Paliperidone (oral)

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# Black Box Warning

# Overview
Paliperidone (oral) is a typical antipsychotic that is FDA approved for the treatment of schizophrenia, schizoaffective disorder. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include tachycardia, hyperprolactinemia,weight gain, constipation, indigestion, akathisia, dyskinesia, dystonia, extrapyramidal disease, parkinsonism, somnolence, tremor, anxiety, nasopharyngitis.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Schizophrenia
- Dosing information
- Recommended dosage: 6 mg PO qd.
- Initial dose titration is not required. Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase in adverse reactions. Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.
- In a longer-term study, INVEGA has been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on INVEGA for 6 weeks. INVEGA should be prescribed at the lowest effective dose for maintaining clinical stability and the physician should periodically reevaluate the long-term usefulness of the drug in individual patients.

### Schizoaffective Disorder
- Dosing information
- Recommended dosage: 6 mg PO qd.
- Initial dose titration is not required.
- Recommended dose range: 3 to 12 mg PO qd
- A general trend for greater effects was seen with higher doses. This trend must be weighed against dose-related increase in adverse reactions. Dosage adjustment, if indicated, should occur only after clinical reassessment. Dose increases, if indicated, generally should occur at intervals of more than 4 days. When dose increases are indicated, increments of 3 mg/day are recommended.
- The maximum recommended dose is 12 mg/day.

### Use with Risperidone
- Concomitant use of INVEGA with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with paliperidone.

### Dosage in Special Populations
- Renal Impairment
- Dosing must be individualized according to the patient's renal function status.
- For patients with mild renal impairment (creatinine clearance  50 mL/min to < 80 mL/min), the recommended initial dose of paliperidone is 3 mg once daily. The dose may then be increased to a maximum of 6 mg once daily based on clinical response and tolerability. For patients with moderate to severe renal impairment (creatinine clearance  10 mL/min to < 50 mL/min), the recommended initial dose of paliperidone is 1.5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As paliperidone has not been studied in patients with creatinine clearance below 10 mL/min, use is not recommended in such patients.
- Hepatic Impairment
- For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A and B), no dose adjustment is recommended. paliperidone has not been studied in patients with severe hepatic impairment.
- Elderly
- Because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status. In general, recommended dosing for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. For patients with moderate to severe renal impairment (creatinine clearance 10 mL/min to < 50 mL/min), the maximum recommended dose of paliperidone is 3 mg once daily.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paliperidone in adult patients.

### NonGuideline-Supported Use

### Bipolar I disorder
- Dosing information
- Not applicable 

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### schizophrenia
- Dosing information for Adolescents (1217 years of age)
- Recommended starting dosage: 3 mg PO qd. Initial dose titration is not required.
- Dose increases, if considered necessary, should be made only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than 5 days. Prescribers should be mindful that, in the adolescent schizophrenia study, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater, while adverse events were dose-related.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paliperidone in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Paliperidone in pediatric patients.

# Contraindications
- Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone and paliperidone. Paliperidone is a metabolite of risperidone and is therefore contraindicated in patients with a known hypersensitivity to risperidone, or to any of the excipients in paliperidone.

# Warnings

### 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. Paliperidone is not approved for the treatment of dementia-related psychosis.

### Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients With Dementia-Related Psychosis
- In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Paliperidone was not marketed at the time these studies were performed. paliperidone is not approved for the treatment of patients with dementia-related psychosis.

### Neuroleptic Malignant Syndrome
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, 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 pathology.
- The management of NMS should include: (1) immediate discontinuation of 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 uncomplicated NMS.
- If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.

### QT Prolongation
- Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone 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. Paliperidone 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 the occurrence 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.
- The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.
- In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended 12 mg dose of paliperidone (Cmax ss = 113 ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study.
- For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the paliperidone 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving INVEGA had a QTcLD exceeding 500 msec at any time in any of these three studies.

### Tardive Dyskinesia
- A syndrome of potentially irreversible, involuntary, dyskinetic movements 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 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 appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.
- There is no known treatment for established Tardive Dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. - Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.
- Given these considerations, paliperidone 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 is known to respond to antipsychotic drugs. 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 treated with paliperidone, drug discontinuation should be considered. However, some patients may require treatment with paliperidone despite the presence of the syndrome.

