Fanapt (iloperidone 2 mg) Dailymed

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia- Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack). (5.2)
• QT prolongation: Prolongs QT interval and may be associated with arrhythmia and sudden death. Avoid use of FANAPT in combination with other drugs that are known to prolong QTc; use caution and consider dose modification when prescribing FANAPT with other drugs that inhibit FANAPT metabolism. Monitor serum potassium and magnesium in patients at risk for electrolyte disturbances. (1, 5.3, 7.1, 7.2, 12.3)
• Neuroleptic Malignant Syndrome (NMS): Manage with immediate discontinuation of drug and close monitoring. (5.4)
• Tardive dyskinesia: Discontinue if clinically appropriate. (5.5)
• Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain. (5.6)
• Orthostatic hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. (5.7)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold. (5.9)
• Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia. Consider discontinuing FANAPT if clinically significant decline in WBC occurs in the absence of other causative factors. (5.10)
• Priapism: Cases have been reported in association with FANAPT treatment. Severe priapism may require surgical intervention. (5.14)
• Potential for cognitive and motor impairment: Use caution when operating machinery. (5.15)
• Intraoperative Floppy Iris Syndrome (IFIS): IFIS during cataract surgery may require modifications to the surgical technique. (5.16)

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks) largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.2)].

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)].

5.3 QT Prolongation

In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), FANAPT was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the QT interval was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (paroxetine 20 mg once daily and ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec.

No cases of torsade de pointes or other severe cardiac arrhythmias were observed during the pre-marketing clinical program.

The use of FANAPT should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). FANAPT should also be avoided in patients with a known genetic susceptibility to congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval; (5) recent acute myocardial infarction; and/or (6) uncompensated heart failure.

Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism [see Drug Interactions (7.1)], and in patients with reduced activity of CYP2D6 [see Clinical Pharmacology (12.3, 12.5)].

It is recommended that patients being considered for FANAPT 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. FANAPT 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. FANAPT should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.

5.4 Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including FANAPT. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue FANAPT and provide intensive symptomatic treatment and monitoring.

5.5 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is impossible to predict, which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and cumulative dose. The syndrome can develop after relatively brief treatment periods at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, FANAPT should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation should be considered. However, some patients may require treatment with FANAPT despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including FANAPT. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.

Schizophrenia

In a 4-week fixed-dose placebo-controlled study of adults with schizophrenia, the mean change from baseline in serum glucose was 6.6 mg/dL and -0.5 mg/dL for FANAPT and placebo treated patients, respectively. The proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) were 10.7% and 2.5% for FANAPT and placebo treated patients, respectively.

In pooled analyses from clinical studies, for adults with schizophrenia remaining on treatment with FANAPT 10-16 mg/day glucose increased, on average, from baseline by 1.8 mg/dL at 3-6 months (N=773) and by 5.4 mg/dL at 6-12 months (N=723) and at >12 months (N=425) of treatment. In a smaller group of patients remaining on treatment with FANAPT 20-24 mg/day, glucose decreased by 3.6 mg/dL at 3-6 months (N=34); by 9 mg/dL at 6-12 months (N=31), and by 18 mg/dL at > 12 months (N=20) of treatment.

Bipolar Mania

In a 4-week fixed dose study of adults with bipolar mania, mean changes from baseline in serum glucose and the proportion of patients with shifts in fasting glucose from Normal (<100 mg/dL) to High (≥126 mg/dL) for patients receiving FANAPT were similar to those for patients receiving placebo.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment.

Schizophrenia

In a 4-week fixed dose study of adults with schizophrenia, the mean change from baseline in fasted total cholesterol was 8.2 mg/dL and -2.2 mg/dL for FANAPT and placebo treated patients, respectively. The effects on LDL were similar to those on total cholesterol (changes of 9 mg/dL and -1.4 mg/dL for FANAPT and placebo treated patients, respectively). Mean changes from baseline in fasted triglycerides were -0.8 mg/dL and 16.5 mg/dL for FANAPT and placebo treated patients, respectively.

The proportion of patients with shifts from normal to high fasted total cholesterol, LDL, and triglycerides were similar for FANAPT and placebo-treated patients. The proportion of patients with shifts in fasted HDL from normal (≥40 mg/dL) to low (<40 mg/dL) was greater for placebo patients (23.8%) compared to patients treated with FANAPT (12.1%).

In pooled analysis from clinical studies, for adults with schizophrenia remaining on treatment with FANAPT, on average, both cholesterol and triglycerides decreased from baseline for adults with schizophrenia remaining on treatment at 3-6 months, 6-12 months, and >12-month time points in both 10-16 mg/day and 20-24 mg/day dose groups.

