FDA Label for Paliperidone

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. Paliperidone extended-release tablets are not approved for the treatment of patients with dementia-related psychosis. [see Warnings and Precautions (5.1)]

1.1 Schizophrenia

Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14.1)].

The efficacy of paliperidone extended-release tablets in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults.

1.2 Schizoaffective Disorder

Paliperidone extended-release tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2)].

The efficacy of paliperidone extended-release tablets in schizoaffective disorder was established in two 6-week trials in adults.

2.1 Schizophrenia

Adults

The recommended dose of paliperidone extended-release tablets for the treatment of schizophrenia in adults is 6 mg administered once daily. 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, paliperidone extended-release tablets have been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on paliperidone extended-release tablets for 6 weeks [see Clinical Studies (14)]. Paliperidone extended-release tablets 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.

Adolescents (12 to 17 years of age)

The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents 12 to 17 years of age is 3 mg administered once daily. 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.

2.2 Schizoaffective Disorder

The recommended dose of paliperidone extended-release tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended dose range of 3 mg to 12 mg once daily. 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.

2.3 Administration Instructions

Paliperidone extended-release tablets can be taken with or without food.

Paliperidone extended-release tablets 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.

2.4 Use With Risperidone

Concomitant use of paliperidone extended-release tablets 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 extended-release tablets.

2.5 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 extended-release tablets 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 extended-release tablets is 1.5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As paliperidone extended-release tablets have not been studied in patients with creatinine clearance below 10 mL/min, use is not recommended in such patients. [See Clinical Pharmacology (12.3)]

Hepatic Impairment

For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A and B), no dose adjustment is recommended [see Clinical Pharmacology (12.3)]. Paliperidone extended-release tablets have 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 extended-release tablets is 3 mg once daily [see Renal Impairment above].

3 Dosage Forms And Strengths

Paliperidone extended-release tablets are available in the following strengths and colors: 1.5 mg (brown), 3 mg (white), 6 mg (beige), and 9 mg (pink). All tablets are capsule shaped and are imprinted with either "A86", "A87", "A88", or "A89".

4 Contraindications

Paliperidone extended-release tablets are contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the paliperidone extended-release tablets formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

5.1 Increased Mortality In Elderly Patients With Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in 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. Paliperidone extended-release tablets are not approved for the treatment of dementia-related psychosis [see Boxed Warning].

5.2 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 extended-release tablets were not marketed at the time these studies were performed. Paliperidone extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

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

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

5.4 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 extended-release tablets (C_{max 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 C_{max 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 extended-release tablets 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving paliperidone extended-release tablets had a QTcLD exceeding 500 msec at any time in any of these three studies.

5.5 Tardive Dyskinesia

A syndrome consisting 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 with duration of treatment and the cumulative dose The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia 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, paliperidone extended-release tablets 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: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient treated with paliperidone extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with paliperidone extended-release tablets despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all 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 extended-release tablets. 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 extended-release tablets were not marketed at the time these studies were performed, it is not known if paliperidone extended-release tablets are 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 extended-release tablets were 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 (12 to 17 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 extended-release tablets were 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 (12 to 17 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 extended-release tablets were 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 extended-release tablets 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 [see Clinical Studies (14.1)] from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) are presented in Table 3b.

In the open-label long-term study the proportion of total subjects treated with paliperidone extended-release tablets with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with paliperidone extended-release tablets, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to paliperidone extended-release tablets 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 extended-release tablets-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.

5.7 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 [see Nonclinical Toxicology (13.1)]. 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.

5.8 Potential For Gastrointestinal Obstruction

Because paliperidone extended-release tablets are non-deformable and do not appreciably change in shape in the gastrointestinal tract, paliperidone extended-release tablets 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 pseudo-obstruction, 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 extended-release tablets should only be used in patients who are able to swallow the tablet whole [see Dosage and Administration (2.3) and Patient Counseling Information (17)].

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.

5.9 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 extended-release tablets (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo.

Paliperidone extended-release tablets 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.

5.10 Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including paliperidone, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.11 Leukopenia, Neutropenia, And Agranulocytosis

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including paliperidone extended-release tablets. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of paliperidone extended-release tablets at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue paliperidone extended-release tabletsin patients with severe neutropenia (absolute neutrophil count < 1,000/mm³)and follow their WBC until recovery.

