INVEGA HAFYERA

WARNING: 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 HAFYERA is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.1) ] . WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA HAFYERA is not approved for use in patients with dementia-related psychosis. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis : Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities). ( 5.2 ) Neuroleptic Malignant Syndrome : Manage with immediate discontinuation of drug and close monitoring. ( 5.3 ) QT Prolongation : Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. ( 5.4 ) Tardive Dyskinesia : Discontinue treatment if clinically appropriate ( 5.5 ) Metabolic Changes : Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. ( 5.6 ) Orthostatic Hypotension and Syncope : Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis : Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or a history of leukopenia or neutropenia. Consider discontinuing INVEGA HAFYERA if a clinically significant decline in WBC occurs in the absence of other causative factors. ( 5.9 ) Hyperprolactinemia : Prolactin elevations occur and persist during chronic administration. ( 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 ) 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 HAFYERA 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, the 1-month paliperidone palmitate extended-release injectable suspension, the 3-month paliperidone extended-release injectable suspension or INVEGA HAFYERA in elderly patients with dementia. These medications 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, discontinue INVEGA HAFYERA 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 paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter Thorough QT study with oral paliperidone in adult patients, and in four fixed-dose efficacy studies and one maintenance study of the 1-month paliperidone palmitate injectable product. In the Thorough 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 (QT interval corrected for heart rate using the population specified linear derived method) 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 approximately 1.3-fold the exposure with the maximum recommended 1,560 mg dose of INVEGA HAFYERA administered in the gluteal muscle (mean C max md =89.3 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 four fixed-dose efficacy studies of the 1-month paliperidone palmitate injectable product, no subject had 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, 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. In the INVEGA HAFYERA randomized double-blind active controlled study in subjects with schizophrenia, during the double-blind Phase, QTcLD exceeding 60 msec was observed in 2 subjects (0.4%) in the INVEGA HAFYERA treatment group and in 2 subjects (0.9%) in the PP3M treatment group. No subject had a QTcLD value of >480 msec at any point in the study. 5.5 Tardive Dyskinesia 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. 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 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 HAFYERA 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 HAFYERA, drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA HAFYERA. However, some patients may require treatment with INVEGA HAFYERA 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 HAFYERA. 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. Data from the randomized double-blind active controlled study with INVEGA HAFYERA in patients with schizophrenia are presented in Table 5. Table 5. Change in Fasting Glucose from the randomized double-blind active controlled study with INVEGA HAFYERA in patients with schizophrenia Total no. of patients The number of subjects with paired fasting data (baseline and any post baseline assessment). Using the conversion factor (1 mg/dL=0.05551 mmol/L) the ADA specified limits are as follows: Normal: <100 mg/dL (<5.551 mmol/L) Impaired: ≥100 mg/dL (≥5.551 mmol/L) to <126 mg/dL (<6.994 mmol/L) High: ≥126 mg/dL (≥6.994 mmol/L) 126 mg/dL=6.994 mmol/L; 140 mg/dL=7.771 mmol/L; 200 mg/dL=11.102 mmol/L; 300 mg/dL=16.653 mmol/L PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension N=195 INVEGA HAFYERA N=423 Normal to high 3% 4% Impaired glucose tolerance to high 4% 5% Normal/impaired glucose tolerance to high 7% 9% <126 mg/dL to >=140 mg/dL 4% 5% <126 mg/dL to >=200 mg/dL 0 1% <126 mg/dL to >=300 mg/dL 0 <1% Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Shifts in lipid parameters from the randomized double-blind active controlled study with INVEGA HAFYERA in patients with schizophrenia are presented in Table 6. Table 6. Shifts in Fasting Lipids in the Double-Blind Phase from the randomized active