### 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 of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
- Hyperglycemia and Diabetes mellitus
- Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with paliperidone. 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. Because paliperidone was not marketed at the time these studies were performed, it is not known if paliperidone is associated with this increased risk.
- 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 anti-diabetic treatment despite discontinuation of the suspect drug.
- Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.
- In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean change in glucose of +3.3 mg/dL at Week 24 (n=570) and +4.6 mg/dL at Week 52 (n=314).
- Data from the placebo-controlled 6-week study in adolescent subjects (1217 years of age) with schizophrenia are presented in Table 1b.
Dyslipidemia
- Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
- Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 2a.
- In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b) triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52 (n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and (d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52 (n=302).
- Data from the placebo-controlled 6-week study in adolescent subjects (1217 years of age) with schizophrenia are presented in Table 2b.
Weight Gain
- Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
- Schizophrenia Trials
- Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of  7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects are presented in Table 3a.
- In the uncontrolled, longer-term open-label extension studies, paliperidone was associated with a mean change in weight of +1.4 kg at Week 24 (n=63) and +2.6 kg at Week 52 (n=302).
- Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind, placebo-controlled study and an open-label extension with a median duration of exposure to paliperidone of 182 days. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of  7% of body weight from the placebo-controlled 6-week study in adolescent subjects (1217 years of age) are presented in Table 3b.
- In the open-label long-term study the proportion of total subjects treated with paliperidone with an increase in body weight of  7% from baseline was 33%. When treating adolescent patients with paliperidone, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to paliperidone in the open-label study (182 days) along with expected normal growth in this population based on age and gender, an assessment of standardized scores relative to normative data provides a more clinically relevant measure of changes in weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant.
- Schizoaffective disorder Trials
- In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, a higher percentage of paliperidone-treated subjects (5%) had an increase in body weight of  7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of  7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.

### Hyperprolactinemia
- Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.
- Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin 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 in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
- 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 considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats. 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, but the available evidence is too limited to be conclusive.

### Potential for Gastrointestinal Obstruction
- Because the paliperidone tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, paliperidone should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable controlled-release formulations. Because of the controlled-release design of the tablet, paliperidone should only be used in patients who are able to swallow the tablet whole.
- A decrease in transit time, e.g., as seen with diarrhea, would be expected to decrease bioavailability and an increase in transit time, e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These changes in bioavailability are more likely when the changes in transit time occur in the upper GI tract.

### Orthostatic Hypotension and Syncope
- Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose trials in subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with paliperidone (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo. paliperidone should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

### Leukopenia, neutropenia, and Agranulocytosis
- Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including paliperidone. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of paliperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
- Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue paliperidone and have their WBC followed until recovery.

### Potential for Cognitive and Motor Impairment
- Somnolence was reported in subjects treated with INVEGA. Antipsychotics, including paliperidone, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

### Seizures
- During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled, 6-week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in 0.22% of subjects treated with paliperidone (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, paliperidone should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

### Dysphagia
- Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Paliperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

### Suicide
- The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for paliperidone should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

### Priapism
- Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

### Thrombotic Thrombocytopenic Purpura(TTP)
- No cases of TTP were observed during clinical studies with paliperidone. Although cases of TTP have been reported in association with risperidone administration, the relationship to risperidone therapy is unknown.

### Body Temperature Regulation
- Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing paliperidone to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

### Antiemetic Effect
- An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumor.

### Use in Patients with Concomitant Illness
- Clinical experience with paliperidone in patients with certain concomitant illnesses is limited.
- Patients with Parkinson's Disease or dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the Neuroleptic Malignant Syndrome.
- Paliperidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with paliperidone, caution should be observed in patients with known cardiovascular disease.

