5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA SUSTENNA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)] .

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. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA, or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia. These medicines are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)] .

5.3 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

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

5.4 QT Prolongation

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of Torsades 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 oral 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 (C max ss = 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg dose of INVEGA SUSTENNA administered in the deltoid muscle (predicted median C max ss = 50 ng/mL). 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.

In the three fixed-dose efficacy studies of oral paliperidone extended release in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec).

In the four fixed-dose efficacy studies of INVEGA SUSTENNA in subjects with schizophrenia and in the long-term study in subjects with schizoaffective disorder, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study in subjects with schizophrenia, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.

5.5 Tardive Dyskinesia

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

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, INVEGA SUSTENNA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA SUSTENNA. 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 hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

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

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 5.

Table 5: Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia
		INVEGA SUSTENNA
	Placebo	39 mg	78 mg	156 mg	234/39 mg *	234/156 mg *	234/234 mg *
* Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1)] .
	Mean change from baseline (mg/dL)
	n=367	n=86	n=244	n=238	n=110	n=126	n=115
Serum Glucose Change from baseline	-1.3	1.3	3.5	0.1	3.4	1.8	-0.2
	Proportion of Patients with Shifts
Serum Glucose Normal to High	4.6%	6.3%	6.4%	3.9%	2.5%	7.0%	6.6%
(<100 mg/dL to ≥126 mg/dL)	(11/241)	(4/64)	(11/173)	(6/154)	(2/79)	(6/86)	(5/76)

In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated, INVEGA SUSTENNA was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA was associated with mean change in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA was associated with a mean change in glucose of +0.3 mg/dL (n=131) compared with a mean change of +4.0 mg/dL in the placebo group (n=120).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 6.

Table 6: Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia
		INVEGA SUSTENNA
	Placebo	39 mg	78 mg	156 mg	234/39 mg *	234/156 mg *	234/234 mg *
* Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1)] .
	Mean change from baseline (mg/dL)
Cholesterol	n=366	n=89	n=244	n=232	n=105	n=119	n=120
Change from baseline	-6.6	-6.4	-5.8	-7.1	-0.9	-4.2	9.4
LDL	n=275	n=80	n=164	n=141	n=104	n=117	n=108
Change from baseline	-6.0	-4.8	-5.6	-4.8	0.9	-2.4	5.2
HDL	n=286	n=89	n=165	n=150	n=105	n=118	n=115
Change from baseline	0.7	2.1	0.6	0.3	1.5	1.1	0.0
Triglycerides	n=366	n=89	n=244	n=232	n=105	n=119	n=120
Change from baseline	-16.7	7.6	-9.0	-11.5	-14.1	-20.0	11.9
	Proportion of Patients with Shifts
Cholesterol
Normal to High	3.2%	2.0%	2.0%	2.1%	0%	3.1%	7.1%
(<200 mg/dL to ≥240 mg/dL)	(7/222)	(1/51)	(3/147)	(3/141)	(0/69)	(2/65)	(6/84)
LDL
Normal to High	1.1%	0%	0%	0%	0%	0%	0%
(<100 mg/dL to ≥160 mg/dL)	(1/95)	(0/29)	(0/67)	(0/46)	(0/41)	(0/37)	(0/44)
HDL
Normal to Low	13.8%	14.8%	9.6%	14.2%	12.7%	10.5%	16.0%
(≥40 mg/dL to <40 mg/dL)	(28/203)	(9/61)	(11/115)	(15/106)	(9/71)	(8/76)	(13/81)
Triglycerides
Normal to High	3.6%	6.1%	9.2%	7.2%	1.3%	3.7%	10.7%
(<150 mg/dL to ≥200 mg/dL)	(8/221)	(3/49)	(14/153)	(10/139)	(1/79)	(3/82)	(9/84)

In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest dose available (234 mg) was evaluated, the mean changes from baseline in lipid values are presented in Table 7.

Table 7: Change in Fasting Lipids from Long-term Open-label Pharmacokinetic and Safety Study in Subjects with Schizophrenia
	INVEGA SUSTENNA 234 mg
	Week 29	Week 53
	Mean change from baseline (mg/dL)
Cholesterol	n=112	n=100
Change from baseline	-1.2	0.1
LDL	n=107	n=89
Change from baseline	-2.7	-2.3
HDL	n=112	n=98
Change from baseline	-0.8	-2.6
Triglycerides	n=112	n=100
Change from baseline	16.2	37.4

The mean changes from baseline in lipid values during the initial 25-week open-label period and at the endpoint of the subsequent 15-month double-blind period in a long-term study in subjects with schizoaffective disorder are presented in Table 8.

