1 INDICATIONS AND USAGE INVEGA TRINZA (paliperidone palmitate), a 3-month injection, is indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension) for at least four months [see Dosage and Administration (2.2) and Clinical Studies (14) ] .

INVEGA TRINZA, a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension) for at least four months.

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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 (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism.

( 6 ) 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 include data from two clinical trials.

One is a long-term maintenance trial, in which 506 subjects with schizophrenia received several doses of the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase, of which 379 subjects continued to receive a single injection of INVEGA TRINZA during the open-label phase, and 160 subjects were subsequently randomized to receive at least one dose of INVEGA TRINZA and 145 subjects received placebo during the double-blind placebo-controlled phase.

The mean (SD) duration of exposure during the double-blind phase was 150 (79) days in the placebo group and 175 (90) days in the INVEGA TRINZA group.

The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of INVEGA TRINZA concomitantly with other oral antipsychotics.

Adverse Reactions in a Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the open-label phase, or in the INVEGA TRINZA group and at least twice the incidence in the placebo group during the double-blind phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism.

Discontinuation of Treatment Due to Adverse Events: The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the open-label phase.

During the double-blind phase, no INVEGA TRINZA-treated subject and one placebo-treated subject discontinued due to adverse events.

Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA TRINZA - Treated Patients: The safety profile of INVEGA TRINZA was similar to that seen with the 1-month paliperidone extended-release injectable suspension.

Table 8 lists the adverse reactions reported in a long-term maintenance trial in subjects with schizophrenia.

Table 8.

Incidences of Adverse Reactions 2% or More of INVEGA TRINZA-Treated Patients (and Greater than Placebo) for the Open-Label and Double-Blind Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia --- Open Label----- ------------ Double Blind ------------- Paliperidone Palmitate During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA prior to randomization to either placebo or INVEGA TRINZA in the subsequent double-blind phase [see Clinical Studies (14)] .

Placebo INVEGA TRINZA System Organ Class (N=506) (N=145) (N=160) Adverse Reaction The following terms were combined: Injection site reaction includes Injection site reaction, Injection site erythema, Injection site extravasation, Injection site induration, Injection site inflammation, Injection site mass, Injection site nodule, Injection site pain, Injection site swelling.

Weight increased includes Weight increased, Waist circumference increased.

Upper respiratory tract infection includes Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis.

Akathisia includes Akathisia, Restlessness.

Parkinsonism includes Parkinsonism, Cogwheel rigidity, Drooling, Extrapyramidal disorder, Hypokinesia, Muscle rigidity, Muscle tightness, Musculoskeletal stiffness, Salivary hypersecretion.

% Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events.

% % Table includes adverse reactions that were reported in 2% or more of subjects in the INVEGA TRINZA group during the double-blind phase and which occurred at greater incidence than in the placebo group.

General disorders and administration site conditions Injection site reaction 12 0 3 Infections and infestations Upper respiratory tract infection 5 4 10 Urinary tract infection <1 1 3 Metabolism and nutrition disorders Weight increased 10 3 9 Nervous system disorders Akathisia 5 2 5 Headache 7 4 9 Parkinsonism 5 0 4 Demographic Differences An examination of population subgroups in the long-term maintenance trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older.

Extrapyramidal Symptoms (EPS) Data from the long-term maintenance trial provided information regarding EPS.

Several methods were used to measure EPS: (1) the Simpson-Angus 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 9), and (5) incidence of spontaneous reports of EPS (Table 10).

Table 9.

Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication Percentage of Subjects Open-label Phase Double-blind Phase Paliperidone Palmitate During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA [see Clinical Studies (14)] .

Placebo INVEGA TRINZA Scale (N=506) % (N=145) % (N=160) % Parkinsonism For Parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at any time (Global score defined as total sum of items score divided by the number of items) 6 3 6 Akathisia For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at any time 3 1 4 Dyskinesia For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at any time 1 3 3 Use of Anticholinergic Medications Percent of subjects who received anticholinergic medications to treat EPS 11 9 11 Table 10.

Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Percentage of Subjects Open-label Phase Double-blind Phase Paliperidone Palmitate During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA [see Clinical Studies (14)] .

Placebo INVEGA TRINZA EPS Group (N=506) % (N=145) % (N=160) % Parkinsonism group includes: Cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonism Hyperkinesia group includes: Akathisia, restlessness Dystonia group includes: Blepharospasm, dystonia, muscle spasms Overall percentage of subjects with EPS-related adverse events 10 3 8 Parkinsonism 4 0 4 Hyperkinesia 5 2 5 Tremor 2 0 1 Dyskinesia <1 1 1 Dystonia 1 0 1 After injection of INVEGA TRINZA in the open-label phase, 12 (3.2%) subjects had EPS that were new or worsened in severity, with events under the groupings of hyperkinesia (1.6%) and parkinsonism (1.3%) being the most common.

After injection of INVEGA TRINZA in the open-label or double-blind phases, one subject discontinued from the open-label phase due to restlessness.

An examination of the time to EPS during the double-blind phase showed no clustering of these events at visits that would be expected to correspond to median peak plasma concentrations of paliperidone for subjects randomized to INVEGA TRINZA.

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.

Redness and swelling were observed in 2% or less of subjects in the INVEGA TRINZA and placebo groups during the double-blind phase of the long-term maintenance study, and were rated mild based on investigator ratings using a 4-point scale (0=absent; 1=mild; 2=moderate; 3=severe).

There were no reports of induration in either group during the double-blind phase, and no subjects discontinued due to INVEGA TRINZA injection.

Subject ratings of injection site pain.

Subject evaluations of injection pain during the double-blind phase also were similar for placebo and INVEGA TRINZA.

Subject ratings of injection site pain in the single-dose Phase 1 study allowed for assessment of the temporal course of injection site pain.

Residual injection pain peaked 1 or 6 hours after injection, and trended downward 3 days after the injection.

Deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA TRINZA The following additional adverse reactions were identified in the long-term maintenance trial.

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, or 5) occurred at an incidence lower than that of placebo-treated patients.

Cardiac disorders: tachycardia Gastrointestinal disorders: nausea, vomiting Metabolism and nutrition disorders: hyperinsulinemia Psychiatric disorders: anxiety Additional Adverse Reactions Reported in Clinical Trials with the 1-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 paliperidone palmitate extended-release injectable suspension: Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome Ear and labyrinth disorders: vertigo 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, fatigue Immune system disorders: hypersensitivity Investigations: electrocardiogram abnormal Metabolism and nutrition disorders: decreased appetite, increased appetite Musculoskeletal and connective tissue disorders: back pain, 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, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction Respiratory, thoracic and mediastinal disorders: cough Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria Vascular disorders : hypertension 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, musculoskeletal pain, 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/breast pain, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders: rash papular Vascular disorders : hypotension, ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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) sections of the package inserts for those products.