### Monitoring: Laboratory Tests
- No specific laboratory tests are recommended.

# Adverse Reactions

## Clinical Trials Experience

### Overall Adverse Reaction Profile
- The following adverse reactions are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis.
- Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis.
- Neuroleptic Malignant Syndrome.
- QT prolongation.
- Tardive Dyskinesia.
- Metabolic changes.
- hyperprolactinemia.
- Potential for gastrointestinal obstruction.
- orthostatic hypotension and syncope.
- leukopenia, neutropenia, and agranulocytosis.
- Potential for cognitive and motor impairment.
- seizures.
- Dysphagia.
- Suicide.
- Priapism.
- Thrombotic thrombocytopenic purpura (TTP).
- Disruption of body temperature regulation.
- Antiemetic effect.
- Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies.
- Diseases or conditions that could affect metabolism or hemodynamic responses.
- The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with paliperidone and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with paliperidone and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.
- The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of paliperidone-treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of paliperidone-treated subjects.
- The safety of paliperidone was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received paliperidone at fixed doses ranging from 3 mg to 12 mg once daily.
- The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received paliperidone at daily doses within the range of 3 mg to 15 mg (n=104), is also included.
- The safety of paliperidone was evaluated in 150 adolescent subjects 1217 years of age with schizophrenia who received paliperidone in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.
- The safety of paliperidone was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of paliperidone: 6 mg with the option to reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. In the other study, 214 subjects received flexible doses of paliperidone (312 mg once daily). Both studies included subjects who received paliperidone either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
- Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of paliperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for paliperidone often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials 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.

### Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials  schizophrenia in Adults and Adolescents
- Adult Patients with schizophrenia
- Table 4 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or more of subjects treated with paliperidone in any of the dose groups, and for which the incidence in paliperidone-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.
- Adolescent Patients with schizophrenia
- Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 1217 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with paliperidone in any of the dose groups, and for which the incidence in paliperidone-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

### Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials  Schizoaffective Disorder in Adults
- Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with paliperidone and for which the incidence in paliperidone-treated subjects was greater than the incidence in subjects treated with placebo.
- Monotherapy versus Adjunctive Therapy
- The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received paliperidone as monotherapy and 190 (45%) subjects received paliperidone as an adjunct to mood stabilizers and/or antidepressants. When comparing these 2 subpopulations, only nausea occurred at a greater frequency ( 3% difference) in subjects receiving paliperidone as monotherapy.

### Discontinuations Due to Adverse Reactions
- Schizophrenia Trials.
- The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in paliperidone- and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in paliperidone- and placebo-treated subjects, respectively).
- Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (<1% of paliperidone-treated subjects).
- Schizoaffective disorder Trials
- The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and <1% in paliperidone- and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in paliperidone- and placebo-treated subjects, respectively).

### Dose-Related Adverse Reactions
- Schizophrenia Trials
- Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with paliperidone, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.
- In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the adverse reactions that occurred with >2% incidence in the subjects treated with paliperidone, the incidences of the following adverse reactions increased with dose: tachycardia, akathisia, extrapyramidal symptoms, somnolence, and headache.
- Schizoaffective disorder Trials
- In a placebo-controlled, 6-week, high- and low-dose study in adult subjects with schizoaffective disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of paliperidone compared with subjects who received lower doses.

### Demographic Differences
- An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on the basis of gender or race alone; there was also no difference on the basis of age.

### Extrapyramidal Symptoms (EPS)
- Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates parkinsonism, (2) the Barnes akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS (Table 7), and (4) incidence of spontaneous reports of EPS (Table 8).
- For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and paliperidone 3 mg and 6 mg doses for any of these EPS measures.
- Compared to data from the studies in adults subjects with schizophrenia, pooled data from the two placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types and frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous reports of EPS-related adverse events. For subjects with schizoaffective disorder, there was no dose-related increase in EPS observed for parkinsonism with the Simpson-Angus scale or akathisia with the Barnes akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of anticholinergic medications.
- Table 9 shows the EPS data from the pooled schizoaffective disorder trials.
- The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies (Table 10).
- Dystonia.
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

### Laboratory Test Abnormalities
- In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between paliperidone and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between paliperidone and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, paliperidone was associated with increases in serum prolactin.

### Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone
- The following additional adverse reactions occurred in < 2% of paliperidone-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by paliperidone-treated subjects who participated in other clinical studies.
Cardiac disorders: bradycardia, palpitations
Eye disorders: eye movement disorder
Gastrointestinal disorders: flatulence
General disorders: edema
Immune system disorders: anaphylactic reaction
Infections and infestations: urinary tract infection
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased
Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity
Nervous system disorders: opisthotonus
Psychiatric disorders: agitation, insomnia, nightmare
Reproductive system and breast disorders: breast discomfort, menstruation irregular, retrograde ejaculation
Respiratory, thoracic and mediastinal disorders: nasal congestion
Skin and subcutaneous tissue disorders: pruritus, rash
Vascular disorders: hypertension
- The safety of paliperidone was also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone in adults with schizophrenia. In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase.

### Adverse Reactions Reported With Risperidone
- Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.

## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, ileus, priapism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention.

