These Highlights Do Not Include All The Information Needed To Use Invega Trinza Safely And Effectively. See Full Prescribing Information For Invega Trinza.

Deltoid Injection

The recommended needle size for administration of INVEGA TRINZA into the deltoid muscle is determined by the patient's weight:

• For patients weighing less than 90 kg, the 1-inch, 22 gauge thin wall needle is recommended.
• For patients weighing 90 kg or more, the 1½-inch, 22 gauge thin wall needle is recommended.

Administer into the center of the deltoid muscle. Deltoid injections should be alternated between the two deltoid muscles.

Storage and Handling

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F and 86°F) are permitted. Do not mix with any other product or diluent.

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

Paliperidone has not been systematically studied in animals or humans for its potential for abuse.

In the long-term maintenance trial there were no reports of seizures or convulsions. In the pivotal clinical studies with the 1-month paliperidone palmitate extended-release injectable suspension which included four fixed-dose, double-blind, placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the 1-month injection 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 TRINZA 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.

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 TRINZA, priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

INVEGA TRINZA ^® contains paliperidone palmitate. The active ingredient, paliperidone, is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. INVEGA TRINZA contains a racemic mixture of (+)- and (-)- paliperidone palmitate. The chemical name is (9 RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4 H-pyrido [1,2- a] pyrimadin-9-yl hexadecanoate. Its molecular formula is C ₃₉H ₅₇FN ₄O ₄ and its molecular weight is 664.89. The structural formula is:

Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate.

INVEGA TRINZA is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 273 mg, 410 mg, 546 mg, and 819 mg paliperidone palmitate in single-dose prefilled syringes. The drug product hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 175 mg, 263 mg, 350 mg, and 525 mg of paliperidone, respectively. The inactive ingredients are polysorbate 20 (10 mg/mL), polyethylene glycol 4000 (75 mg/mL), citric acid monohydrate (7.5 mg/mL), sodium dihydrogen phosphate monohydrate (6 mg/mL), sodium hydroxide (5.4 mg/mL used as an alkalizing agent to set the pH at 7), and water for injection.

INVEGA TRINZA is provided in a single-dose prefilled syringe (cyclic-olefin-copolymer) with either 175 mg (0.875 mL), 263 mg (1.315 mL), 350 mg (1.75 mL), or 525 mg (2.625 mL) paliperidone (as 273 mg, 410 mg, 546 mg, or 819 mg paliperidone palmitate) suspension with a plunger stopper and tip cap (bromobutyl rubber), a backstop, and 2 types of commercially available needles: a thin walled 22G, 1 ½-inch safety needle and a thin walled 22G, 1-inch safety needle.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. INVEGA TRINZA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Safety and effectiveness of INVEGA TRINZA in patients less than 18 years of age have not been established. Use of INVEGA TRINZA is not recommended in pediatric patients because of the potential longer duration of an adverse event compared to shorter-acting products. In clinical trials of oral paliperidone, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies.

Clinical studies of INVEGA TRINZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3)] , who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, monitor renal function and adjust dosage [see Dosage and Administration (2.5)].

The efficacy of INVEGA TRINZA for the treatment of schizophrenia in patients who have been adequately treated for at least 4 months with INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension) was evaluated in a long-term double-blind, placebo-controlled randomized-withdrawal trial designed to evaluate time to relapse involving adult subjects who met DSM-IV-TR criteria for schizophrenia.

Patients could enter the study with acute symptoms (if previously treated with oral antipsychotics) or be clinically stable (if treated with long-acting injectable antipsychotics [LAI]). All patients who previously received oral antipsychotics received the paliperidone palmitate 1-month initiation regimen (deltoid injections of 234 mg and 156 mg one week apart), while those patients switching from LAI medication were treated with the 1-month paliperidone palmitate extended-release injectable suspension in place of the next scheduled injection. Specifically:

• For patients entering the study who were already being treated with the 1-month paliperidone palmitate extended-release injectable suspension, their dosing remained unchanged. Patients who were currently receiving the 39 mg dose of 1-month paliperidone palmitate were not eligible to enroll in the study.
• Patients entering the study who were being treated with 25 mg, 37.5 mg, or 50 mg of RISPERDAL CONSTA (risperidone long-acting injection) were switched to 78 mg, 117 mg, or 156 mg, respectively, of the 1-month paliperidone palmitate administered in the deltoid muscle.
• Patients entering the study who were being treated with any other LAI product were switched to 234 mg of the 1-month paliperidone palmitate administered in the deltoid muscle.

