Fanapt, Page 1

Fanapt® tablets are indicated for the treatment of adults with schizophrenia. The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials.

FANAPT- iloperidone tablet
FANAPT- iloperidone
Novartis Pharmaceuticals Corporation

WARNING: 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. Analysis of seventeen placebo-controlled trials (modal duration 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 the risk of death 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 the placebo group. 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.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. FANAPT is not approved for the treatment of patients with Dementia-Related Psychosis. [see Warnings and Precautions (5.1)]

1 INDICATIONS AND USAGE

FANAPT® tablets are indicated for the treatment of adults with schizophrenia. Efficacy was established in two short-term (4- and 6-week) placebo- and active-controlled studies of adult patients with schizophrenia [see Clinical Studies (14)].

When deciding among the alternative treatments available for this condition, the prescriber should consider the finding that FANAPT is associated with prolongation of the QTc interval [see Warnings and Precautions (5.2)]. Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia which can result in sudden death. In many cases this would lead to the conclusion that other drugs should be tried first. Whether FANAPT will cause torsade de pointes or increase the rate of sudden death is not yet known.

Patients must be titrated to an effective dose of FANAPT. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require a similar titration. Prescribers should be mindful of this delay when selecting an antipsychotic drug for the treatment of schizophrenia [see Dosage and Administration (2.1) and Clinical Studies (14)].

The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use FANAPT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Usual Dose

FANAPT must be titrated slowly from a low starting dose to avoid orthostatic hypotension due to its alpha-adrenergic blocking properties. The recommended starting dose for FANAPT tablets is 1 mg twice daily. Increases to reach the target dose range of 6-12 mg twice daily may be made with daily dosage adjustments to 2 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, 10 mg twice daily, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively. Efficacy was demonstrated with FANAPT in a dose range of 6 to 12 mg twice daily. Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of FANAPT. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require similar titration. Prescribers should also be aware that some adverse effects associated with FANAPT use are dose related.

The maximum recommended dose is 12 mg twice daily (24 mg/day); FANAPT doses above 24 mg/day have not been systematically evaluated in the clinical trials.

FANAPT can be administered without regard to meals.

2.2 Dosage in Special Populations

Dosage adjustments are not routinely indicated on the basis of age, gender, race, or renal impairment status [see Use in Specific Populations (8.6, 8.7)].

Dosage adjustment for patients taking FANAPT concomitantly with potential CYP2D6 inhibitors: FANAPT dose should be reduced by one-half when administered concomitantly with strong CYP2D6 inhibitors such as fluoxetine or paroxetine. When the CYP2D6 inhibitor is withdrawn from the combination therapy, FANAPT dose should then be increased to where it was before [see Drug Interactions (7.1)].

Dosage adjustment for patients taking FANAPT concomitantly with potential CYP3A4 inhibitors: FANAPT dose should be reduced 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, FANAPT dose should be increased to where it was before [see Drug Interactions (7.1)].

Dosage adjustment for patients taking FANAPT who are poor metabolizers of CYP2D6: FANAPT dose should be reduced by one-half for poor metabolizers of CYP2D6 [see Pharmacokinetics (12.3)].

Hepatic Impairment:FANAPT is not recommended for patients with hepatic impairment.

2.3 Maintenance Treatment

Although there is no body of evidence available to answer the question of how long the patient treated with FANAPT should be maintained, it is generally recommended that responding patients be continued beyond the acute response. Patients should be periodically reassessed to determine the need for maintenance treatment.

2.4 Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address re-initiation of treatment, it is recommended that the initiation titration schedule be followed whenever patients have had an interval off FANAPT of more than 3 days.

2.5 Switching f rom Other Antipsychotics

There are no specific data to address how patients with schizophrenia can be switched from other antipsychotics to FANAPT or how FANAPT can be used concomitantly with other antipsychotics. Although immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

3DOSAGE FORMS AND STRENGTHS

FANAPT tablets are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg. The tablets are white, round, flat, beveled-edged and identified with a logo “Tablet Imprint ” debossed on one side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side.

4 CONTRAINDICATIONS

FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product. Reactions have included pruritus and urticaria.

5 WARNINGS AND PRECAUTIONS

5.1 Increased Risks in Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. FANAPT is not approved for the treatment of patients with dementia-related psychosis [s ee Boxed Warning ] .

Cerebrovascular Adverse Events, Including Stroke

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

5.2 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 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)].

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 ms.

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.

5.3 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. 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.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of this syndrome should include: (1) immediate discontinuation of the antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4 Tardive Dyskinesia

Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, which may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely on prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to 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 are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic administered increases. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask 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 minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) 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, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

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.

5.5 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. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because FANAPT was not marketed at the time these studies were performed, it is not known if FANAPT is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

5.6 Weight Gain

Based on the pooled data from the four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the proportions of patients having a weight gain of ≥ 7% body weight was 12% for FANAPT 10-16 mg/day, 18% for FANAPT 20-24 mg/day, and 13% for FANAPT (combined doses) versus 4% for placebo. The mean weight change from baseline to endpoint in the short-term studies was -0.1 kg for placebo versus 2.0 kg for FANAPT-treated patients. Across all short- and long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.

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