Bipolar Mania

In a 4-week fixed dose study of adults with bipolar mania, the mean changes from baseline for fasted total cholesterol, LDL, HDL, and triglycerides for FANAPT were similar to those for placebo-treated patients. The proportion of patients with shifts in fasted total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL) was greater for FANAPT treated patients (10.7%) than placebo-treated patients (7.2%). Shifts from normal to high LDL and triglycerides and from normal to low HDL occurred at rates for FANAPT similar to those for placebo treated patients.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Monitor weight at baseline and frequently thereafter.

Schizophrenia

Across all short- and long-term studies of adults with schizophrenia, the overall mean change from baseline at endpoint was 2.1 kg.

In 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adults with schizophrenia the mean change in weight (kg) was -0.1, 2, and 2.7 for placebo, FANAPT 10-16 mg/day, and FANAPT 20-24 mg/day groups, respectively. The proportion of patients with weight gain >7% increase from baseline was 4%, 12%, and 18% for placebo, FANAPT 10-16 mg/day, and FANAPT 20-24 mg/day groups, respectively.

Bipolar Mania

In a 4-week fixed dose study of adults with bipolar mania the mean change in weight (kg) was 1.6 and 4.6 kg for placebo and FANAPT 24 mg/day groups, respectively. The proportion of patients with weight gain ≥7% increase from baseline was 14% and 35%, for placebo and FANAPT 24 mg/day groups, respectively.

5.7 Orthostatic Hypotension and Syncope

FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects its alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-term studies in patients with schizophrenia, where the dose was increased slowly, as recommended above, syncope was reported in 0.4% (5/1,344) of patients treated with FANAPT, compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of patients given 20 mg to 24 mg/day, 3% of patients given 10 mg to 16 mg/day, and 1% of patients given placebo.

In a double-blind placebo-controlled short-term study in patients with bipolar mania, syncope was reported in 0.5% (1/206) of patients treated with FANAPT, compared with 0% (0/208) on placebo. In this study, orthostatic hypotension was reported in 4% (9/206) of patients treated with FANAPT and 2% (5/208) of patients given placebo.

More rapid titration would be expected to increase the rate of orthostatic hypotension and syncope.

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.

5.8 Falls

Antipsychotics, including FANAPT, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9Seizures

Like other antipsychotic drugs, FANAPT may cause seizures. The risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.

5.10Leukopenia, Neutropenia and Agranulocytosis

In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.

Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue FANAPT at the first sign of a decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue FANAPT in patients with absolute neutrophil count <1000/mm³ and follow their WBC until recovery.

5.11Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and rats treated with FANAPT [see Nonclinical Toxicology (13)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

In a short-term placebo-controlled trial (4-weeks) in patients with schizophrenia, the mean change from baseline to endpoint in plasma prolactin levels for the FANAPT 24 mg/day-treated group was an increase of 2.6 ng/mL compared to a decrease of 6.3 ng/mL in the placebo-group. In placebo-controlled trials in patients with schizophrenia, elevated plasma prolactin levels (≥1.15xULN) were observed in 26% of adults treated with FANAPT compared to 12% in the placebo group. In the short-term trials, FANAPT was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic agents. In pooled analysis from clinical studies including longer term trials, in 3210 adults treated with iloperidone, gynecomastia was reported in 2 male subjects (0.1%) compared to 0% in placebo-treated patients, and galactorrhea was reported in 8 female subjects (0.2%) compared to 3 female subjects (0.5%) in placebo-treated patients.

In a short-term, placebo-controlled trial (4-weeks) in patients with bipolar mania, the mean change from baseline to endpoint in plasma prolactin levels for the FANAPT group was an increase of 15.66 ng/mL compared to a decrease of 0.58 ng/mL for the placebo group. In this trial, elevated plasma prolactin levels (≥1.15xULN) were observed in 35% of adults treated with FANAPT compared to 1% of the placebo group.

5.12Body Temperature Regulation

Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use FANAPT with caution in patients who may experience these conditions.

5.13 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients. Antipsychotic drugs, including FANAPT, should be used cautiously in patients at risk for aspiration.

5.14Priapism

Four cases of priapism were reported in the pre-marketing FANAPT program (3 in the clinical studies for schizophrenia and 1 in the clinical study for manic and mixed episodes associated with bipolar I disorder). Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. FANAPT shares this pharmacologic activity. Severe priapism may require surgical intervention.

5.15Potential for Cognitive and Motor Impairment

FANAPT, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking or motor skills. In short-term, placebo-controlled trials of schizophrenia, somnolence (including sedation) was reported in 12% (104/874) of adult patients treated with FANAPT at doses of 10 mg/day or greater versus 5.3% (31/587) treated with placebo. In a short-term, placebo-controlled trial of bipolar mania, somnolence (including sedation) was reported in 8% (16/206) of adult patients treated with FANAPT versus 3% (6/208) treated with placebo.

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

5.16Intraoperative Floppy Iris Syndrome (IFIS)

IFIS has been observed during cataract surgery in some patients on or previously treated with alpha-1 adrenergic blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha1 blocker therapy prior to cataract surgery. The initiation of therapy with FANAPT in patients for whom cataract or glaucoma surgery is scheduled is not recommended.