This study consisted of the following three treatment periods:

• A 17-week flexible-dose open-label period with the 1-month paliperidone palmitate (first part of a 29-week open-label stabilization phase). A total of 506 patients entered this phase of the study. Dosing of the 1-month paliperidone palmitate was individualized based on symptom response, tolerability, and previous medication history. Specifically, the dose could be adjusted at the week 5 and 9 injections and the injection site could be deltoid or gluteal. The week 13 dose had to be the same as the week 9 dose. Patients had to be clinically stable at the end of this period before receiving INVEGA TRINZA at the week 17 visit. Clinical stability was defined as achieving a PANSS total score <70 at week 17. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210.
• A 12-week open-label treatment period with INVEGA TRINZA (second part of a 29-week open-label stabilization phase). A total of 379 patients received a single-dose of INVEGA TRINZA which was a 3.5 multiple of the last dose of the 1-month paliperidone palmitate. Patients had to remain clinically stable before entry into the next period (double-blind). Clinical stability was defined as achieving a PANSS total score <70 and scores of ≤ 4 for seven specific PANSS items.
• A variable length double-blind treatment period. In this period, 305 stabilized patients were randomized 1:1 to continue treatment with INVEGA TRINZA or placebo until relapse, early withdrawal, or the end of study. Patients were randomized to the same dose of INVEGA TRINZA they received during the open-label phase (i.e., 273 mg, 410 mg, 546 mg, or 819 mg) or to placebo administered every 12 weeks. The numbers (%) of patients entering double-blind on each of the dose levels were 6 (4%) for 273 mg, 15 (9%) for 410 mg, 78 (49%) for 546 mg, and 61 (38%) for 819 mg.

The primary efficacy variable was time to first relapse. Relapse was pre-defined as emergence of one or more of the following: psychiatric hospitalization, ≥ 25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was ≤ 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of ≥ 5 (if the maximum baseline score was ≤ 3) or ≥ 6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items.

A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with INVEGA TRINZA compared to placebo, and the study was stopped early because efficacy was demonstrated. The most common reason for relapse observed across both treatment groups was increase in the PANSS total score value, followed by psychiatric hospitalization.

Twenty-three percent (23%) of patients in the placebo group and 7.4% of patients in the INVEGA TRINZA group experienced a relapse event. The time to relapse was statistically significantly longer in patients randomized to the INVEGA TRINZA group than compared to placebo-treated patients. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 4.

An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.

Figure 4: Kaplan-Meier Plot of Cumulative Proportion of Patients with Relapse ^a Over Time – Interim Analysis.

^aThe median time to relapse in the placebo group was 274 days. The median time to relapse in the INVEGA TRINZA group could not be estimated due to low percentage (7.4%) of subjects with relapse.

INVEGA TRINZA is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA TRINZA formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.

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 2-fold the exposure with the maximum recommended 819 mg dose of INVEGA TRINZA administered in the deltoid muscle (predicted median C _{max ss}=56 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 long-term maintenance trial of INVEGA TRINZA in subjects with schizophrenia, an increase in QTcLD exceeding 60 msec was observed in 1 subject (< 1%) in the open-label phase, no subject had an increase in QTcLD exceeding 60 msec after treatment with INVEGA TRINZA in the double-blind phase, and no subject had a QTcLD value of > 480 msec at any point in the study.

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)]

Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John's Wort) during a dosing interval for INVEGA TRINZA. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets. ( 7.2, 12.3)

Use of INVEGA TRINZA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Use of INVEGA TRINZA in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) is based on the previous dose of the 1-month paliperidone palmitate extended-release injectable suspension that the patient was stabilized on prior to initiation of INVEGA TRINZA [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .

INVEGA TRINZA ^®

paliperidone palmitate extended-release injectable suspension

For intramuscular injection only.

Do not administer by any other route.

Important

INVEGA TRINZA should be administered by a healthcare professional as a single injection. DO NOT divide dose into multiple injections.

INVEGA TRINZA is intended for intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel.

Read complete instructions prior to use.

Dosing

This medication should be administered once every 3 months.

Preparation

Peel off tab label from the syringe and place in patient record.

INVEGA TRINZA requires longer and more vigorous shaking than INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension). Shake the syringe vigorously, with the syringe tip pointing up, for at least 15 seconds within 5 minutes prior to administration (see Step 2).

Thin Wall Safety Needle Selection

Thin wall safety needles are designed to be used with INVEGA TRINZA. Therefore, it is important to only use the needles provided in the INVEGA TRINZA kit.

Dose pack contents

1 Select needle

Needle selection is determined by injection area and patient weight.

2 Prepare for injection

Check suspension

After shaking the syringe for at least 15 seconds, check the liquid in the viewing window.

The suspension should appear uniform and milky white in color.

It is also normal to see small air bubbles.

Open needle pouch and remove cap

First, open needle pouch by peeling the cover back half way. Place on a clean surface.

Then, holding the syringe upright, twist and pull the rubber cap to remove.

Grasp needle pouch

Fold back needle cover and plastic tray. Then, firmly grasp the needle sheath through the pouch, as shown.

Attach needle

Hold the syringe pointing up. Attach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leakage prior to administration.

Remove needle sheath

Pull the needle sheath away from the needle in a straight motion.

Do not twist the sheath, as this may loosen the needle from the syringe.

Remove air bubbles

Hold the syringe upright and tap gently to make any air bubbles rise to the top.