5.12 Potential For Cognitive And Motor Impairment

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with paliperidone extended-release tablets [see Adverse Reactions (6.2)]. Antipsychotics, including paliperidone extended-release tablets, 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.

5.13 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 extended-release tablets (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, paliperidone extended-release tablets 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.

5.14 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 extended-release tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.15 Priapism

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

5.16 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 extended-release tablets 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.

6 Adverse Reactions

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

• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning andWarnings and Precautions (5.1)]
• Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• QT prolongation [see Warnings and Precautions (5.4)]
• Tardive dyskinesia [see Warnings and Precautions (5.5)]
• Metabolic changes [see Warnings and Precautions (5.6)]
• Hyperprolactinemia [see Warnings and Precautions (5.7)]
• Potential for gastrointestinal obstruction [see Warnings and Precautions (5.8)]
• Orthostatic hypotension and syncope [see Warnings and Precautions (5.9)]
• Falls [see Warnings and Precautions (5.10)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.11)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.12)]
• Seizures [see Warnings and Precautions (5.13)]
• Dysphagia [see Warnings and Precautions (5.14)]
• Priapism [see Warnings and Precautions (5.15)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.17)]

6.1 Clinical Trials Experience

The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with paliperidone extended-release tablets 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 extended-release tablets 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 extended-release tablets-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 extended-release tablets-treated subjects. [See Adverse Reactions (6.4)].

The safety of paliperidone extended-release tablets was evaluated in 1,205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received paliperidone extended-release tablets 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 extended-release tablets  at daily doses within the range of 3 mg to 15 mg (n = 104), is also included.

The safety of paliperidone extended-release tablets was evaluated in 150 adolescent subjects 12 to 17 years of age with schizophrenia who received paliperidone extended-release tablets 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 extended-release tablets 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 extended-release tablets: 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 extended-release tablets (3 mg to 12 mg once daily). Both studies included subjects who received paliperidone extended-release tablets 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 extended-release tablets (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for paliperidone extended-release tablets 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 extended-release tabletsin any of the dose groups, and for which the incidence in paliperidone extended-release tablets-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 4. Adverse Reactions Reported by ≥ 2% of PaliperidoneExtended-Release Tablets-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials*

* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily paliperidone extended-release tablets doses of 3 mg and 9 mg, the second study included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg [see Clinical Studies (14)]. Extrapyramidal symptoms includes the terms dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity, oculogyration, parkinsonism, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Adverse reactions for which the paliperidone extended-release tablets incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting.

Adolescent Patients with Schizophrenia

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12 to 17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with paliperidone extended-release tablets in any of the dose groups, and for which the incidence in paliperidone extended-release tablets-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 5. Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablets-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial*

* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Extrapyramidal symptoms includes the terms oculogyric crisis, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus, bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, muscle contractions involuntary, parkinsonian gait, parkinsonism, tremor, and restlessness. Somnolence includes the terms somnolence, sedation, and hypersomnia. Insomnia includes the terms insomnia and initial insomnia. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Hypertension includes the terms hypertension and blood pressure increased. Gynecomastia includes the terms gynecomastia and breast swelling.

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 extended-release tabletsand for which the incidence in paliperidone extended-release tablets-treated subjects was greater than the incidence in subjects treated with placebo.

Table 6. Adverse Drug Reactions Reported by ≥ 2% of PaliperidoneExtended-Release Tablets-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials *

* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily paliperidone extended-release tablets doses of 6 mg (with the option to reduce to 3 mg) and  12 mg (with the option to reduce to 9 mg). The second study included flexible once-daily doses of 3 mg to 12 mg. Among the 420 subjects treated with paliperidone extended-release tablets, 230 (55%) received paliperidone extended-release tablets as monotherapy and 190 (45%) received paliperidone extended-release tablets as an adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia, drooling, dyskinesia, dystonia, hypertonia, muscle rigidity, muscle twitching, oculogyration, parkinsonian gait, parkinsonism, restlessness, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased.