# Drug Interactions

### Potential for paliperidone to Affect Other Drugs
- Given the primary CNS effects of paliperidone, paliperidone should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.
- Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when paliperidone is administered with other therapeutic agents that have this potential.
- Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.
- Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations.
- No in vivo data are available and the clinical relevance is unknown.
- Pharmacokinetic interaction between lithium and paliperidone is unlikely.
- In a drug interaction study, co-administration of paliperidone (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when paliperidone 315 mg/day was added to their existing valproate treatment.

### Potential for Other Drugs to Affect paliperidone
- Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate.
- Co-administration of paliperidone 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of paliperidone should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone should be re-evaluated and decreased if necessary.
- Paliperidone is metabolized to a limited extent by CYP2D6. In an interaction study in healthy subjects in which a single 3 mg dose of paliperidone was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.
- Co-administration of a single dose of paliperidone 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for paliperidone should be considered when paliperidone is co-administered with valproate after clinical assessment.
- Pharmacokinetic interaction between lithium and paliperidone is unlikely.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well controlled studies of paliperidone in pregnant women.
Use of first generation antipsychotic drugs during the last trimester of pregnancy has been associated with extrapyramidal symptoms in the neonate. These symptoms are usually self-limited. It is not known whether paliperidone, when taken near the end of pregnancy, will lead to similar neonatal signs and symptoms.
- In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated during the period of organogenesis with up to 8 times the maximum recommended human dose of paliperidone (on a mg/m2 basis).
- In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, there were increases in pup deaths seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m2 basis.
- Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- Paliperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paliperidone (oral) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Paliperidone (oral) during labor and delivery.

### Nursing Mothers
- Paliperidone is excreted in human breast milk. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone.

### Pediatric Use
- Safety and effectiveness of paliperidone in the treatment of schizophrenia were evaluated in 150 adolescent subjects 1217 years of age with schizophrenia who received paliperidone in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.
- Safety and effectiveness of paliperidone for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of paliperidone for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied.
- In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 23 times those in adolescents.
- Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the maximum recommended human dose of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.
The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

### Geriatic Use
- The safety, tolerability, and efficacy of paliperidone were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of paliperidone (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of paliperidone (3 mg to 15 mg once daily). There were no subjects  65 years of age in the schizoaffective disorder studies.
- Overall, of the total number of subjects in schizophrenia clinical studies of paliperidone (n = 1796), including those who received paliperidone or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment, who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

### Gender
There is no FDA guidance on the use of Paliperidone (oral) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Paliperidone (oral) with respect to specific racial populations.

### Renal Impairment
Dosing must be individualized according to the patient's renal function status

### Hepatic Impairment
No dosage adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Paliperidone (oral) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Paliperidone (oral) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral
- Paliperidone can be taken with or without food.
- paliperidone must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

### Monitoring
FDA Package Insert for Paliperidone contains no information regarding drug monitoring.

# IV Compatibility
There is limited information about the IV Compatibility.

# Overdosage

### Human Experience
- While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of paliperidone was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.
- Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

### Management of Overdosage
- There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered.
- In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
- The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
- Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.
- Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

## DRUG ABUSE AND DEPENDENCE

### Controlled Substance
- Paliperidone  is not a controlled substance.

### Abuse
- Paliperidone has not been systematically studied in animals or humans for its potential for abuse. It is not possible to predict the extent to which a CNS-active drug 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 paliperidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

### Dependence
- Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

# Pharmacology

## Mechanism of Action
- Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

## Structure
There is limited information regarding Paliperidone (oral) Structure in the drug label.

## Pharmacodynamics
- Paliperidone is a centrally active dopamine Type 2 (D2) antagonist and with predominant serotonin Type 2 (5HT2A) activity. Paliperidone is also active as an antagonist at 1 and 2 adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or 1- and 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