Remove air by pressing the plunger rod upward carefully until a drop of liquid comes out of the needle tip.

3 Inject

Inject dose

Slowly inject the entire contents of the syringe intramuscularly, deep into the selected deltoid or gluteal muscle.

Do not administer by any other route.

4 After injection

Secure needle

After the injection is complete, use your thumb or a flat surface to secure the needle in the safety device.

The needle is secure when a "click" sound is heard.

Dispose properly

Dispose of the syringe and unused needle in an approved sharps container.

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560, USA

For patent information: www.janssenpatents.com

© Johnson & Johnson and its affiliates 2015

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 2/2025

No cases of overdose were reported in premarketing studies with paliperidone palmitate injection. Because INVEGA TRINZA is to be administered by healthcare professionals, the potential for overdosage by patients is low.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D ₂) and serotonin Type 2 (5HT _2A) receptors with binding affinities (Ki values) of 1.6–2.8 nM for D ₂ and 0.8–1.2 nM for 5HT _2A receptors. Paliperidone is also active as an antagonist at histamine H ₁ and α ₁ and α ₂ adrenergic receptors with binding affinities of 32 nM, 4 nM, 17 nM, respectively. Paliperidone has no affinity for cholinergic muscarinic or β ₁- and β ₂-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar.

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.

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 TRINZA 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 treated with INVEGA TRINZA, drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA TRINZA. However, some patients may require treatment with INVEGA TRINZA despite the presence of the syndrome.

INVEGA TRINZA has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)] .

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)] .

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.

In a long-term maintenance trial of INVEGA TRINZA, 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 double-blind phase were noted in a higher percentage of males in the INVEGA TRINZA group than in the placebo group (46% vs. 25%) and in a higher percentage of females in the INVEGA TRINZA group than in the placebo group (32% vs. 15%). During the double-blind phase, 1 female (2.4%) in the INVEGA TRINZA group experienced an adverse reaction of amenorrhea, while no potentially prolactin-related adverse reactions were noted among females in the placebo group. There were no potentially prolactin-related adverse reactions among males in either group.

Prior to the double-blind phase (during the 29-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline in males (N=368) were 17.1 (13.55) ng/mL and 51.6 (40.85) ng/mL in females (N=122). Twelve weeks after a single injection of INVEGA TRINZA at the end of the open-label phase, mean (SD) prolactin values were 25.8 (13.49) ng/mL in males (N=322) and 70.6 (40.23) ng/mL in females (N=107). During the open-label phases 27% of females and 42% 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 (7.9% vs. 3.7%). Amenorrhea (4.7%) and galactorrhea (3.1%) were the most commonly observed (≥3%) potentially prolactin-related adverse reactions in females. Among males in the open-label phase, no potentially prolactin-related adverse reaction was observed with a rate greater than 3%.

Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)] . Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unclear. However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D ₂) and serotonin Type 2 (5HT _2A) receptor antagonism.

INVEGA TRINZA (paliperidone) is not a controlled substance.

• 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 TRINZA 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: 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)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include:
  • Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.6)
  • Dyslipidemia: Undesirable alterations have been observed. ( 5.6)
  • Weight Gain: Significant weight gain has been reported. Monitor 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:Monitor complete blood count in patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia. Consider discontinuation if clinically significant decline in WBC 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)

• Use INVEGA TRINZA only after the patient has been adequately treated with the 1-month paliperidone palmitate extended-release injectable suspension for at least four months. ( 2.2)
• INVEGA TRINZA should be administered once every 3 months. ( 2.1)
• For intramuscular injection only. ( 2.1)
• Each injection must be administered only by a healthcare professional. ( 2.1)
• For deltoid injection: For patients weighing less than 90 kg, use the 1-inch 22 gauge thin wall needle. For patients weighing 90 kg or more, use the 1½-inch 22 gauge thin wall needle.
• For gluteal injection: Regardless of patient weight, use the1½-inch 22 gauge thin wall needle.
• Prior to administration, shake the prefilled syringe vigorously for at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension. ( 2.1)
• Initiate INVEGA TRINZA when the next 1-month paliperidone palmitate dose is scheduled with an INVEGA TRINZA dose based on the previous 1-month injection dose as shown below. ( 2.2)
  
  
  INVEGA TRINZA Doses for Adult Patients Adequately Treated with INVEGA SUSTENNA

  If the Last Dose of INVEGA SUSTENNA is:	Initiate INVEGA TRINZA at the Following Dose:
  78 mg	273 mg
  117 mg	410 mg
  156 mg	546 mg
  234 mg	819 mg

  
  
  Conversion from the INVEGA SUSTENNA 39 mg dose was not studied.
• Missed Doses: Missing doses of INVEGA TRINZA should be avoided. To manage missed doses on exceptional occasions, refer to the Full Prescribing Information. ( 2.3)
• Moderate to severe renal impairment (creatinine clearance < 50 mL/min): INVEGA TRINZA is not recommended. ( 2.5)
• Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min): Adjust dosage and stabilize the patient using INVEGA SUSTENNA, then transition to INVEGA TRINZA. See above table. ( 2.5)

INVEGA TRINZA is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 273 mg/0.88 mL, 410 mg/1.32 mL, 546 mg/1.75 mL, and 819 mg/2.63 mL paliperidone palmitate in single-dose prefilled syringes.