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 extended-release tablets as monotherapy and 190 (45%) subjects received paliperidone extended-release tablets 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 extended-release tablets 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 extended-release tablets- and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in paliperidone extended-release tablets- 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 extended-release tablets-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 extended-release tablets- and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in paliperidone extended-release tablets- 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 extended-release tablets, 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 extended-release tablets, 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 extended-release tablets 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 [see Use in Specific Populations (8.5)].

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 extended-release tablets 3 mg and 6 mg doses for any of these EPS measures.

Table 7. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults

* For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of items score divided by the number of items)

† For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2

‡ Percent of patients who received anticholinergic medications to treat emergent EPS

Table 8. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adults

Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia

Dystonia group includes: Dystonia, muscle spasms, oculogyration, trismus

Hyperkinesia group includes: Akathisia, hyperkinesia

Parkinsonism group includes: Bradykinesia, cogwheel rigidity, drooling, hypertonia, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism

Tremor group includes: Tremor

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.

Table 9. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizoaffective Disorder Studies in Adults

Dyskinesia group includes: Dyskinesia, muscle twitching

Dystonia group includes: Dystonia, muscle spasms, oculogyration

Hyperkinesia group includes: Akathisia, hyperkinesia, restlessness

Parkinsonism group includes: Bradykinesia, drooling, hypertonia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonian gait, parkinsonism

Tremor group includes: Tremor

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).

Table 10. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adolescent Subjects

Hyperkinesia group includes: Akathisia

Dystonia group includes: Dystonia, muscle contracture, oculogyric crisis, tongue paralysis, torticollis

Tremor group includes: Tremor

Parkinsonism group includes: Cogwheel rigidity, extrapyramidal disorder, muscle rigidity

Dyskinesia group includes: Dyskinesia, muscle contractions involuntary

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 extended-release tablets 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 extended-release tablets 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 extended-release tablets were associated with increases in serum prolactin [see Warnings and Precautions (5.7)].

Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone Extended-Release Tablets

The following additional adverse reactions occurred in < 2% of paliperidone extended-release tablets-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 extended-release tablets-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 extended-release tablets was also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone extended-release tablets in adults with schizophrenia [see Clinical Studies (14)]. 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.

6.2 Postmarketing Experience

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

6.3 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.

7.1 Potential For Paliperidone Extended-Release Tablets To Affect Other Drugs

Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], paliperidone extended-release tablets 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 extended-release tablets are administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.9)].

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 extended-release tablets is unlikely.

In a drug interaction study, co-administration of paliperidone extended-release tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2,000 mg once daily) did not affect the steady-state pharmacokinetics (AUC_24h and C_max,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 extended-release tablets 3 mg/day to 15 mg/day were added to their existing valproate treatment.

7.2 Potential For Other Drugs To Affect Paliperidone Extended-Release Tablets

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 extended-release tablets 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 C_max 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 extended-release tablets should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone extended-release tablets should be re-evaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an interaction study in healthy subjects in which a single 3 mg dose of paliperidone extended-release tablets 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 extended-release tablets 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C_max and AUC of paliperidone. Dosage reduction for paliperidone extended-release tablets should be considered when paliperidone extended-release tablets are co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and paliperidone extended-release tablets is unlikely.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including paliperidone, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including paliperidone, during pregnancy (see Clinical Considerations).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the maximum recommended human dose (MRHD) based on mg/m² body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including paliperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI 0.88 to 1.81) in a subgroup of 1,566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m² body surface area.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m² body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m² body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m² body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m² body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams (see RISPERDAL^® package insert).

8.2 Lactation

Risk Summary

Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for paliperidone extended-release tablets and any potential adverse effects on the breastfed child from paliperidone or from the mother's underlying condition.

Clinical Considerations

Infants exposed to paliperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

8.3 Females And Males Of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with paliperidone extended-release tablets may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.7)].

8.4 Pediatric Use

Safety and effectiveness of paliperidone extended-release tablets in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12 to 17 years of age with schizophrenia who received paliperidone extended-release tablets 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 extended-release tablets for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of paliperidone extended-release tablets for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied.

