Paliperidone: Package Insert and Label Information (Page 2 of 5)

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 the paliperidone extended-release tablets are non-deformable and does 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 extended-release tablets, 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 tablets in patients with severe neutropenia (absolute neutrophil count < 1000/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 and WARNINGS 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 were evaluated in 1205 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 were evaluated in 150 adolescent subjects 12 years to 17 years of age with schizophrenia who received paliperidone extended-release tablets in the dose range of 1.5 mg/day to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

The safety of paliperidone extended-release tablets were 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 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 4. Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablet -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 tablet 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 tablet 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.
	Percentage of Patients
	Paliperidone Extended-Release Tablets
Body System or Organ Class	Placebo	3 mg once daily	6 mg once daily	9 mg once daily	12 mg once daily
Dictionary-Derived Term	(N = 355)	(N = 127)	(N = 235)	(N = 246)	(N = 242)
Total percentage of subjects with adverse reactions	37	48	47	53	59
Cardiac disorders
Atrioventricular block first degree	1	2	0	2	1
Bundle branch block	2	3	1	3	< 1
Sinus arrhythmia	0	2	1	1	< 1
Tachycardia	7	14	12	12	14
Gastrointestinal disorders
Abdominal pain upper	1	1	3	2	2
Dry mouth	1	2	3	1	3
Salivary hypersecretion	< 1	0	< 1	1	4
General disorders
Asthenia	1	2	< 1	2	2
Fatigue	1	2	1	2	2
Nervous system disorders
Akathisia	4	4	3	8	10
Dizziness	4	6	5	4	5
Extrapyramidal symptoms	8	10	7	20	18
Headache	12	11	12	14	14
Somnolence	7	6	9	10	11
Vascular disorders
Orthostatic hypotension	1	2	1	2	4

Adolescent Patients with Schizophrenia

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12 years 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 tablet-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 Tablet-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.
	Percentage of Patients
	Paliperidone Extended-Release Tablets
Body System or Organ Class	Placebo	1.5 mg once daily	3 mg once daily	6 mg once daily	12 mg once daily
Dictionary-Derived Term	(N = 51)	(N = 54)	(N = 16)	(N = 45)	(N = 35)
Total percentage of subjects with adverse reactions	43	37	50	58	74
Cardiac disorders
Tachycardia	0	0	6	9	6
Eye disorders
Vision blurred	0	0	0	0	3
Gastrointestinal disorders
Dry mouth	2	0	0	0	3
Salivary hypersecretion	0	2	6	2	0
Swollen tongue	0	0	0	0	3
Vomiting	10	0	6	11	3
General disorders
Asthenia	0	0	0	2	3
Fatigue	0	4	0	2	3
Infections and infestations
Nasopharyngitis	2	4	0	4	0
Investigations
Weight increased	0	7	6	2	3
Nervous system disorders
Akathisia	0	4	6	11	17
Dizziness	0	2	6	2	3
Extrapyramidal symptoms	0	4	19	18	23
Headache	4	9	6	4	14
Lethargy	0	0	0	0	3
Somnolence	4	9	13	20	26
Tongue paralysis	0	0	0	0	3
Psychiatric disorders
Anxiety	4	0	0	2	9
Reproductive system and breast disorders
Amenorrhea	0	0	6	0	0
Galactorrhea	0	0	0	4	0
Gynecomastia	0	0	0	0	3
Respiratory, thoracic and mediastinal disorders
Epistaxis	0	0	0	2	0

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

Table 6. Adverse Drug Reactions Reported by ≥2% of Paliperidone Extended-Release Tablet-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 tablet 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.
		Percentage of Patients
		Paliperidone Extended-Release Tablets	Paliperidone Extended-Release Tablets	Paliperidone Extended-Release Tablets
Body System or Organ Class	Placebo	3 mg to 6 mg once-daily fixed-dose range	9 mg to 12 mg once-daily fixed-dose range	3 mg to 12 mg once-daily flexible dose
Dictionary-Derived Term	(N = 202)	(N = 108)	(N = 98)	(N = 214)
Total percentage of subjects with adverse reactions	32	48	50	43
Cardiac disorders
Tachycardia	2	3	1	2
Gastrointestinal disorders
Abdominal discomfort/ Abdominal pain upper	1	1	0	3
Constipation	2	4	5	4
Dyspepsia	2	5	6	6
Nausea	6	8	8	5
Stomach discomfort	1	0	1	2
General disorders
Asthenia	1	3	4	< 1
Infections and Infestations
Nasopharyngitis	1	2	5	3
Rhinitis	0	1	3	1
Upper respiratory tract infection	1	2	2	2
Investigations
Weight increased	1	5	4	4
Metabolism and nutrition disorders
Decreased appetite	< 1	1	0	2
Increased appetite	< 1	3	2	2
Musculoskeletal and connective tissue disorders
Back pain	1	1	1	3
Myalgia	< 1	2	4	1
Nervous system disorders
Akathisia	4	4	6	6
Dysarthria	0	1	4	2
Extrapyramidal symptoms	8	20	17	12
Somnolence	5	12	12	8
Psychiatric disorders
Sleep disorder	<1	2	3	0
Respiratory, thoracic and mediastinal disorders
Cough	1	1	3	1
Pharyngolaryngeal pain	<1	0	2	1

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 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
	Percentage of Patients
	Paliperidone Extended – Release Tablets
	Placebo	3 mg once – daily	6 mg once – daily	9 mg once – daily	12 mg once – daily
EPS Group	( N = 355 )	( N = 127 )	( N = 235 )	( N = 246 )	( N = 242 )
Parkinsonism *	9	11	3	15	14
Akathisia †	6	6	4	7	9
Use of anticholinergic medications ‡	10	10	9	22	22

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
	Percentage of Patients
	Paliperidone Extended – Release Tablets
	Placebo	3 mg once – daily	6 mg once – daily	9 mg once – daily	12 mg once – daily
EPS Group	( N = 355 )	( N = 127 )	( N = 235 )	( N = 246 )	( N = 242 )
Overall percentage of patients with EPS- related AE	11	13	10	25	26
Dyskinesia	3	5	3	8	9
Dystonia	1	1	1	5	5
Hyperkinesia	4	4	3	8	10
Parkinsonism	2	3	3	7	6
Tremor	3	3	3	4	3

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
	Percentage of Patients
	Paliperidone Extended-Release Tablets
	Placebo	3 mg to 6 mg once-daily fixed-dose range	9 mg to 12 mg once-daily fixed-dose range	3 mg to 12 mg once-daily flexible dose
EPS Group	(N = 202)	(N = 108)	(N = 98)	(N = 214)
Overall percentage of patients with EPS-related AE	11	23	22	17
Dyskinesia	1	3	1	1
Dystonia	1	2	3	2
Hyperkinesia	5	5	8	7
Parkinsonism	3	14	7	7
Tremor	3	12	11	5

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
	Percentage of Patients
	Paliperidone Extended-Release Tablets
	Placebo	1.5 mg once-daily	3 mg once-daily	6 mg once-daily	12 mg once-daily
EPS Group	(N = 51)	(N = 54)	(N = 16)	(N = 45)	(N = 35)
Overall percentage of patients with EPS- related AE	0	6	25	22	40
Hyperkinesia	0	4	6	11	17
Dystonia	0	2	0	11	14
Tremor	0	2	6	7	11
Parkinsonism	0	0	6	2	14
Dyskinesia	0	2	6	2	6

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

Opisthotonos

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 were also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone 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.