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.

Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone and INVEGA TRINZA overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone.

Consider the prolonged-release characteristics of INVEGA TRINZA and the long apparent half-life of paliperidone when assessing treatment needs and recovery.

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1)

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.

INVEGA TRINZA should be administered once every 3 months.

Each injection must be administered only by a healthcare professional.

Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration. It is important to shake the syringe vigorously for at least 15 seconds to ensure a homogeneous suspension. Inject INVEGA TRINZA within 5 minutes of shaking vigorously [see Dosage and Administration (2.8)] .

INVEGA TRINZA is intended for intramuscular use only. Do not administer by any other route. Avoid inadvertent injection into a blood vessel. Administer the dose in a single injection; do not administer the dose in divided injections. Inject slowly, deep into the deltoid or gluteal muscle.

INVEGA TRINZA must be administered using only the thin wall needles that are provided in the INVEGA TRINZA pack. Do not use needles from the 1-month paliperidone palmitate extended-release injectable suspension pack or other commercially-available needles to reduce the risk of blockage.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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 TRINZA and provide symptomatic treatment and monitoring.

INVEGA TRINZA ^® is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 273 mg/0.88 mL, 410 mg/1.32 mL, 546 mg/1.75 mL, and 819 mg/2.63 mL paliperidone palmitate in single-dose prefilled syringes. The single-use kit contains a prefilled syringe and 2 safety needles (a thin walled 22G, 1-inch safety needle and a thin walled 22G, 1½-inch safety needle).

273 mg paliperidone palmitate kit (NDC 50458-606-01)

410 mg paliperidone palmitate kit (NDC 50458-607-01)

546 mg paliperidone palmitate kit (NDC 50458-608-01)

819 mg paliperidone palmitate kit (NDC 50458-609-01)

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. In the long-term maintenance trial, syncope was reported in < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase; there were no cases reported during the double-blind phase in either treatment group. In the long-term maintenance trial, orthostatic hypotension was reported as an adverse event by < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension and < 1% (1/379) of subjects after receiving a single-dose of INVEGA TRINZA during the open-label phase; there were no cases reported during the double-blind phase in either treatment group.

INVEGA TRINZA 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.

Injection site toxicity was assessed in minipigs injected intramuscularly with the 3-month paliperidone palmitate extended-release injectable suspension at doses up to 819 mg, which is equal to the MRHD. Injection site inflammatory reactions were greater and more advanced than reactions to the 1-month paliperidone palmitate extended-release injectable suspension. Reversibility of these findings was not examined.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA TRINZA 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.

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

273 mg

Each single-dose prefilled syringe contains

273 mg (0.88 mL) paliperidone palmitate.

NDC 50458-606-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®273 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

410 mg

Each single-dose prefilled syringe contains

410 mg (1.32 mL) paliperidone palmitate.

NDC 50458-607-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®410 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

546 mg

Each single-dose prefilled syringe contains

546 mg (1.75 mL) paliperidone palmitate.

NDC 50458-608-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®546 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

819 mg

Each single-dose prefilled syringe contains

819 mg (2.63 mL) paliperidone palmitate.

NDC 50458-609-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®819 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

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

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

Since paliperidone is the major active metabolite of risperidone, caution should be exercised when INVEGA TRINZA is coadministered with risperidone or oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA TRINZA with other antipsychotics is limited.

For intramuscular injection only. Do not administer by any other route.

Important

INVEGA TRINZA should be administered by a healthcare professional as a single injection. DO NOT divide dose into multiple injections.

INVEGA TRINZA is intended for intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel.

Read complete instructions prior to use.

Dosing

This medication should be administered once every 3 months.

Preparation

Peel off tab label from the syringe and place in patient record.

INVEGA TRINZA requires longer and more vigorous shaking than INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension). Shake the syringe vigorously, with the syringe tip pointing up, for at least 15 seconds within 5 minutes prior to administration (see Step 2).

Thin Wall Safety Needle Selection

Thin wall safety needles are designed to be used with INVEGA TRINZA. Therefore, it is important to only use the needles provided in the INVEGA TRINZA kit.

Dose pack contents

1 Select needle

Needle selection is determined by injection area and patient weight.

2 Prepare for injection

Check suspension

After shaking the syringe for at least 15 seconds, check the liquid in the viewing window.

The suspension should appear uniform and milky white in color.

It is also normal to see small air bubbles.

Open needle pouch and remove cap

First, open needle pouch by peeling the cover back half way. Place on a clean surface.

Then, holding the syringe upright, twist and pull the rubber cap to remove.

Grasp needle pouch

Fold back needle cover and plastic tray. Then, firmly grasp the needle sheath through the pouch, as shown.

