INVEGA (paliperidone 6 mg) Dailymed

• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack, including fatalities). INVEGA^® is not approved for use in patients with dementia-related psychosis (5.2)
• Neuroleptic Malignant Syndrome : Manage with immediate discontinuation of drug and close monitoring (5.3)
• QT Prolongation: Increase in QT interval, avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval (5.4)
• Tardive Dyskinesia: Discontinue drug if clinically appropriate (5.5)
• Hyperglycemia and Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes (5.6)
• Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration (5.7)
• Gastrointestinal Narrowing: Obstructive symptoms may result in patients with gastrointestinal disease (5.8)
• Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension (5.9)
• Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including INVEGA^®. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of INVEGA^® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.10)
• Potential for Cognitive and Motor Impairment : Use caution when operating machinery (5.11)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.12)
• Suicide: Closely supervise high-risk patients (5.14)

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. INVEGA^® (paliperidone) is 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. INVEGA^® was not marketed at the time these studies were performed. INVEGA^® is 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

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

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported.

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 INVEGA^® (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 INVEGA^® 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving INVEGA^® had a QTcLD exceeding 500 msec at any time in any of these three studies.

5.5 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon.

There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, INVEGA^® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA^®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA^® despite the presence of the syndrome.

5.6 Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has 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 INVEGA^®. 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 INVEGA^® was not marketed at the time these studies were performed, it is not known if INVEGA^® is associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

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 INVEGA^® tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, INVEGA^® should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable controlled-release formulations. Because of the controlled-release design of the tablet, INVEGA^® should only be used in patients who are able to swallow the tablet whole [see Dosage and Administration (2.3) and Patient Counseling Information (17.8)].

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 INVEGA^® (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo. INVEGA^® 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 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including INVEGA^®. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of INVEGA^® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm³) should discontinue INVEGA^® and have their WBC followed until recovery.

5.11 Potential for Cognitive and Motor Impairment

Somnolence was reported in subjects treated with INVEGA^® [see Adverse Reactions (6.1, 6.2)]. Antipsychotics, including INVEGA^®, 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.

5.12 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 INVEGA^® (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, INVEGA^® 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.

5.13 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. INVEGA^® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.14 Suicide

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

5.15 Priapism

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

5.16 Thrombotic Thrombocytopenic Purpura (TTP)

No cases of TTP were observed during clinical studies with paliperidone. Although cases of TTP have been reported in association with risperidone administration, the relationship to risperidone therapy is unknown.

5.17 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 INVEGA^® 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.

5.18 Antiemetic Effect

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

5.19 Use in Patients with Concomitant Illness

Clinical experience with INVEGA^® in patients with certain concomitant illnesses is limited [see Clinical Pharmacology (12.3)].

Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

INVEGA^® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with INVEGA^®, caution should be observed in patients with known cardiovascular disease [see Warnings and Precautions (5.9)].

5.20 Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

6 Adverse Reactions

The following 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 events, 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)]
• Hyperglycemia and diabetes mellitus [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)]
• Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.10)]
• Potential for cognitive and motor impairment [see Warnings and Precautions (5.11)]
• Seizures [see Warnings and Precautions (5.12)]
• Dysphagia [see Warnings and Precautions (5.13)]
• Suicide [see Warnings and Precautions (5.14)]
• Priapism [see Warnings and Precautions (5.15)]
• Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.16)]
• Disruption of body temperature regulation [see Warnings and Precautions (5.17)]
• Antiemetic effect [see Warnings and Precautions (5.18)]
• Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.19)]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.19)]

The most common adverse reactions in clinical trials in subjects with schizophrenia (reported in 5% or more of subjects treated with INVEGA^® 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 patients with schizoaffective disorder (reported in 5% or more of subjects treated with INVEGA^® 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 subjects with schizophrenia (causing discontinuation in 2% of INVEGA^®-treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of INVEGA^®-treated subjects. [See Adverse Reactions (6.4)].

The safety of INVEGA^® was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA^® 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 INVEGA^® at daily doses within the range of 3 mg to 15 mg (n=104), is also included.

The safety of INVEGA^® 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 INVEGA^®: 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 INVEGA^® (3–12 mg once daily). Both studies included subjects who received INVEGA^® 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 INVEGA^® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for INVEGA^® 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.


The most common adverse reactions (incidence ≥ 5% and at least twice that for placebo) were extrapyramidal symptoms, tachycardia, and akathisia in the schizophrenia trials, and extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis in the schizoaffective disorder trials. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia

Table 1 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies, uling those that occurred in 2% or more of subjects treated with INVEGA^® in any of the dose groups, and for which the incidence in INVEGA^®-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 1. Adverse Reactions Reported by ≥ 2% of INVEGA^®-Treated 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 INVEGA^® dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily INVEGA^® 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 INVEGA^® incidence was equal to or less than placebo are not uled in the table, but included the following: vomiting.