Juvenile Animal Studies

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 at MRHD of 12 mg/day. 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 2 to 3 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 MRHD 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 extended-release tablets on growth and sexual maturation have not been fully evaluated in children and adolescents.

8.5 Geriatric Use

The safety, tolerability, and efficacy of paliperidone extended-release tablets 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 extended-release tablets (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 extended-release tablets (3 mg to 15 mg once daily) [see Clinical Studies (14)]. 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 extended-release tablets (n = 1,796), including those who received paliperidone extended-release tablets 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 [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.5)].

8.6 Renal Impairment

Dosing must be individualized according to the patient's renal function status [see Dosage and Administration (2.5)].

8.7 Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone extended-release tablets have not been studied in patients with severe hepatic impairment.

8.8 Patients With Parkinson’S Disease Or Lewy Body Dementia

Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to paliperidone extended-release tablets. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

9.1 Controlled Substance

Paliperidone is not a controlled substance.

9.2 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 extended-release tablets misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

9.3 Dependence

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

10.1 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 extended-release tablets 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.

10.2 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. 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.

11 Description

Paliperidone extended-release tablets contain paliperidone,an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. Paliperidone contains a racemic mixture of (+)- and (-)- paliperidone. The chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C₂₃H₂₇FN₄O₃ and its molecular weight is 426.49. The structural formula is:

Chemical Structure - paliperidone extended release tablets 1

Paliperidone is sparingly soluble in 0.1N HCl and methylene chloride; practically insoluble in water, 0.1N NaOH, and hexane; and slightly soluble in N,N-dimethylformamide.

Paliperidone extended-release tablets are intended for oral administration and are available in 1.5 mg (brown), 3 mg (white), 6 mg (beige), and 9 mg (pink) strengths. Paliperidone extended-release tablets utilize OROS^® osmotic drug-release technology.

Inactive ingredients are butylated hydroxytoluene, cellulose acetate, ferric oxide red, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polyethylene oxides, povidone, stearic acid and sodium chloride. The film coating of 1.5 mg and 6 mg tablets contains ferric oxide red, ferric oxide yellow, ferrosoferric oxide, hypromellose, polyethylene glycol and titanium dioxide. The film coating of 3 mg tablets contains lactose monohydrate, hypromellose, titanium dioxide and triacetin. The film coating of 9 mg tablets contains ferric oxide red, hypromellose, polyethylene glycol and titanium dioxide.

The imprinting ink contains ammonium hydroxide, ferrosoferric oxide, isopropyl alcohol, N-butyl alcohol, shellac glaze and propylene glycol.

Delivery System Components and Performance

Paliperidone extended-release tablets use osmotic pressure to deliver paliperidone at a controlled rate. The delivery system, which resembles a capsule-shaped tablet in appearance, consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There is one precision laser-drilled orifice on the drug-layer dome of the tablet. Each tablet strength has a different colored water-dispersible overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible color overcoat erodes quickly. Water then enters the tablet through the semipermeable membrane that controls the rate at which water enters the tablet core, which, in turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifice. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components.

12.1 Mechanism Of Action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in schizophrenia is unclear. However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D₂) and serotonin Type 2 (5HT_2A) receptor antagonism.

12.2 Pharmacodynamics

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D₂) and serotonin Type 2 (5HT_2A) receptors, with binding affinities (Ki values) of 1.6nM to 2.8 nM for D₂ and 0.8 nM to 1.2 nM for 5HT_2A receptors. Paliperidone is also active as an antagonist at the  α₁ and α₂ 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 β₁- and β₂-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

12.3 Pharmacokinetics

Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C_max) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following paliperidone extended-release tablets 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 4 to 5 days of dosing with paliperidone extended-release tablets in most subjects. The mean steady-state peak:trough ratio for a paliperidone extended-release tablets dose of 9 mg was 1.7 with a range of 1.2 to 3.1.

Following administration of paliperidone extended-release tablets, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies with paliperidone administered orally have not been performed.

Carcinogenicity studies with 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 MRHD of risperidone based on mg/m² body surface area (see risperidone package insert). 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 to human risk is unclear [see Warnings and Precautions (5.7)].

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 which is 2 times the MRHD based on mg/m² body surface area. 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 MRHD based on mg/m² body surface area.

