PALIPERIDONE: Package Insert and Label Information (Page 3 of 6)

6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder in Adults.

Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with paliperidone and for which the incidence in paliperidone-treated subjects was greater than the incidence in subjects treated with placebo.

Table 6. Adverse Drug Reactions Reported by ≥ 2% of Paliperidone-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 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 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 to 12 mg. Among the 420 subjects treated with paliperidone, 230 (55%) received paliperidone as monotherapy and 190 (45%) received paliperidone 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
	Placebo	Paliperidone 3 – 6 mg once – daily fixed – dose range	Paliperidone 9 – 12 mg once – daily fixed – dose range	Paliperidone 3 – 12 mg once – daily flexible dose range
Body System or Organ Class 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
AbdominalDiscomfort/Abdominal painupper	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
Pharyngolargeal 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 as monotherapy and 190 (45%) subjects received paliperidone as an adjunct to mood stabilizers and/or antidepressants. When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving paliperidone as monotherapy.

6.4 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 were 3% and 1% in paliperidone-and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in paliperidone-and placebo-treated subjects, respectively).
Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (<1% of paliperidone-treated subjects).

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and <1% in paliperidone — and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in paliperidone- and placebo-treated subjects, respectively).

6.5 Dose-Related Adverse Reactions

Schizophrenia Trials

Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with paliperidone, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the adverse reactions that occurred with >2% incidence in the subjects treated with paliperidone, the incidences of the following adverse reactions increased with dose: tachycardia, akathisia, extrapyramidal symptoms, somnolence, and headache.

Schizoaffective Disorder Trials

In a placebo-controlled, 6-week, high- and low-dose study in adult subjects with schizoaffective disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of paliperidone compared with subjects who received lower doses.

6.6 Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in adult in subjects with schizophrenia and in the two placebo-controlled, 6-week studies in 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)].

6.7 Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS (Table 7), and (4) incidence of spontaneous reports of EPS (Table 8). For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and paliperidone 3 mg and 6 mg doses for any of these EPS measures.

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 † 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
	Placebo	3 – 6 mg once – daily fixed – dose range	9 – 12 mg once – daily fixed – dose range	3 – 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
EPS Group	Placebo ( N = 51 )	1 . 5 mg once daily ( N = 54 )	3 mg once daily ( N = 16 )	6 mg once daily ( N = 45 )	12 mg once daily ( 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.