	Percent of Patients Reporting Event
		INVEGA®
	Placebo	3 mgonce daily	6 mgonce daily	9 mgonce daily	12 mgonce daily
Body System or Organ Class  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

6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials Schizoaffective Disorder

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

Table 2. Adverse Drug Reactions Reported by ≥ 2% of INVEGA^®-Treated Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials

	Placebo	INVEGA® 3–6 mg once-daily fixed-dose range	INVEGA® 9–12 mg once-dailyfixed-dose range	INVEGA® 3–12 mg once-dailyflexible-dose
Body System or Organ Class	(N=202)	(N=108)	(N=98)	(N=214)
  Dictionary-Derived Term
* Table includes adverse reactions that were reported in 2% or more of subjects in any of the INVEGA® dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily INVEGA® 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 INVEGA®, 230 (55%) received INVEGA® as monotherapy and 190 (45%) received INVEGA® 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.
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 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 INVEGA^® as monotherapy and 190 (45%) subjects received INVEGA^® 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 INVEGA^® as monotherapy.

6.3 Other Adverse Reactions Observed During Premarketing Evaluation of INVEGA

The following additional adverse reactions occurred in < 2% of INVEGA^®-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by INVEGA^®-treated subjects who participated in other clinical studies.

Cardiac disorders: bradycardia, bundle branch block left, palpitations

Endocrine disorders: hyperprolactinemia

Eye disorders: vision blurred

Gastrointestinal disorders: abdominal pain, flatulence, small intestinal obstruction, swollen tongue

General disorders: edema, edema peripheral

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: electrocardiogram abnormal

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Nervous system disorders: cerebrovascular accident, convulsion, dizziness postural, grand mal convulsion, lethargy, syncope, transient ischemic attack, additional extrapyramidal symptoms (cogwheel rigidity, muscle spasms, musculoskeletal pain, torticollis, trismus)

Psychiatric disorders: agitation, nightmare

Reproductive system and breast disorders: amenorrhea, breast discharge, breast engorgement, breast tenderness, breast pain, erectile dysfunction, galactorrhea, gynecomastia, menstruation irregular, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion, pneumonia aspiration

Skin and subcutaneous tissue disorders: pruritus, rash, rash papular

Vascular disorders: hypotension, ischemia

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 INVEGA^®- and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in INVEGA^®- and placebo-treated subjects, respectively).

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo‑controlled 6-week studies were 1% and <1% in INVEGA^®- and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in INVEGA^®- 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 subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with INVEGA^®, 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.

Schizoaffective Disorder Trials

In a placebo-controlled, 6-week, high- and low-dose study in 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 INVEGA^® 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 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 3 ), and (4) incidence of spontaneous reports of EPS ( Table 4 ). 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 INVEGA^® 3 mg and 6 mg doses for any of these EPS measures.

Table 3. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies

	Percentage of Patients
		INVEGA®
	Placebo	3 mg	6 mg	9 mg	12 mg
		once daily	once daily	once daily	once daily
EPS Group	(N=355)	(N=127)	(N=235)	(N=246)	(N=242)
Parkinsonism For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of lis score divided by the number of lis)	9	11	3	15	14
Akathisia For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2	6	6	4	7	9
Use of anticholinergic medications Percent of patients who received anticholinergic medications to treat emergent EPS	10	10	9	22	22

Table 4. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies

	Percentage of Patients
		INVEGA®
	Placebo	3 mg	6 mg	9 mg	12 mg
		once daily	once daily	once daily	once daily
EPS Group	(N=355)	(N=127)	(N=235)	(N=246)	(N=242)
Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia Dystonia group includes: Dystonia, muscle spasms, oculogyration, trismusHyperkinesia group includes: Akathisia, hyperkinesiaParkinsonism group includes: Bradykinesia, cogwheel rigidity, drooling, hypertonia, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism Tremor group includes: Tremor
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 schizophrenia, pooled data from the two placebo-controlled 6-week studies in 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 5 shows the EPS data from the pooled schizoaffective disorder trials.

Table 5. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizoaffective Disorder Studies

	Percentage of Patients
		INVEGA®
	Placebo	3–6 mg once-dailyfixed-dose range	9–12 mg once-dailyfixed-dose range	3–12 mg once-dailyflexible dose
EPS Group	(N=202)	(N=108)	(N=98)	(N=214)
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
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

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.

6.8 Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia and from the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between INVEGA^® 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 INVEGA^® 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, INVEGA^® was associated with increases in serum prolactin [see Warnings and Precautions (5.7)].

6.9 Weight Gain

Schizophrenia Trials

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia, the proportions of subjects meeting a weight gain criterion of ≥ 7% of body weight were compared, revealing a similar incidence of weight gain for INVEGA^® 3 mg and 6 mg (7% and 6%, respectively) compared with placebo (5%), and a higher incidence of weight gain for INVEGA^® 9 mg and 12 mg (9% and 9%, respectively).

Schizoaffective Disorder Trials

In the pooled data from the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder, a higher percentage of INVEGA^®-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.

6.10 Other Findings Observed During Clinical Trials

The safety of INVEGA^® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA^® 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.

6.11 Postmarketing Experience

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

6.12 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.