Side Effects of Fanapt (iloperidone)

Fanapt (iloperidone) is an atypical antipsychotic used to treat schizophrenia. Atypical antipsychotics differ from typical antipsychotics because they cause a lesser degree of movement (extrapyramidal) side effects and constipation.

The exact mechanism of action of Fanapt is not known, but like other anti-psychotics, it is believed Fanapt affects the way the brain works by interfering with communication among the brain's nerves.

Nerves communicate with each other by making and releasing chemicals called neurotransmitters. The neurotransmitters travel to other nearby nerves where they attach to receptors on the nerves.

The attachment of the neurotransmitters either stimulates or inhibits the function of the nearby nerves. Fanapt blocks several of the receptors on nerves including dopamine type 2, serotonin type 2, and alpha 2 adrenergic receptors. It is believed that many psychotic illnesses are caused by abnormal communication among nerves in the brain and that by altering communication through neurotransmitters, Fanapt can alter the psychotic state.

Common side effects of Fanapt include

• dizziness,
• dry mouth,
• fatigue,
• nasal congestion,
• dizziness on standing,
• drowsiness,
• fast heart rate, and
• weight gain.

Serious side effects of Fanapt include

• increased risk of stroke in elderly patients with dementia-related psychosis,
• neuroleptic malignant syndrome (NMS) (symptoms include high fever, sweating (diaphoresis),
• severe muscle stiffness or rigidity,
• confusion,
• loss of consciousness,
• high blood pressure,
• rapid heartbeat, and changes in breathing,
• extrapyramidal side effects (EPS) (painful spasms of the oral, throat, or neck muscles that may cause problems with speech, swallowing, and stiff neck; restlessness or difficulty sitting still; drug induced Parkinson's symptoms; tardive dyskinesia), 
• metabolic changes including (high blood sugar, diabetes mellitus, increased blood cholesterol, and weight gain),
• high blood levels of prolactin (menstrual abnormalities, leakage of milk from the breast, development of breasts in males, and erection problems in men), and
• seizures.

Drug interactions of Fanapt include other drugs also associated with dizziness on standing (orthostatic hypotension) because Fanapt can reduce blood pressure. Fanapt is broken down by enzymes in the liver. Drugs that block the action of these enzymes such as ketoconazole, fluoxetine, and paroxetine increase blood levels of Fanapt. The risk of abnormal heartbeats increases when Fanapt is combined with other drugs that cause abnormal heartbeats.

Currently there is no data on the use of Fanapt during pregnancy. Fanapt should only be used during pregnancy if the potential benefit to the mother outweighs the potential for side effects in the fetus. Fetuses exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and withdrawal symptoms after birth. A pregnancy exposure registry has been established to monitor the use of atypical antipsychotics, including Fanapt, during pregnancy.

Fanapt has not been evaluated in nursing mothers. Consult your doctor before breastfeeding.

The most common side effects include

• dizziness,
• dry mouth,
• fatigue,
• nasal congestion,
• orthostatic hypotension,
• somnolence,
• tachycardia, and
• weight gain.

Less common but serious side effects include:

• Increased risk of stroke in elderly patients with dementia-related psychosis.
• Neuroleptic malignant syndrome (NMS). NMS is a rare but serious side effects associated with the use of antipsychotics. NMS may result in death and must be treated in the hospital.
  • Signs and symptoms of NMS may include high fever, sweating (diaphoresis), severe muscle stiffness or rigidity, confusion, loss of consciousness, high blood pressure, rapid heartbeat, and changes in breathing.

Extrapyramidal side effects (EPS) including:

• Dystonia: painful spasms of the oral, throat, or neck muscles that may cause problems with speech, swallowing, and stiff neck.
• Akathisia: feelings of restlessness or difficulty sitting still.
• Pseudoparkinsonism: drug induced Parkinson's symptoms.
• Tardive dyskinesia (TD): TD usually occurs after long term use of antipsychotics and usually presents with movement problems affecting the tongue, lips, jaw, face, and extremities.
• Metabolic changes including high blood sugar (hyperglycemia), diabetes mellitus, increase in blood cholesterol, and weight gain.
• High blood levels of prolactin. Prolactin is a hormone that allows the production of breast milk. High levels of prolactin may cause menstrual abnormalities, leakage of milk from the breast, development of breasts in males, and erection problems in men.
• Seizures may occur.
• Iloperidone causes sedation and slows thinking and movement. Patients should avoid potentially dangerous activities such as driving and operating machinery until they are certain that iloperidone does not impair their ability to perform such tasks.

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 3229 patients exposed to Fanapt at doses of 10 mg/day or greater, for the treatment of schizophrenia.
• Of these, 999 received Fanapt for at least 6 months, with 657 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.
• The information presented in these sections was derived from pooled data from 4 placebo-controlled, 4- or 6week, 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 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 Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Trials in Adult Patients*

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 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 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.

Laboratory Test Abnormalities In Clinical Trials

• There were no differences between Fanapt and placebo in the incidence of discontinuation due to changes in hematology, urinalysis, or serum chemistry.
• 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 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  (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 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.

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:

• retrograde ejaculation and hypersensitivity reactions, including
  • anaphylaxis;
  • angioedema;
  • throat tightness;
  • oropharyngeal swelling;
  • swelling of the face, lips, mouth, and tongue;
  • urticaria;
  •  rash; and
  • pruritus).

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.

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.

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.
• 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.

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.
• 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.

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.
• 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.

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 Cmax 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 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.

Drug Abuse And Dependence

Controlled Substance

• Fanapt is not a controlled substance.

Abuse

• 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).