Iloperidone

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

It is recommended that patients being considered for iloperidone treatment who are at risk for significant electrolyte disturbances have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. Iloperidone should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.

Reduce the dose of iloperidone by one-half when administered concomitantly with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin. When the CYP3A4 inhibitor is withdrawn from the combination therapy, increase the dose of iloperidone to where it was before.

Co-administration of ketoconazole with iloperidone, increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55%, and 35%, respectively.

Reduce the dose of iloperidone 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 When the CYP2D6 inhibitor is withdrawn from the combination therapy, increase the dose of iloperidone to where it was before.

Coadministration of fluoxetine with iloperidone increased exposure (area under curve, [AUC]) 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.

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.

Coadministration of iloperidone with inhibitors of both CYP2D6 and CYP3A4 did not add to the effect of either inhibitor given alone. Reduce the dose of iloperidone by about one-half if administered concomitantly with both a CYP2D6 and CYP3A4 inhibitor same as if it is coadministered with only one inhibitor. When the inhibitors of CYP2D6 and CYP3A4 are withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level.

Patients with moderate hepatic impairment (Child-Pugh class B) may require dose reduction.

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

Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.

Antipsychotic drugs, including iloperidone, should be used cautiously in patients at risk for aspiration.

Dosage recommendations for use in patients who are known CYP2D6 poor metabolizers

Reduce the dose of iloperidone by one-half for CYP2D6 poor metabolizers. The table below includes dosage recommendations for iloperidone in adults who are CYP2D6 poor metabolizers.

Dosage recommendations for iloperidone in adults with schizophrenia or bipolar i disorder who are CYP2D6 poor metabolizers:

Risk Summary

Neonates whose mothers are exposed to antipsychotic drugs, including iloperidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. The limited available data with iloperidone 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/m² 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/m² basis. 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, 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/m² basis) 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/m² basis) 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/m² basis. 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.

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 iloperidone.

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.

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.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with iloperidone does not affect them adversely.

Clinical trials 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 iloperidone consisting of 3,229 patients exposed to iloperidone at doses of 10 mg/day or greater, for the treatment of schizophrenia and from a clinical trial database for iloperidone consisting of 312 patients exposed to iloperidone at doses of 24 mg/day, for the treatment of bipolar mania. Of these, 999 received iloperidone for at least 6 months, with 657 exposed to iloperidone for at least 12 months for the treatment of schizophrenia and 69 received iloperidone for at least 6 months, with 28 exposed to iloperidone for at least 12 months for the treatment of bipolar mania. All of these patients who received iloperidone were participating in multiple-dose clinical trials. The conditions and duration of treatment with iloperidone 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 iloperidone at daily doses within a range of 10 to 24 mg (n=874).

Adverse Reactions Occurring at an Incidence of 2% or More among iloperidone-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 iloperidone in any of the dose groups, and for which the incidence in iloperidonetreated 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:

^* Table includes adverse reactions that were reported in 2% or more of patients in any of the iloperidone dose groups and which occurred at greater incidence than in the placebo group. Figures rounded to the nearest integer.

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 iloperidone.

Table 4. Adverse reactions occurring in ≥2% of adult patients treated with iloperidone and ˃ placebo in a short-term, fixed-dose, placebo-controlled bipolar mania trial:

^* The following terms were combined:
Tachycardia includes: heart rate increased, sinus tachycardia, postural orthostatic tachycardia syndrome, and tachycardia
Nausea includes: nausea and vomiting
Hepatic enzyme increased includes: predominantly alanine aminotransferase increased and including aspartate aminotransferase increased, hepatic enzyme increased, and transaminase increased)
Weight increased includes: weight increased and BMI increased
Dizziness includes: dizziness and postural dizziness
Headache includes: Headache and Tension headache
Somnolence includes: predominantly sedation and including sedation complication and somnolence
Urinary urgency and Polyuria includes: hypertonic bladder, micturition urgency, polyuria, and urinary incontinence
Sexual Dysfunction includes: ejaculation failure, erectile dysfunction, retrograde ejaculation, and ejaculation delayed
Hypotension includes: orthostatic hypotension
Fatigue includes: lethargy
^** Patients with poor CYP2D6 metabolizer status received 12 mg/day.

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 iloperidone, and for which the incidence in patients treated with iloperidone 20-24 mg/day were twice than the incidence in patients treated with iloperidone 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 iloperidone 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 iloperidone 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:

^* Patients with poor CYP2D6 metabolizer status received 12 mg/day.

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 iloperidone-treated (5%) and placebo-treated (5%) patients. The types of adverse reactions that led to discontinuation were similar for the iloperidone- 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 iloperidone-treated (8.7%) patients than placebo-treated (5.3%) patients. Adverse reactions that led to discontinuation in more than one iloperidone-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 iloperidone 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 iloperidone-treated patients with acute mania compared to 1.5% of placebo treated subjects. AST elevations were less common.

Hematocrit

In short-term placebo-controlled trials (4- to 6-weeks) in patients with schizophrenia, 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.

In a short-term placebo-controlled trial (4 weeks) in patients with bipolar mania, there were 3.5% (7/200) iloperidone-treated patients with hematocrit at least one time below the extended normal range (<0.85xLLN) during post-randomization treatment, compared to 0.5% (1/196) on placebo.

Analysis of clinical laboratory data following administration of iloperidone 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 iloperidone 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 iloperidone

Patients with schizophrenia

The following is a list of MedDRA terms that reflect adverse reactions in patients treated with iloperidone at multiple doses ≥4 mg/day during any phase of a trial with the database of 3,210 iloperidone-treated patients with schizophrenia. All reported reactions are included except those already listed in Table 3, or other parts of the Adverse Reactions (6), those considered in the Warnings and Precautions (5), 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