Paliperidone (Page 4 of 10)

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 Paliperidone Extended-Release Tablets-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials*

Percentage of Patients

Paliperidone Extended-Release Tablets

Placebo

3 mg once daily

6 mg once daily

9 mg once daily

12 mg once daily

Body System or Organ Class

(N = 355)

(N = 127)

(N = 235)

(N = 246)

(N = 242)

Dictionary-Derived Term

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

* 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 *

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

Body System or Organ Class

(N = 51)

(N = 54)

(N = 16)

(N = 45)

(N = 35)

Dictionary-Derived Term

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

* 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 Paliperidone Extended-Release Tablets-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials *

Percentage of Patients

Paliperidone Extended-Release Tablets

Paliperidone Extended-Release Tablets

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

Body System or Organ Class

(N = 202)

(N = 108)

(N = 98)

(N = 214)

Dictionary-Derived Term

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

* 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

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

* 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

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

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

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

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

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

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.

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