Attach needle

Hold the syringe pointing up. Attach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leakage prior to administration.

Remove needle sheath

Pull the needle sheath away from the needle in a straight motion.

Do not twist the sheath, as this may loosen the needle from the syringe.

Remove air bubbles

Hold the syringe upright and tap gently to make any air bubbles rise to the top.

Remove air by pressing the plunger rod upward carefully until a drop of liquid comes out of the needle tip.

3 Inject

Inject dose

Slowly inject the entire contents of the syringe intramuscularly, deep into the selected deltoid or gluteal muscle.

Do not administer by any other route.

4 After injection

Secure needle

After the injection is complete, use your thumb or a flat surface to secure the needle in the safety device. The needle is secure when a "click" sound is heard.

Dispose properly

Dispose of the syringe and unused needle in an approved sharps container.

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA TRINZA. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

INVEGA TRINZA has not been systematically studied in patients with renal impairment [see Clinical Pharmacology (12.3)] . For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), adjust dosage and stabilize the patient using the 1-month paliperidone palmitate extended-release injectable suspension, then transition to INVEGA TRINZA (see Table 1) [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]. Refer to the Prescribing Information of the 1-month paliperidone palmitate extended-release injectable suspension product for the recommended dosage in patients with mild renal impairment.

INVEGA TRINZA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)] .

Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)] , results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. In addition, consider the 3-month dosing interval and long half-life of INVEGA TRINZA [see Dosage and Administration (2.1)and Clinical Pharmacology (12.3)] .

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA TRINZA is required when administered concomitantly with valproate [see Clinical Pharmacology (12.3)]. Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA TRINZA [see Clinical Pharmacology (12.3)] .

Pharmacokinetic interaction between lithium and INVEGA TRINZA is unlikely.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely. [See Clinical Pharmacology (12.3)]

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 TRINZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)] .

For switching from INVEGA TRINZA to oral paliperidone extended-release tablets, the daily dosing of the paliperidone extended-release tablets should be started 3 months after the last INVEGA TRINZA dose and transitioned over the next several months following the last INVEGA TRINZA dose as described in Table 4. Table 4 provides dose conversion regimens to allow patients previously stabilized on different doses of INVEGA TRINZA to attain similar paliperidone exposure with once daily paliperidone extended-release tablets.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA TRINZA is not approved for use in patients with dementia-related psychosis. [see Warnings and Precautions (5.1)] .

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, or INVEGA TRINZA 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)] .

For switching from INVEGA TRINZA to INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension), the 1-month paliperidone palmitate extended-release injectable suspension should be started 3 months after the last INVEGA TRINZA dose, using the equivalent 3.5-fold lower dose as shown in Table 3. The 1-month paliperidone palmitate extended-release injectable suspension should then continue, dosed at monthly intervals.

Deltoid Injection

The recommended needle size for administration of INVEGA TRINZA into the deltoid muscle is determined by the patient's weight:

• For patients weighing less than 90 kg, the 1-inch, 22 gauge thin wall needle is recommended.
• For patients weighing 90 kg or more, the 1½-inch, 22 gauge thin wall needle is recommended.

Administer into the center of the deltoid muscle. Deltoid injections should be alternated between the two deltoid muscles.

Storage and Handling

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F and 86°F) are permitted. Do not mix with any other product or diluent.

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

Paliperidone has not been systematically studied in animals or humans for its potential for abuse.

In the long-term maintenance trial there were no reports of seizures or convulsions. In the pivotal clinical studies with the 1-month paliperidone palmitate extended-release injectable suspension which included four fixed-dose, double-blind, placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the 1-month injection 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 TRINZA 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.

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 TRINZA, priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

INVEGA TRINZA ^® contains paliperidone palmitate. The active ingredient, paliperidone, is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. INVEGA TRINZA contains a racemic mixture of (+)- and (-)- paliperidone palmitate. The chemical name is (9 RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4 H-pyrido [1,2- a] pyrimadin-9-yl hexadecanoate. Its molecular formula is C ₃₉H ₅₇FN ₄O ₄ and its molecular weight is 664.89. The structural formula is:

Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate.

INVEGA TRINZA is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 273 mg, 410 mg, 546 mg, and 819 mg paliperidone palmitate in single-dose prefilled syringes. The drug product hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 175 mg, 263 mg, 350 mg, and 525 mg of paliperidone, respectively. The inactive ingredients are polysorbate 20 (10 mg/mL), polyethylene glycol 4000 (75 mg/mL), citric acid monohydrate (7.5 mg/mL), sodium dihydrogen phosphate monohydrate (6 mg/mL), sodium hydroxide (5.4 mg/mL used as an alkalizing agent to set the pH at 7), and water for injection.