## Pharmacokinetics
- Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (Cmax) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following paliperidone administration are dose-proportional within the available dose range. The terminal elimination half-life of paliperidone is approximately 23 hours.
- Steady-state concentrations of paliperidone are attained within 45 days of dosing with paliperidone in most subjects. The mean steady-state peak:trough ratio for an paliperidone dose of 9 mg was 1.7 with a range of 1.23.1.
- Following administration of paliperidone, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.
Absorption and Distribution
- The absolute oral bioavailability of paliperidone following paliperidone administration is 28%.
- Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean Cmax and AUC values of paliperidone that were increased by 60% and 54%, respectively, compared with administration under fasting conditions. Clinical trials establishing the safety and efficacy of paliperidone were carried out in subjects without regard to the timing of meals. While paliperidone can be taken without regard to food, the presence of food at the time of paliperidone administration may increase exposure to paliperidone.
- Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of racemic paliperidone is 74%.
Metabolism and Elimination
- Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone.
- One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone to 5 healthy volunteers, 59% (range 51%  67%) of the dose was excreted unchanged into urine, 32% (26%  41%) of the dose was recovered as metabolites, and 6%  12% of the dose was not recovered. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four primary metabolic pathways have been identified in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission.
- Population pharmacokinetic analyses found no difference in exposure or clearance of paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.
Special Populations
Renal Impairment
- The dose of paliperidone should be reduced in patients with moderate or severe renal impairment. The disposition of a single dose paliperidone 3 mg extended-release tablet was studied in adult subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared to healthy subjects. The mean terminal elimination half-life of paliperidone was 24 hours, 40 hours, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl  80 mL/min).
Hepatic Impairment
- In a study in adult subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment.
- Adolescents (1217 years of age)
- Paliperidone systemic exposure in adolescents weighing  51 kg ( 112 lbs) was similar to that in adults. In adolescents weighing < 51 kg (< 112 lbs), a 23% higher exposure was observed; this is considered not to be clinically significant. Age did not influence the paliperidone exposure.
Elderly
- No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance.
Race
- No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in Japanese and Caucasians.
Gender
- No dosage adjustment is recommended based on gender. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in men and women.
Smoking
- No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Carcinogenicity studies of paliperidone have not been performed.
- Carcinogenicity studies of risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. risperidone was administered in the diet at daily doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the maximum recommended human dose of risperidone on a mg/m2 basis. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents in terms of human risk is unknown.
Mutagenesis
- No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo rat micronucleus test.
Impairment of Fertility
- In a study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, which is half of the maximum recommended human dose on a mg/m2 basis.
- The fertility of male rats was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg  5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration. Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).

# Clinical Studies

### Schizophrenia
- The acute efficacy of paliperidone (3 mg to 15 mg once daily) was established in three placebo-controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in non-elderly adult subjects (mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were carried out in North America, Eastern Europe, Western Europe, and Asia. The doses studied among these three trials included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15 mg/day. Dosing was in the morning without regard to meals.
- Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacy was also evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in the domains of socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors.
- In all 3 studies (n = 1665), paliperidone was superior to placebo on the PANSS at all doses. Mean effects at all doses were fairly similar, although the higher doses in all studies were numerically superior. paliperidone was also superior to placebo on the PSP in these trials.
- An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age (there were few patients over 65), or geographic region. There were insufficient data to explore differential effects based on race.
- In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had clinically responded (defined as PANSS score  70 or  4 on pre-defined PANSS subscales, as well as having been on a stable fixed dose of paliperidone for the last two weeks of an 8-week run-in phase) were entered into a 6-week open-label stabilization phase where they received paliperidone (doses ranging from 3 mg to 15 mg once daily). After the stabilization phase, patients were randomized in a double-blind manner to either continue on paliperidone at their achieved stable dose, or to placebo, until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as significant increase in PANSS (or pre-defined PANSS subscales), hospitalization, clinically significant suicidal or homicidal ideation, or deliberate injury to self or others. An interim analysis of the data showed a significantly longer time to relapse in patients treated with paliperidone compared to placebo, and the trial was stopped early because maintenance of efficacy was demonstrated.
- The efficacy of paliperidone in adolescent subjects with schizophrenia was established in a randomized, double-blind, parallel-group, placebo-controlled, 6-week study using a fixed-dose weight-based treatment group design over the dose range of 1.5 to 12 mg/day. The study was carried out in the US, India, Romania, Russia, and Ukraine, and involved subjects 1217 years of age meeting DSM-IV criteria for schizophrenia, with diagnosis confirmation using the Kiddie Schedule for Affective Disorders and schizophrenia-Present and Lifetime Version (K-SADS-PL).
- Eligible subjects were randomly assigned to 1 of 4 treatment groups: a placebo group or paliperidone Low, Medium, or High dose groups. Doses were administered based on body weight to minimize the risk of exposing lower-weight adolescents to high doses of paliperidone. Subjects weighing between 29 kg and less than 51 kg at the baseline visit were randomly assigned to receive placebo or 1.5 mg (Low dose), 3 mg (Medium dose), or 6 mg (High dose) of paliperidone daily, and subjects weighing at least 51 kg at the baseline visit were randomly assigned to receive placebo or 1.5 mg (Low dose), 6 mg (Medium dose), or 12 mg (High dose) of paliperidone daily. Dosing was in the morning without regard to meals.
- Efficacy was evaluated using PANSS. Overall, this study demonstrated the efficacy of paliperidone in adolescents with schizophrenia in the dose range of 3 to 12 mg/day. Doses within this broad range were shown to be effective, however, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater. Although paliperidone was adequately tolerated within the dose range of 3 to 12 mg/day, adverse events were dose related.