controlled study with INVEGA HAFYERA in patients with schizophrenia PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension. N=194 INVEGA HAFYERA N=423 For each fasting parameter, subjects with both Baseline (DB) record and any post baseline (DB) record during Double-Blind Phase are included in the denominator. Fasting Cholesterol (mg/dL) <200 mg/dL to >=240 mg/dL 2 (1%) 3 (0.7%) Fasting HDL Cholesterol (mg/dL) >=40 mg/dL to <40 mg/dL 28 (14%) 55 (13%) Fasting LDL Cholesterol (mg/dL) <100 mg/dL to >=160 mg/dL 1 (0.5%) 2 (0.5%) Fasting Triglycerides (mg/dL) <150 mg/dL to >=200 mg/dL 22 (11%) 22 (5%) Change in Body Weight Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. In the randomized active controlled clinical study of INVEGA HAFYERA, the overall mean weight change during the double-blind Phase was similar to PP3M. 5.7 Orthostatic Hypotension and Syncope Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. Use INVEGA HAFYERA 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 paliperidone palmitate, 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 HAFYERA. 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 HAFYERA 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 treated promptly if such symptoms or signs occur. Discontinue INVEGA HAFYERA 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. Median prolactin levels remained relatively stable throughout the open-label and double-blind phases in male subjects, whereas in female subjects, median prolactin levels increased. During the double-blind phase, median prolactin levels continued to increase after dosing in both the INVEGA HAFYERA and PP3M groups, returning to baseline level at Month 6 and at Month 12 (end of double-blind phase). During the double-blind phase, prolactin levels relative to reference range (>13.13 ng/mL in males and >26.72 ng/mL in females) from maintenance baseline were noted in a similar percentage of subjects in the INVEGA HAFYERA and PP3M groups in both males (35% vs 36%) and females (29% vs. 30%). In the INVEGA HAFYERA group, 14 females (2.9%) and 4 males (0.8%) experienced potentially prolactin-related adverse reactions, while 6 females (2.7%) and 1 male (0.4%) in the PP3M experienced potentially prolactin-related adverse reactions. 5.11 Potential for Cognitive and Motor Impairment Somnolence and sedation were reported as adverse reactions in patients treated with INVEGA HAFYERA [see Adverse Reactions (6.1) ] . Antipsychotics, including INVEGA HAFYERA, 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 6-month paliperidone palmitate extended-release injectable suspension double-blind active controlled trial there were no reports of seizures or convulsions, nor were any reports made in the long-term maintenance trial of PP3M. In the pivotal clinical studies with PP1M which included four fixed-dose, double-blind, placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the PP1M 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 HAFYERA 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 HAFYERA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. 5.14 Priapism A case (0.2%) of priapism was reported in the clinical trial with INVEGA HAFYERA. Priapism has been reported with oral paliperidone during postmarketing surveillance. Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. 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 HAFYERA 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.

<table width="80%" ID="table5"><caption>Table 5. Change in Fasting Glucose from the randomized double-blind active controlled study with INVEGA HAFYERA in patients with schizophrenia</caption><col width="40%" align="left" valign="bottom"/><col width="30%" align="center" valign="bottom"/><col width="30%" align="center" valign="bottom"/><thead><tr styleCode="Botrule"><th>Total no. of patients <footnote ID="K2401">The number of subjects with paired fasting data (baseline and any post baseline assessment). Using the conversion factor (1 mg/dL=0.05551 mmol/L) the ADA specified limits are as follows: Normal: &lt;100 mg/dL (&lt;5.551 mmol/L) Impaired: &#x2265;100 mg/dL (&#x2265;5.551 mmol/L) to &lt;126 mg/dL (&lt;6.994 mmol/L) High: &#x2265;126 mg/dL (&#x2265;6.994 mmol/L) 126 mg/dL=6.994 mmol/L; 140 mg/dL=7.771 mmol/L; 200 mg/dL=11.102 mmol/L; 300 mg/dL=16.653 mmol/L </footnote></th><th>PP3M <footnote ID="K2415">PP3M &#x2013; Every-three-month paliperidone palmitate extended-release injectable suspension</footnote> N=195 </th><th>INVEGA HAFYERA N=423 </th></tr></thead><tbody><tr><td>Normal to high</td><td>3%</td><td>4%</td></tr><tr><td>Impaired glucose tolerance to high</td><td>4%</td><td>5%</td></tr><tr><td>Normal/impaired glucose tolerance to high</td><td>7%</td><td>9%</td></tr><tr><td>&lt;126 mg/dL to &gt;=140 mg/dL</td><td>4%</td><td>5%</td></tr><tr><td>&lt;126 mg/dL to &gt;=200 mg/dL</td><td>0</td><td>1%</td></tr><tr><td>&lt;126 mg/dL to &gt;=300 mg/dL</td><td>0</td><td>&lt;1%</td></tr></tbody></table>

