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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 2070 patients exposed to FANAPT at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 806 received FANAPT for at least 6 months, with 463 exposed to FANAPT for at least 12 months. 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.
Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions, reactions were grouped in standardized categories using MedDRA terminology.
The stated frequencies of adverse reactions represent the proportions of individuals who experienced a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
The information presented in these sections 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 7 enumerates the pooled incidences of treatment-emergent 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 7: Percentage of Treatment-Emergent Adverse
Reactions in Short-Term, Fixed-or Flexible-Dose, Placebo-Controlled Trials in
|Body System or Organ Class Dictionary-derived Term||Placebo % (N=587)||FANAPT 10-16 mg/day % (N=483)||FANAPT 20-24 mg/day % (N=391)|
|Body as a Whole|
|Upper Respiratory Tract Infection||1||2||3|
|Nervous System Disorders|
|Ejaculation Failure||< 1||2||2|
|Hypotension||< 1||< 1||3|
|* Table includes adverse reactions that were reported in 2% or more of patients in any of the FANAPT dose groups and which occurred at greater incidence than in the placebo group. Figures rounded to the nearest integer.|
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 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, 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.
Extrapyramidal Symptoms (EPS) in Clinical Trials
Pooled data from the 4 placebo-controlled, 4-or 6-week, fixed-or flexible-dose studies provided information regarding treatment-emergent EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 8.
Table 8: Percentage of EPS Compared to Placebo
|Adverse Event Term||Placebo (%)
|FANAPT 10-16 mg/day (%)
|FANAPT 20-24 mg/day (%)
|All EPS events||11.6||13.5||15.1|
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, there was no difference in the incidence of discontinuation due to adverse events between FANAPT-treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to discontinuation were similar for the FANAPT-and placebo-treated patients.
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 did not reveal any evidence of differences in safety on the basis of age, gender or race [see WARNINGS AND PRECAUTIONS].
Laboratory Test Abnormalities in Clinical Trials
In short-term placebo-controlled trials (4-to 6-weeks), there were 1.0% (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) on placebo. 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.
Other Reactions During the Pre-marketing Evaluation of FANAPT
The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions in patients treated with FANAPT at multiple doses ≥ 4 mg/day during any phase of a trial with the database of 3210 FANAPT-treated patients. All reported reactions are included except those already listed in Table 7, or other parts of the ADVERSE REACTIONS section, 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. It is important to emphasize that, although the reactions reported occurred during treatment with FANAPT, they were not necessarily caused by it.
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 7 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.
Endocrine Disorders: InFrequent – hypothyroidism
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
Metabolism and Nutrition Disorders: InFrequent – increased appetite, dehydration, hypokalemia, fluid retention
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
Reproductive System and Breast Disorders: Frequent – erectile dysfunction; InFrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis.
The following adverse reactions have been identified during postapproval use of FANAPT-: retrograde ejaculation. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Read the Fanapt (iloperidone tablets) Side Effects Center for a complete guide to possible side effects
Given the primary CNS effects of FANAPT, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. Due to its -alpha1-adrenergic receptor antagonism, FANAPT has the potential to enhance the effect of certain antihypertensive agents.
Potential For Other Drugs To Affect FANAPT
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.
Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels.
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. Iloperidone doses should be reduced by about one-half when administered with ketoconazole or other strong inhibitors of CYP3A4 (e.g., itraconazole). Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level.
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. Iloperidone doses should be reduced by one-half when administered with fluoxetine. When fluoxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to the previous level.
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. Iloperidone doses should be reduced by one-half when administered with paroxetine. When paroxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to previous levels.
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. So giving iloperidone with inhibitors of both of its metabolic pathways did not add to the effect of either inhibitor given alone. Iloperidone doses should therefore be reduced by about one-half if administered concomitantly with both a CYP2D6 and CYP3A4 inhibitor.
Potential For FANAPT To Affect Other Drugs
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.
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 (Cmax )of dextromethorphan. Thus, an interaction between iloperidone and other CYP2D6 substrates is unlikely.
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 Cmax. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.
Drugs That Prolong The QT Interval
FANAPT should not be used with any other drugs that prolong the QT interval [see WARNINGS AND PRECAUTIONS].
Drug Abuse And Dependence
FANAPT is not a controlled substance.
FANAPT has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this experience the extent to which a CNS active drug, FANAPT, will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of FANAPT misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behavior).
Read the Fanapt Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/1/2014
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