Table 8: Change in Fasting Lipids from an Open-Label and Double-Blind Periods of a Long-Term Study in Subjects with Schizoaffective Disorder
	Open-Label Period	Double-Blind Period
	INVEGA SUSTENNA	Placebo	INVEGA SUSTENNA
	Mean change from baseline (mg/dL)
Cholesterol	n=198	n=119	n=132
Change from baseline	-3.9	-4.2	2.3
LDL	n=198	n=117	n=130
Change from baseline	-2.7	-2.8	5.9
HDL	n=198	n=119	n=131
Change from baseline	-2.7	-0.9	-0.7
Triglycerides	n=198	n=119	n=132
Change from baseline	7.0	2.5	-12.3

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies in subjects with schizophrenia are presented in Table 9.

Table 9: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia
		INVEGA SUSTENNA
	Placebo	39 mg	78 mg	156 mg	234/39 mg *	234/156 mg *	234/234 mg *
* Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [see Clinical Studies (14.1)] .
	n=451	n=116	n=280	n=267	n=137	n=144	n=145
Weight (kg) Change from baseline	-0.4	0.4	0.8	1.4	0.4	0.7	1.4
Weight Gain ≥ 7% increase from baseline	3.3%	6.0%	8.9%	9.0%	5.8%	8.3%	13.1%

In a long-term open-label pharmacokinetic and safety study in which the highest dose available (234 mg) was evaluated, INVEGA SUSTENNA was associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA was associated with a mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of ≥ 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA was associated with a mean change in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of ≥ 7% (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of ≥ 7% (n=168).

5.7 Orthostatic Hypotension and Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. Syncope was reported in < 1% (4/1293) of subjects treated with INVEGA SUSTENNA in the recommended dose range of 39 mg to 234 mg in the four fixed-dose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies in subjects with schizophrenia, orthostatic hypotension was reported as an adverse event by < 1% (2/1293) of INVEGA SUSTENNA-treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic hypotension and syncope in the long-term studies in subjects with schizophrenia and schizoaffective disorder were similar to those observed in the short-term studies.

INVEGA SUSTENNA 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.

5.8 Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA, 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.

5.9 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA SUSTENNA. 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 INVEGA SUSTENNA 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 INVEGA SUSTENNA in patients with severe neutropenia (absolute neutrophil count < 1000/mm 3) and follow their WBC until recovery.

5.10 Hyperprolactinemia

Like other drugs that antagonize dopamine D 2 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)] . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

Prolactin data from two long-term, double-blind, placebo-controlled studies with INVEGA SUSTENNA are presented below; one study was in a population of patients with schizophrenia; the second study was in patients with schizoaffective disorder.

Schizophrenia

In a long-term maintenance trial of INVEGA SUSTENNA in schizophrenia patients (Study PSY-3001), see Clinical Studies (14.1), elevations of prolactin to above the reference range (> 18 ng/mL in males and > 30 ng/mL in females) relative to open-label baseline at any time during the double-blind phase were noted in a higher percentage of the patients in the INVEGA SUSTENNA group than those in the placebo group in males (51.9% vs. 29.0%) and in females (50.5% vs. 42.9%). During the double-blind phase, 4 females (4.2%) in the INVEGA SUSTENNA group experienced potentially prolactin-related adverse reactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), while 2 females (2.2%) in the placebo group experienced potentially prolactin-related adverse reactions (amenorrhea N=1; breast pain N=1). One male (0.9%) in the INVEGA SUSTENNA group experienced erectile dysfunction and 1 male (0.9%) in placebo group experienced gynecomastia.

Prior to the double-blind phase (during the 33-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label phases 49.2% of females and 47.7% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (5.3% vs. 1.8%). Amenorrhea (2.5%) in females and no single potentially prolactin-related adverse reaction in males were observed with a rate greater than 2%.

Schizoaffective Disorder

In a long-term maintenance trial of INVEGA SUSTENNA in patients with schizoaffective disorder (Study SCA-3004) see Clinical Studies (14.2), elevations of prolactin to above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) relative to open-label baseline at any time during the 15-month double-blind phase were noted in a higher percentage of patients in the INVEGA SUSTENNA group than those in the placebo group in males (55.6% vs. 23.2%) and in females (44.3% vs. 25.0%). During the 15-month double-blind phase, 11 females (13.9%) in the INVEGA SUSTENNA group had 14 potentially prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while 5 females (5.8%) in the placebo group had 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea N=2; galactorrhea N=1). Six males (7.1%) in the INVEGA SUSTENNA group experienced 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction N=1), while 1 male (1.2%) in the placebo group experienced adverse reaction of blood prolactin increased.

Prior to the 15-month double-blind phase (during the 25-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302). At the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). During the open-label phase, 48.9% of females and 53.3% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (10.0% vs. 9.0%). Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with a rate greater than 2%.

5.11 Potential for Cognitive and Motor Impairment

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA SUSTENNA [see Adverse Reactions (6.1)] . Antipsychotics, including INVEGA SUSTENNA, 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

In the four fixed-dose double-blind placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with INVEGA SUSTENNA in the recommended dose range of 39 mg to 234 mg experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.

Like other antipsychotic drugs, INVEGA SUSTENNA 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. INVEGA SUSTENNA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.14 Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with INVEGA SUSTENNA, priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

5.15 Disruption of 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 SUSTENNA 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.