<table width="80%" ID="table6"><caption>Table 6. Shifts in Fasting Lipids in the Double-Blind Phase from the randomized active controlled study with INVEGA HAFYERA in patients with schizophrenia</caption><col width="40%" align="left" valign="bottom"/><col width="30%" align="center" valign="bottom"/><col width="30%" align="center" valign="bottom"/><thead><tr><th/><th>PP3M <footnote ID="K2507">PP3M &#x2013; Every-three-month paliperidone palmitate extended-release injectable suspension.</footnote> N=194 </th><th>INVEGA HAFYERA N=423 </th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top">For each fasting parameter, subjects with both Baseline (DB) record and any post baseline (DB) record during Double-Blind Phase are included in the denominator.</td></tr></tfoot><tbody><tr><td>Fasting Cholesterol (mg/dL)</td><td/><td/></tr><tr><td> &lt;200 mg/dL to &gt;=240 mg/dL</td><td>2 (1%)</td><td>3 (0.7%)</td></tr><tr><td>Fasting HDL Cholesterol (mg/dL)</td><td/><td/></tr><tr><td> &gt;=40 mg/dL to &lt;40 mg/dL</td><td>28 (14%)</td><td>55 (13%)</td></tr><tr><td>Fasting LDL Cholesterol (mg/dL)</td><td/><td/></tr><tr><td> &lt;100 mg/dL to &gt;=160 mg/dL</td><td>1 (0.5%)</td><td>2 (0.5%)</td></tr><tr><td>Fasting Triglycerides (mg/dL)</td><td/><td/></tr><tr><td> &lt;150 mg/dL to &gt;=200 mg/dL</td><td>22 (11%)</td><td>22 (5%)</td></tr></tbody></table>

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 reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ] QT prolongation [see Warnings and Precautions (5.4) ] Tardive dyskinesia [see Warnings and Precautions (5.5) ] Metabolic changes [see Warnings and Precautions (5.6) ] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9) ] Hyperprolactinemia [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) ] Priapism [see Warnings and Precautions (5.14) ] Disruption of body temperature regulation [see Warnings and Precautions (5.15) ] The most common adverse reactions were upper respiratory tract infection, injection site reaction, weight increased, headache, and parkinsonism. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Patient Exposure The data described in this section is derived from the randomized double-blind active controlled non-inferiority study of INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. During the double-blind phase, 478 patients were randomized to receive 2 injection cycles of INVEGA HAFYERA over a 12-month duration. The mean (SD) duration of exposure was 329.8 (86.97) days in the INVEGA HAFYERA group and 336.4 (80.89) days in the PP3M group during the double-blind phase: Adverse Reactions in the Double-Blind, Active-Controlled Clinical Trial Commonly Observed Adverse Reactions : The most common adverse reactions (incidence at least 5% in the double-blind Phase) of the INVEGA HAFYERA clinical trial were, upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism. Discontinuation of Treatment Due to Adverse Reactions : In the double-blind phase of the INVEGA HAFYERA clinical trial 1.3% of subjects in the INVEGA HAFYERA group and 0.4% of subjects in the 3-month paliperidone palmitate extended-release injectable suspension group discontinued due to adverse reactions. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA HAFYERA-Treated Patients : Table 7 lists the adverse reactions reported in the INVEGA HAFYERA clinical trial. Table 7. Incidences of Adverse Reactions 2% or More of INVEGA HAFYERA-Treated Patients for the Double-Blind Phase of the Randomized Double-blind Active Controlled Trial in Patients with Schizophrenia Double Blind System Organ Class PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension (N=224) % INVEGA HAFYERA (N=478) % Adverse Reaction Gastrointestinal disorders Diarrhea The following terms were combined: Diarrhea includes: Diarrhea, Diarrhea infectious. Injection site reaction: includes Injection site reaction, Injection site discomfort, Injection site erythema, Injection site hemorrhage, Injection site induration, Injection site nodule, Injection site oedema, Injection site pain, Injection site swelling. Weight increased includes: Weight increased, Body mass index increased, Obesity, Waist circumference increased. Upper respiratory tract infection includes: Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis, Viral pharyngitis, Viral upper respiratory tract infection. Back pain includes: Back pain, Neck pain, Spinal pain. Musculoskeletal pain includes: Musculoskeletal pain, Musculoskeletal chest pain, Myalgia, Pain in extremity. Akathisia includes: Akathisia, Restless legs syndrome, Restlessness. Extrapyramidal symptoms includes: blepharospasms, bradykinesia, drooling, dyskinesia, dystonia, hypokinesia, musculoskeletal stiffness, muscle rigidity, muscle spasms, oculogyric crisis, Parkinsonism, Parkinsonism rest tremor, reduced facial expression, tardive dyskinesia. Insomnia includes: Insomnia, Initial insomnia, Middle insomnia. Psychosis includes: acute psychosis, delusion, delusion of reference, hallucination (auditory), psychotic disorder, psychotic symptom, and schizophrenia. 