The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the MRHD of 12 mg/day based on mg/m² body surface area, 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 to 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m² body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).

16 How Supplied/Storage And Handling

Paliperidone extended-release tablets are available in the following strengths and packages. All tablets are capsule-shaped.

1.5 mg tablets are brown, capsule-shaped, film-coated tablets, with a small orifice on one end, and imprinted with “A86” on the body. They are available in bottles of 30 with child-resistant closure (NDC 27808-222-01).

 3 mg tablets are white, capsule-shaped, film-coated tablets, with a small orifice on one end, and imprinted with “A87” on the body. They are available in bottles of 30 with child-resistant closure (NDC 27808-223-01).

 6 mg tablets are beige, capsule-shaped, film-coated tablets, with a small orifice on one end, and imprinted with “A88” on the body. They are available in bottles of 30 with child-resistant closure (NDC 27808-224-01).

 9 mg tablets are pink, capsule-shaped, film-coated tablets, with a small orifice on one end, and imprinted with “A89” on the body. They are available in bottles of 30 with child-resistant closure (NDC 27808-225-01)

17 Patient Counseling Information

Physicians are advised to discuss the following issues with patients for whom they prescribe paliperidone extended-release tablets.

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact their healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)].

Leukopenia/ Neutropenia

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia they should have their CBC monitored while taking paliperidone extended-release tablets [see Warnings and Precautions (5.11)].

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of paliperidone extended-release tablets. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.7)].

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that paliperidone extended-release tablets therapy does not affect them adversely [see Warnings and Precautions (5.12)].

Priapism

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.15)].

Heat Exposure and Dehydration

Counsel patients on the importance of avoiding overheating and dehydration [see Warnings and Precautions (5.16)].

Concomitant Medication

Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)].

Alcohol

Advise patients to avoid alcohol while taking paliperidone extended-release tablets [see Drug Interactions (7.1)].

Administration

Patients should be informed that paliperidone extended-release tablets 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 [see Dosage and Administration (2.3)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with paliperidone extended-release tablets. Advise patients that paliperidone may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to paliperidone during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women using paliperidone extended-release tablets to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that paliperidone may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

The brands listed are trademarks of their respective owners.

Manufactured by:

CSPC Ouyi Pharmaceutical Co., Ltd.

Shijiazhuang, Hebei, China, 052160

Manufactured for:

Tris Pharma, Inc.

Monmouth Junction, NJ 08852

www.trispharma.com

LB8649 Rev.00 06/2021

Principal Display Panel - 1.5 Mg Tablet Bottle Label

NDC 27808-222-01

Paliperidone
Extended-Release Tablets

1.5mg

Tablets should be swallowed whole.
Do not divide, crush, or chew.
Paliperidone should be taken once daily.

Rx only
30 Tablets

CSPC Ouyi Pharmaceutical Co., Ltd.

1.5mgbottlelabel30 - paliperidone extended release tablets 2

Principal Display Panel - 3 Mg Tablet Bottle Label

NDC 27808-223-01

Paliperidone
Extended-Release Tablets

3mg

Tablets should be swallowed whole.
Do not divide, crush, or chew.
Paliperidone should be taken once daily.

Rx only
30 Tablets

CSPC Ouyi Pharmaceutical Co., Ltd.

3mgbottlelabel30s - paliperidone extended release tablets 3

Principal Display Panel - 6 Mg Tablet Bottle Label

NDC 27808-224-01

Paliperidone
Extended-Release Tablets

6mg

Tablets should be swallowed whole.
Do not divide, crush, or chew.
Paliperidone should be taken once daily.

Rx only
30 Tablets

CSPC Ouyi Pharmaceutical Co., Ltd.

6mgbottlelabel - paliperidone extended release tablets 4

Principal Display Panel - 9 Mg Tablet Bottle Label

NDC 27808-225-01

Paliperidone
Extended-Release Tablets

9mg

Tablets should be swallowed whole.
Do not divide, crush, or chew.
Paliperidone should be taken once daily.

Rx only
30 Tablets

CSPC Ouyi Pharmaceutical Co., Ltd.

9mgbottlelabel30s - paliperidone extended release tablets 5