INVEGA TRINZA is provided in a single-dose prefilled syringe (cyclic-olefin-copolymer) with either 175 mg (0.875 mL), 263 mg (1.315 mL), 350 mg (1.75 mL), or 525 mg (2.625 mL) paliperidone (as 273 mg, 410 mg, 546 mg, or 819 mg paliperidone palmitate) suspension with a plunger stopper and tip cap (bromobutyl rubber), a backstop, and 2 types of commercially available needles: a thin walled 22G, 1 ½-inch safety needle and a thin walled 22G, 1-inch safety needle.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. INVEGA TRINZA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Safety and effectiveness of INVEGA TRINZA in patients less than 18 years of age have not been established. Use of INVEGA TRINZA is not recommended in pediatric patients because of the potential longer duration of an adverse event compared to shorter-acting products. In clinical trials of oral paliperidone, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies.

Clinical studies of INVEGA TRINZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3)] , who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, monitor renal function and adjust dosage [see Dosage and Administration (2.5)].

The efficacy of INVEGA TRINZA for the treatment of schizophrenia in patients who have been adequately treated for at least 4 months with INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension) was evaluated in a long-term double-blind, placebo-controlled randomized-withdrawal trial designed to evaluate time to relapse involving adult subjects who met DSM-IV-TR criteria for schizophrenia.

Patients could enter the study with acute symptoms (if previously treated with oral antipsychotics) or be clinically stable (if treated with long-acting injectable antipsychotics [LAI]). All patients who previously received oral antipsychotics received the paliperidone palmitate 1-month initiation regimen (deltoid injections of 234 mg and 156 mg one week apart), while those patients switching from LAI medication were treated with the 1-month paliperidone palmitate extended-release injectable suspension in place of the next scheduled injection. Specifically:

• For patients entering the study who were already being treated with the 1-month paliperidone palmitate extended-release injectable suspension, their dosing remained unchanged. Patients who were currently receiving the 39 mg dose of 1-month paliperidone palmitate were not eligible to enroll in the study.
• Patients entering the study who were being treated with 25 mg, 37.5 mg, or 50 mg of RISPERDAL CONSTA (risperidone long-acting injection) were switched to 78 mg, 117 mg, or 156 mg, respectively, of the 1-month paliperidone palmitate administered in the deltoid muscle.
• Patients entering the study who were being treated with any other LAI product were switched to 234 mg of the 1-month paliperidone palmitate administered in the deltoid muscle.

This study consisted of the following three treatment periods:

• A 17-week flexible-dose open-label period with the 1-month paliperidone palmitate (first part of a 29-week open-label stabilization phase). A total of 506 patients entered this phase of the study. Dosing of the 1-month paliperidone palmitate was individualized based on symptom response, tolerability, and previous medication history. Specifically, the dose could be adjusted at the week 5 and 9 injections and the injection site could be deltoid or gluteal. The week 13 dose had to be the same as the week 9 dose. Patients had to be clinically stable at the end of this period before receiving INVEGA TRINZA at the week 17 visit. Clinical stability was defined as achieving a PANSS total score <70 at week 17. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210.
• A 12-week open-label treatment period with INVEGA TRINZA (second part of a 29-week open-label stabilization phase). A total of 379 patients received a single-dose of INVEGA TRINZA which was a 3.5 multiple of the last dose of the 1-month paliperidone palmitate. Patients had to remain clinically stable before entry into the next period (double-blind). Clinical stability was defined as achieving a PANSS total score <70 and scores of ≤ 4 for seven specific PANSS items.
• A variable length double-blind treatment period. In this period, 305 stabilized patients were randomized 1:1 to continue treatment with INVEGA TRINZA or placebo until relapse, early withdrawal, or the end of study. Patients were randomized to the same dose of INVEGA TRINZA they received during the open-label phase (i.e., 273 mg, 410 mg, 546 mg, or 819 mg) or to placebo administered every 12 weeks. The numbers (%) of patients entering double-blind on each of the dose levels were 6 (4%) for 273 mg, 15 (9%) for 410 mg, 78 (49%) for 546 mg, and 61 (38%) for 819 mg.

The primary efficacy variable was time to first relapse. Relapse was pre-defined as emergence of one or more of the following: psychiatric hospitalization, ≥ 25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was ≤ 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of ≥ 5 (if the maximum baseline score was ≤ 3) or ≥ 6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items.

A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with INVEGA TRINZA compared to placebo, and the study was stopped early because efficacy was demonstrated. The most common reason for relapse observed across both treatment groups was increase in the PANSS total score value, followed by psychiatric hospitalization.

Twenty-three percent (23%) of patients in the placebo group and 7.4% of patients in the INVEGA TRINZA group experienced a relapse event. The time to relapse was statistically significantly longer in patients randomized to the INVEGA TRINZA group than compared to placebo-treated patients. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 4.

An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.

Figure 4: Kaplan-Meier Plot of Cumulative Proportion of Patients with Relapse ^a Over Time – Interim Analysis.

^aThe median time to relapse in the placebo group was 274 days. The median time to relapse in the INVEGA TRINZA group could not be estimated due to low percentage (7.4%) of subjects with relapse.

INVEGA TRINZA is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA TRINZA formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.