1 2 General disorders and administration site conditions Injection site reaction 5 11 Infections and infestations Upper respiratory tract infection 13 12 Urinary tract infection 1 3 Metabolism and nutrition disorders Weight increased 8 9 Musculoskeletal and connective tissue disorders Back pain 1 3 Musculoskeletal pain 1 3 Nervous system disorders Akathisia 4 4 Headache 5 7 Extrapyramidal symptoms 5 7 Psychiatric disorders Psychosis 3 3 Anxiety 0 3 Insomnia 2 3 Demographic Differences An examination of population subgroups in the INVEGA HAFYERA trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone. Extrapyramidal Symptoms (EPS) Data from the randomized double-blind active controlled study provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus Rating Scale Global Score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale Global Clinical Rating Score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 8) and (5) incidence of spontaneous reports of EPS (Table 9). Table 8. Extrapyramidal Symptoms (EPS) Assessed by Rating Scales Incidence and Use of Anticholinergic Medication During the Double-blind Phase PP3M PP3M - Every-three-month paliperidone palmitate extended-release injectable suspension (N=224) % INVEGA HAFYERA (N=478) % Note: Percentages are calculated based on number of subjects in the DB Safety analysis set per treatment group. Use of Anticholinergic Medication Use of Anti-EPS Medication During the Double-blind Phase 13 15 Parkinsonism Percent of subjects with Simpson-Angus Scale Global Score >0.3(Global Score defined as total sum of items score divided by the number of items). 6 7 Akathisia Percent of subjects with Barnes Akathisia Rating Scale Global Clinical Rating Score ≥2 3 3 Dyskinesia Percent of subjects with a score ≥3 on any of the first seven items or a score ≥2 on two or more of any of the first seven items of the Abnormal Involuntary Movement Scale 1 1 Table 9. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Double-blind Phase EPS Group PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension Parkinsonism group includes: Bradykinesia, drooling, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism, parkinsonian rest tremor, reduced facial expression Hyperkinesia group includes: Akathisia, restlessness, restless legs syndrome Dyskinesia group includes: Dyskinesia, muscle twitching, tardive dyskinesia Dystonia group includes: Blepharospasm, dystonia, muscle spasms, oculogyric crisis (N=224) % INVEGA HAFYERA (N=478) % Overall percentage of subjects with EPS-related adverse events 9 10 Parkinsonism 4 5 Hyperkinesia 4 4 Tremor 0 <1 Dyskinesia 1 2 Dystonia 1 1 Dystonia 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. Pain Assessment and Local Injection Site Reactions Investigator ratings of injection site . Induration, redness and swelling were observed in 13% in the INVEGA HAFYERA group and 9% in the PP3M group during the double-blind Phase. Investigator evaluation of tenderness was higher for subjects in the INVEGA HAFYERA group versus the 3-month paliperidone palmitate extended-release injectable suspension group (31% vs. 19%) during the double-blind Phase. Active INVEGA HAFYERA medication was given at double-blind baseline and Month 6, while placebo medication was given at the other injection times. Subject ratings of injection site pain . The average score for the subject's evaluation of injection pain on a scale of 0 to 100 was approximately 16 at the open-label Phase end point and approximately 5 in both groups at the double-blind Phase end point. Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA HAFYERA The following additional adverse reactions were identified in the randomized double-blind active controlled study. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications. Blood and lymphatic system disorders : anemia Cardiac disorders : bradycardia, tachycardia Ear and labyrinth disorders : vertigo Gastrointestinal disorders : constipation, nausea, vomiting General disorders and administration site conditions : fatigue Hepatobiliary disorders : transaminases increased Infections and infestations : cystitis, respiratory tract infection, tonsillitis Metabolism and nutritional disorders : decreased appetite, increased appetite, weight decreased Psychiatric disorders : depression Reproductive system and breast disorders : breast pain, menstrual disorder Skin and subcutaneous tissue disorders : rash Vascular disorders : hypertension Additional Adverse Reactions Reported in Clinical Trials with the 1-Month and 3-Month Paliperidone Palmitate Extended-Release Injectable Suspension The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month and 3-month paliperidone palmitate extended-release injectable suspensions that are not listed elsewhere: Cardiac disorders : atrioventricular block first degree, bundle branch block, palpitations, postural orthostatic tachycardia syndrome Eye disorders : eye movement disorder, eye rolling, oculogyric crisis, vision blurred Gastrointestinal disorders : abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache General disorders and administration site conditions : asthenia, chest discomfort Immune system disorders : hypersensitivity Investigations : electrocardiogram abnormal Metabolism and nutrition disorders : hyperinsulinemia Musculoskeletal and connective tissue disorders : myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity Nervous system disorders : bradykinesia, cerebrovascular accident, convulsion, dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia, psychomotor hyperactivity, syncope Psychiatric disorders : agitation, nightmare Reproductive system and breast disorders : breast discharge, erectile dysfunction, gynecomastia, sexual dysfunction Respiratory, thoracic and mediastinal disorders : cough Skin and subcutaneous tissue disorders : drug eruption, eczema, pruritus, pruritus generalized, urticaria Vascular disorders : hypotension, orthostatic hypotension Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone: Cardiac disorders : bundle branch block left, sinus arrhythmia Gastrointestinal disorders : abdominal pain, constipation, flatulence, small intestinal obstruction General disorders and administration site conditions : edema, edema peripheral Immune system disorders : anaphylactic reaction Musculoskeletal and connective tissue disorders : arthralgia, torticollis, trismus Nervous system disorders : grand mal convulsion, parkinsonian gait, transient ischemic attack Psychiatric disorders : sleep disorder Reproductive system and breast disorders : breast engorgement, breast tenderness, retrograde ejaculation Respiratory, thoracic and mediastinal disorders : nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders : rash papular Vascular disorders : ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention. Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone. Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6) section of the Prescribing Information for those products.

<table width="80%" ID="table7"><caption>Table 7. Incidences of Adverse Reactions 2% or More of INVEGA HAFYERA-Treated Patients for the Double-Blind Phase of the Randomized Double-blind Active Controlled Trial in Patients with Schizophrenia</caption><col width="40%" align="left" valign="bottom"/><col width="30%" align="center" valign="bottom"/><col width="30%" align="center" valign="bottom"/><thead><tr><th/><th colspan="2" align="center">Double Blind</th></tr><tr styleCode="Botrule"><th>System Organ Class</th><th>PP3M <footnote ID="K3074">PP3M &#x2013; Every-three-month paliperidone palmitate extended-release injectable suspension</footnote> (N=224) % </th><th>INVEGA HAFYERA (N=478) % </th></tr></thead><tbody><tr><td colspan="3">Adverse Reaction</td></tr><tr><td><content styleCode="bold">Gastrointestinal disorders</content></td><td/><td/></tr><tr><td>Diarrhea <footnote ID="t7f">The following terms were combined: Diarrhea includes: Diarrhea, Diarrhea infectious. Injection site reaction: includes Injection site reaction, Injection site discomfort, Injection site erythema, Injection site hemorrhage, Injection site induration, Injection site nodule, Injection site oedema, Injection site pain, Injection site swelling. Weight increased includes: Weight increased, Body mass index increased, Obesity, Waist circumference increased. Upper respiratory tract infection includes: Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis, Viral pharyngitis, Viral upper respiratory tract infection. Back pain includes: Back pain, Neck pain, Spinal pain. Musculoskeletal pain includes: Musculoskeletal pain, Musculoskeletal chest pain, Myalgia, Pain in extremity. Akathisia includes: Akathisia, Restless legs syndrome, Restlessness. Extrapyramidal symptoms includes: blepharospasms, bradykinesia, drooling, dyskinesia, dystonia, hypokinesia, musculoskeletal stiffness, muscle rigidity, muscle spasms, oculogyric crisis, Parkinsonism, Parkinsonism