) Gastrointestinal Disorders: Infrequent – gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare – aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis General Disorders and Administrative Site Conditions: Infrequent – edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare – hyperthermia Hepatobiliary Disorders: Infrequent – cholelithiasis Investigations: Frequent: weight decreased; Infrequent – hemoglobin decreased, neutrophil count increased, hematocrit decreased Metabolism and Nutrition Disorders: Infrequent – increased appetite, dehydration, hypokalemia, fluid retention Musculoskeletal and Connective Tissue Disorders: Frequent – myalgia, muscle spasms; Rare – torticollis Nervous System Disorders: Infrequent – paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome Psychiatric Disorders: Frequent – restlessness, aggression, delusion; Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression Renal and Urinary Disorders: Frequent – urinary incontinence; Infrequent – dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal failure acute Reproductive System and Breast Disorders: Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis Respiratory, Thoracic and Mediastinal Disorders: Infrequent – epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, sleep apnea syndrome, dyspnea exertional

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of FANAPT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure: retrograde ejaculation and hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; and pruritus).

Clinically Important Drug Interactions with FANAPT Table 7 presents clinically important drug interactions with FANAPT. Table 7: Clinically Important Drug Interactions with FANAPT Strong CYP2D6 Inhibitors Clinical Impact Coadministration of fluoxetine with iloperidone increased exposure (area under curve, ) of iloperidone and its metabolite P88, by about 2- to 3- fold, and decreased the AUC of its metabolite P95 by one-half. Coadministration of paroxetine with iloperidone 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.

Intervention Reduce the dose of FANAPT by one-half when administered with strong CYP2D6 inhibitors. When a strong CYP2D6 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Strong CYP3A4 Inhibitors Clinical Impact Co-administration of ketoconazole with iloperidone, increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55%, and 35%, respectively.

When the CYP3A4 inhibitor is withdrawn from the combination therapy, the FANAPT dose should be returned to the previous level. Concomitant use of Strong CYP2D6 and Strong CYP3A4 Inhibitors Clinical Impact Coadministration of iloperidone with paroxetine and ketoconazole 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. Intervention Coadministration of FANAPT with inhibitors of both CYP2D6 and CYP3A4 did not add to the effect of either inhibitor given alone.

When the inhibitors of CYP2D6 and CYP3A4 are withdrawn from the combination therapy, the FANAPT dose should be returned to the previous level.

Drugs that Prolong the QT Interval

Concomitant use of drugs that prolong the QT interval may add to the QT effects of FANAPT and increase the risk of cardiac arrhythmia. Avoid the use of FANAPT in combination with any other drugs that prolong the QT interval.

Drugs that Lower Blood Pressure

Concomitant use of FANAPT with medications that lower blood pressure could potentially cause symptomatic hypotension. Avoid coadministration of FANAPT with alpha-adrenergic blocking agents and adjust medications that affect blood pressure as needed.

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.

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/m 2 basis. 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/m 2 basis. However, it increased early intrauterine deaths and decreased fetal viability at term at the highest dose which was also a maternally toxic dose. 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 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. 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.

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.

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.

Pediatric Use Safety and effectiveness of FANAPT have not been established in pediatric patients.

FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product. Anaphylaxis, angioedema, and other hypersensitivity reactions have been reported. Known hypersensitivity to FANAPT or to any components in the formulation.

Management of Overdose There is no specific antidote for FANAPT. Therefore appropriate supportive measures should be instituted. In case of acute overdose, the healthcare provider should establish and maintain an airway and ensure adequate oxygenation and ventilation.

Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias.

If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of FANAPT. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of FANAPT, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of FANAPT-induced alpha blockade).

In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision should continue until the patient recovers. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.