6 Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.1)]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.2)]
• QT Prolongation [see Warnings and Precautions (5.3)]
• Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)]
• Tardive Dyskinesia [see Warnings and Precautions (5.5)]
• Metabolic Changes [see Warnings and Precautions (5.6)]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.7)]
• Falls [see Warnings and Precautions (5.8)]
• Seizures [see Warnings and Precautions (5.9)]
• Leukopenia, Neutropenia and Agranulocytosis [see Warnings and Precautions (5.10)]
• Hyperprolactinemia [see Warnings and Precautions (5.11)]
• Body Temperature Regulation [see Warnings and Precautions (5.12)]
• Dysphagia [see Warnings and Precautions (5.13)]
• Priapism [see Warnings and Precautions (5.14)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.15)]
• Intraoperative Floppy Iris Syndrome [see Warnings and Precautions (5.16)]

Commonly observed adverse reactions (incidence ≥5% and 2-fold greater than placebo) were (6.1):

• Schizophrenia: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased.
• Bipolar mania: tachycardia, dizziness, dry mouth, hepatic enzymes increased, nasal congestion, weight increased, hypotension, and somnolence.

To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals Inc. at 1-844-GO-VANDA (1-844-468-2632) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 [see Clinical Studies (14.2)]. Of these, 999 received FANAPT for at least 6 months, with 657 exposed to FANAPT for at least 12 months for the treatment of schizophrenia and 69 received FANAPT for at least 6 months, with 28 exposed to FANAPT for at least 12 months 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, uling 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*

* 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.
Body System or Organ Class	Placebo(%)	FANAPT 10-16 mg/day(%)	FANAPT 20-24 mg/day(%)
Dictionary-derived Term	(N=587)	(N=483)	(N=391)
Body as a Whole
Arthralgia	2	3	3
Fatigue	3	4	6
Musculoskeletal Stiffness	1	1	3
Weight Increased	1	1	9
Cardiac Disorders
Tachycardia	1	3	12
Eye Disorders
Vision Blurred	2	3	1
Gastrointestinal Disorders
Nausea	8	7	10
Dry Mouth	1	8	10
Diarrhea	4	5	7
Abdominal Discomfort	1	1	3
Infections
Nasopharyngitis	3	4	3
Upper Respiratory Tract Infection	1	2	3
Nervous System Disorders
Dizziness	7	10	20
Somnolence	5	9	15
Extrapyramidal Disorder	4	5	4
Tremor	2	3	3
Lethargy	1	3	1
Reproductive System
Ejaculation Failure	<1	2	2
Respiratory
Nasal Congestion	2	5	8
Dyspnea	<1	2	2
Skin
Rash	2	3	2
Vascular Disorders
Orthostatic Hypotension	1	3	5
Hypotension	<1	<1	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

*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.
System Organ Class Preferred Terms	PlaceboN=208%	FANAPT 24 mg/day** N=206%
Cardiac disorders
Tachycardia*	5	23
Gastrointestinal disorders
Dry mouth	2	9
Nausea*	3	4
Investigations
Hepatic enzyme increased*	1	8
Weight increased*	1	6
Nervous system disorders
Dizziness*	1	12
Headache*	4	5
Somnolence*	3	8
Akathisia	0	4
Renal and urinary disorders
Urinary urgency and Polyuria*	0	3
Reproductive system and breast disorders
Sexual Dysfunction*	0.5	4
Respiratory, thoracic, and mediastinal disorders
Nasal congestion	1	6
Vascular disorders
Hypotension*	3	6
General disorders and administration site conditions
Fatigue*	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

	Placebo (%)	FANAPT 10-16 mg/day (%)	FANAPT 20-24 mg/day (%)
Preferred Term	(N=587)	(N=483)	(N=391)
All EPS events	11.6	13.5	15.1
Tremor	1.9	2.5	3.1
Akathisia	2.7	1.7	2.3
Dyskinesia	1.5	1.7	1
Dystonia	0.7	1	0.8
Bradykinesia	0	0.6	0.5
Parkinsonism	0	0.2	0.3

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.
Preferred Term	Placebo (%)	FANAPT 24 mg/day* (%)
	N=208	N=206
All EPS events	0	8.3
Akathisia	0	4.4
Extrapyramidal Disorder	0	1
Blepharospasm	0	0.5
Dystonia	0	0.5
Muscle Spasm	0	0.5
Restlessness	0	0.5
Torticollis	0	0.5
Tremor	0	0.5

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.

Hematocrit

In short-term placebo-controlled trials (4- to 6-weeks) in patients with schizophrenia, there were 1.0% (13/1342) FANAPT-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) FANAPT-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 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 [see Clinical Pharmacology (12.2)]

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 ul 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 uled 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 uled 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 uled in Table 3 appear in this uling); 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

6.2 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).