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 2-fold the exposure with the maximum recommended 819 mg dose of INVEGA TRINZA administered in the deltoid muscle (predicted median C _{max ss}=56 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 long-term maintenance trial of INVEGA TRINZA in subjects with schizophrenia, an increase in QTcLD exceeding 60 msec was observed in 1 subject (< 1%) in the open-label phase, no subject had an increase in QTcLD exceeding 60 msec after treatment with INVEGA TRINZA in the double-blind phase, and no subject had a QTcLD value of > 480 msec at any point in the study.

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)]

Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John's Wort) during a dosing interval for INVEGA TRINZA. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets. ( 7.2, 12.3)

Use of INVEGA TRINZA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Use of INVEGA TRINZA in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) is based on the previous dose of the 1-month paliperidone palmitate extended-release injectable suspension that the patient was stabilized on prior to initiation of INVEGA TRINZA [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .

INVEGA TRINZA ^®

paliperidone palmitate extended-release injectable suspension

For intramuscular injection only.

Do not administer by any other route.

Important

INVEGA TRINZA should be administered by a healthcare professional as a single injection. DO NOT divide dose into multiple injections.

INVEGA TRINZA is intended for intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel.

Read complete instructions prior to use.

Dosing

This medication should be administered once every 3 months.

Preparation

Peel off tab label from the syringe and place in patient record.

INVEGA TRINZA requires longer and more vigorous shaking than INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension). Shake the syringe vigorously, with the syringe tip pointing up, for at least 15 seconds within 5 minutes prior to administration (see Step 2).

Thin Wall Safety Needle Selection

Thin wall safety needles are designed to be used with INVEGA TRINZA. Therefore, it is important to only use the needles provided in the INVEGA TRINZA kit.

Dose pack contents

1 Select needle

Needle selection is determined by injection area and patient weight.

2 Prepare for injection

Check suspension

After shaking the syringe for at least 15 seconds, check the liquid in the viewing window.

The suspension should appear uniform and milky white in color.

It is also normal to see small air bubbles.

Open needle pouch and remove cap

First, open needle pouch by peeling the cover back half way. Place on a clean surface.

Then, holding the syringe upright, twist and pull the rubber cap to remove.

Grasp needle pouch

Fold back needle cover and plastic tray. Then, firmly grasp the needle sheath through the pouch, as shown.

Attach needle

Hold the syringe pointing up. Attach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leakage prior to administration.

Remove needle sheath

Pull the needle sheath away from the needle in a straight motion.

Do not twist the sheath, as this may loosen the needle from the syringe.

Remove air bubbles

Hold the syringe upright and tap gently to make any air bubbles rise to the top.

Remove air by pressing the plunger rod upward carefully until a drop of liquid comes out of the needle tip.

3 Inject

Inject dose

Slowly inject the entire contents of the syringe intramuscularly, deep into the selected deltoid or gluteal muscle.

Do not administer by any other route.

4 After injection

Secure needle

After the injection is complete, use your thumb or a flat surface to secure the needle in the safety device.

The needle is secure when a "click" sound is heard.

Dispose properly

Dispose of the syringe and unused needle in an approved sharps container.

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560, USA

For patent information: www.janssenpatents.com

© Johnson & Johnson and its affiliates 2015

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 2/2025

No cases of overdose were reported in premarketing studies with paliperidone palmitate injection. Because INVEGA TRINZA is to be administered by healthcare professionals, the potential for overdosage by patients is low.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D ₂) and serotonin Type 2 (5HT _2A) receptors with binding affinities (Ki values) of 1.6–2.8 nM for D ₂ and 0.8–1.2 nM for 5HT _2A receptors. Paliperidone is also active as an antagonist at histamine H ₁ and α ₁ and α ₂ adrenergic receptors with binding affinities of 32 nM, 4 nM, 17 nM, respectively. Paliperidone has no affinity for cholinergic muscarinic or β ₁- and β ₂-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar.

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.

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 TRINZA 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 treated with INVEGA TRINZA, drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA TRINZA. However, some patients may require treatment with INVEGA TRINZA despite the presence of the syndrome.

INVEGA TRINZA has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)] .

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)] .

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.

In a long-term maintenance trial of INVEGA TRINZA, 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 double-blind phase were noted in a higher percentage of males in the INVEGA TRINZA group than in the placebo group (46% vs. 25%) and in a higher percentage of females in the INVEGA TRINZA group than in the placebo group (32% vs. 15%). During the double-blind phase, 1 female (2.4%) in the INVEGA TRINZA group experienced an adverse reaction of amenorrhea, while no potentially prolactin-related adverse reactions were noted among females in the placebo group. There were no potentially prolactin-related adverse reactions among males in either group.