rest tremor, reduced facial expression, tardive dyskinesia. Insomnia includes: Insomnia, Initial insomnia, Middle insomnia. Psychosis includes: acute psychosis, delusion, delusion of reference, hallucination (auditory), psychotic disorder, psychotic symptom, and schizophrenia. </footnote></td><td>1</td><td>2</td></tr><tr><td><content styleCode="bold">General disorders and administration site conditions</content></td><td/><td/></tr><tr><td>Injection site reaction <footnoteRef IDREF="t7f"/></td><td>5</td><td>11</td></tr><tr><td><content styleCode="bold">Infections and infestations</content></td><td/><td/></tr><tr><td>Upper respiratory tract infection <footnoteRef IDREF="t7f"/></td><td>13</td><td>12</td></tr><tr><td>Urinary tract infection</td><td>1</td><td>3</td></tr><tr><td><content styleCode="bold">Metabolism and nutrition disorders</content></td><td/><td/></tr><tr><td>Weight increased</td><td>8</td><td>9</td></tr><tr><td><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td/><td/></tr><tr><td>Back pain <footnoteRef IDREF="t7f"/></td><td>1</td><td>3</td></tr><tr><td>Musculoskeletal pain <footnoteRef IDREF="t7f"/></td><td>1</td><td>3</td></tr><tr><td><content styleCode="bold">Nervous system disorders</content></td><td/><td/></tr><tr><td>Akathisia <footnoteRef IDREF="t7f"/></td><td>4</td><td>4</td></tr><tr><td>Headache</td><td>5</td><td>7</td></tr><tr><td>Extrapyramidal symptoms <footnoteRef IDREF="t7f"/></td><td>5</td><td>7</td></tr><tr><td><content styleCode="bold">Psychiatric disorders</content></td><td/><td/></tr><tr><td>Psychosis <footnoteRef IDREF="t7f"/></td><td>3</td><td>3</td></tr><tr><td>Anxiety</td><td>0</td><td>3</td></tr><tr><td>Insomnia <footnoteRef IDREF="t7f"/></td><td>2</td><td>3</td></tr></tbody></table>

<table width="75%" ID="table8"><caption>Table 8. Extrapyramidal Symptoms (EPS) Assessed by Rating Scales Incidence and Use of Anticholinergic Medication During the Double-blind Phase</caption><col width="40%" align="left" valign="bottom"/><col width="30%" align="center" valign="bottom"/><col width="30%" align="center" valign="bottom"/><thead><tr styleCode="Botrule"><th/><th>PP3M <footnote ID="K3357">PP3M - Every-three-month paliperidone palmitate extended-release injectable suspension</footnote> (N=224) % </th><th>INVEGA HAFYERA (N=478) % </th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top">Note: Percentages are calculated based on number of subjects in the DB Safety analysis set per treatment group.</td></tr></tfoot><tbody><tr><td>Use of Anticholinergic Medication <footnote ID="K3380">Use of Anti-EPS Medication During the Double-blind Phase</footnote></td><td>13</td><td>15</td></tr><tr><td>Parkinsonism <footnote ID="K3389">Percent of subjects with Simpson-Angus Scale Global Score &gt;0.3(Global Score defined as total sum of items score divided by the number of items).</footnote></td><td>6</td><td>7</td></tr><tr><td>Akathisia <footnote ID="K3398">Percent of subjects with Barnes Akathisia Rating Scale Global Clinical Rating Score &#x2265;2</footnote></td><td>3</td><td>3</td></tr><tr><td>Dyskinesia <footnote ID="K3407">Percent of subjects with a score &#x2265;3 on any of the first seven items or a score &#x2265;2 on two or more of any of the first seven items of the Abnormal Involuntary Movement Scale</footnote></td><td>1</td><td>1</td></tr></tbody></table>

<table width="75%" ID="table9"><caption>Table 9. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term</caption><col width="40%" align="left" valign="bottom"/><col width="30%" align="center" valign="bottom"/><col width="30%" align="center" valign="bottom"/><thead><tr><th/><th colspan="2" align="center">Double-blind Phase</th></tr><tr><th>EPS Group</th><th>PP3M <footnote ID="K3442">PP3M &#x2013; Every-three-month paliperidone palmitate extended-release injectable suspension Parkinsonism group includes: Bradykinesia, drooling, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism, parkinsonian rest tremor, reduced facial expression Hyperkinesia group includes: Akathisia, restlessness, restless legs syndrome Dyskinesia group includes: Dyskinesia, muscle twitching, tardive dyskinesia Dystonia group includes: Blepharospasm, dystonia, muscle spasms, oculogyric crisis </footnote> (N=224) % </th><th>INVEGA HAFYERA (N=478) % </th></tr></thead><tbody><tr><td valign="middle"><content styleCode="bold">Overall percentage of subjects with EPS-related adverse events</content></td><td valign="middle">9</td><td valign="middle">10</td></tr><tr><td>Parkinsonism</td><td>4</td><td>5</td></tr><tr><td>Hyperkinesia</td><td>4</td><td>4</td></tr><tr><td>Tremor</td><td>0</td><td>&lt;1</td></tr><tr><td>Dyskinesia</td><td>1</td><td>2</td></tr><tr><td>Dystonia</td><td>1</td><td>1</td></tr></tbody></table>