### Schizoaffective disorder
- The acute efficacy of paliperidone (3 mg to 12 mg once daily) in the treatment of schizoaffective disorder was established in two placebo-controlled, 6-week trials in non-elderly adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16 on the Young Mania Rating Scale and/or Hamilton Rating Scale for Depression. The population included subjects with schizoaffective bipolar and depressive types.
- In one of these trials, efficacy was assessed in 211 subjects who received flexible doses of paliperidone (312 mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of two dose levels of paliperidone: 6 mg with the option to reduce to 3 mg (n = 105) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. Both studies included subjects who received paliperidone either as monotherapy  or as an adjunct to mood stabilizers and/or antidepressants (45%). The most commonly used mood stabilizers were valproate and lithium. The most commonly used antidepressants were SSRIs and SNRIs. Paliperidone was dosed in the morning without regard to meals. Studies were carried out in the United States, Eastern Europe, Russia, and Asia.
- Efficacy was evaluated using the PANSS, a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. As secondary outcomes, mood symptoms were evaluated using the Hamilton Depression Rating Scale (HAM-D-21) and the Young Mania Rating Scale (YMRS).
- The paliperidone group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal dose of 8.6 mg/day) and the higher dose group of paliperidone in the 2 dose-level study (12 mg/day with option to reduce to 9 mg/day) were each superior to placebo in the PANSS. Numerical improvements in mood symptoms were also observed, as measured by the HAM-D-21 and YMRS. In the lower dose group of the 2 dose-level study (6 mg/day with option to reduce to 3 mg/day), paliperidone was not significantly different from placebo as measured by the PANSS.
- Taking the results of both studies together, paliperidone improved the symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic region. There were insufficient data to explore differential effects based on race.

# How Supplied
- Paliperidone Extended-Release Tablets are available in the following strengths and packages. All tablets are capsule-shaped.
- 1.5 mg tablets are orange-brown and imprinted with "PAL 1.5", and are available in bottles of 30 (NDC 50458-554-01).
- 3 mg tablets are white and imprinted with "PAL 3", and are available in bottles of 30 (NDC 50458-550-01) and hospital unit dose packs of 100 (NDC 50458-550-10).
- 6 mg tablets are beige and imprinted with "PAL 6", and are available in bottles of 30 (NDC 50458-551-01) and hospital unit dose packs of 100 (NDC 50458-551-10).
- 9 mg tablets are pink and imprinted with "PAL 9", and are available in bottles of 30 (NDC 50458-552-01) and hospital unit dose packs of 100 (NDC 50458-552-10).

## Storage
- Store up to 25C (77F); excursions permitted to 15  30C (59  86F). Protect from moisture.
- Keep out of reach of children.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Physicians are advised to discuss the following issues with patients for whom they prescribe paliperidone.

### Orthostatic hypotension
- Patients should be advised that there is risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose.

### Interference with Cognitive and Motor Performance
- As INVEGA has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that INVEGA therapy does not affect them adversely.

## =Pregnancy
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with INVEGA.

### Nursing
- Caution should be exercised when INVEGA is administered to a nursing woman. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone.

### Concomitant Medication
- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.

### Alcohol
- Patients should be advised to avoid alcohol while taking INVEGA.

### Heat Exposure and dehydration
- Patients should be advised regarding appropriate care in avoiding overheating and dehydration.

### Administration
- Patients should be informed that INVEGA should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice something that looks like a tablet in their stool.

# Precautions with Alcohol
- Patients should be advised to avoid alcohol while taking INVEGA

# Brand Names
- INVEGA

# Look-Alike Drug Names
There is limited information regarding Paliperidone (oral) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price