Prior to the double-blind phase (during the 29-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline in males (N=368) were 17.1 (13.55) ng/mL and 51.6 (40.85) ng/mL in females (N=122). Twelve weeks after a single injection of INVEGA TRINZA at the end of the open-label phase, mean (SD) prolactin values were 25.8 (13.49) ng/mL in males (N=322) and 70.6 (40.23) ng/mL in females (N=107). During the open-label phases 27% of females and 42% 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 (7.9% vs. 3.7%). Amenorrhea (4.7%) and galactorrhea (3.1%) were the most commonly observed (≥3%) potentially prolactin-related adverse reactions in females. Among males in the open-label phase, no potentially prolactin-related adverse reaction was observed with a rate greater than 3%.

Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)] . Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unclear. However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D ₂) and serotonin Type 2 (5HT _2A) receptor antagonism.

INVEGA TRINZA (paliperidone) is not a controlled substance.

• 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 TRINZA 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: 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)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include:
  • Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.6)
  • Dyslipidemia: Undesirable alterations have been observed. ( 5.6)
  • Weight Gain: Significant weight gain has been reported. Monitor 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:Monitor complete blood count in patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia. Consider discontinuation if clinically significant decline in WBC 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)

• Use INVEGA TRINZA only after the patient has been adequately treated with the 1-month paliperidone palmitate extended-release injectable suspension for at least four months. ( 2.2)
• INVEGA TRINZA should be administered once every 3 months. ( 2.1)
• For intramuscular injection only. ( 2.1)
• Each injection must be administered only by a healthcare professional. ( 2.1)
• For deltoid injection: For patients weighing less than 90 kg, use the 1-inch 22 gauge thin wall needle. For patients weighing 90 kg or more, use the 1½-inch 22 gauge thin wall needle.
• For gluteal injection: Regardless of patient weight, use the1½-inch 22 gauge thin wall needle.
• Prior to administration, shake the prefilled syringe vigorously for at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension. ( 2.1)
• Initiate INVEGA TRINZA when the next 1-month paliperidone palmitate dose is scheduled with an INVEGA TRINZA dose based on the previous 1-month injection dose as shown below. ( 2.2)
  
  
  INVEGA TRINZA Doses for Adult Patients Adequately Treated with INVEGA SUSTENNA

  If the Last Dose of INVEGA SUSTENNA is:	Initiate INVEGA TRINZA at the Following Dose:
  78 mg	273 mg
  117 mg	410 mg
  156 mg	546 mg
  234 mg	819 mg

  
  
  Conversion from the INVEGA SUSTENNA 39 mg dose was not studied.
• Missed Doses: Missing doses of INVEGA TRINZA should be avoided. To manage missed doses on exceptional occasions, refer to the Full Prescribing Information. ( 2.3)
• Moderate to severe renal impairment (creatinine clearance < 50 mL/min): INVEGA TRINZA is not recommended. ( 2.5)
• Mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min): Adjust dosage and stabilize the patient using INVEGA SUSTENNA, then transition to INVEGA TRINZA. See above table. ( 2.5)

INVEGA TRINZA is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection in dose strengths of 273 mg/0.88 mL, 410 mg/1.32 mL, 546 mg/1.75 mL, and 819 mg/2.63 mL paliperidone palmitate in single-dose prefilled syringes.

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.

Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone and INVEGA TRINZA overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone.

Consider the prolonged-release characteristics of INVEGA TRINZA and the long apparent half-life of paliperidone when assessing treatment needs and recovery.

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1)

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.

INVEGA TRINZA should be administered once every 3 months.

Each injection must be administered only by a healthcare professional.

Parenteral drug products should be inspected visually for foreign matter and discoloration prior to administration. It is important to shake the syringe vigorously for at least 15 seconds to ensure a homogeneous suspension. Inject INVEGA TRINZA within 5 minutes of shaking vigorously [see Dosage and Administration (2.8)] .

INVEGA TRINZA is intended for intramuscular use only. Do not administer by any other route. Avoid inadvertent injection into a blood vessel. Administer the dose in a single injection; do not administer the dose in divided injections. Inject slowly, deep into the deltoid or gluteal muscle.

INVEGA TRINZA must be administered using only the thin wall needles that are provided in the INVEGA TRINZA pack. Do not use needles from the 1-month paliperidone palmitate extended-release injectable suspension pack or other commercially-available needles to reduce the risk of blockage.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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 TRINZA and provide symptomatic treatment and monitoring.

INVEGA TRINZA ^® is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 273 mg/0.88 mL, 410 mg/1.32 mL, 546 mg/1.75 mL, and 819 mg/2.63 mL paliperidone palmitate in single-dose prefilled syringes. The single-use kit contains a prefilled syringe and 2 safety needles (a thin walled 22G, 1-inch safety needle and a thin walled 22G, 1½-inch safety needle).

273 mg paliperidone palmitate kit (NDC 50458-606-01)

410 mg paliperidone palmitate kit (NDC 50458-607-01)

546 mg paliperidone palmitate kit (NDC 50458-608-01)

819 mg paliperidone palmitate kit (NDC 50458-609-01)

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity. In the long-term maintenance trial, syncope was reported in < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase; there were no cases reported during the double-blind phase in either treatment group. In the long-term maintenance trial, orthostatic hypotension was reported as an adverse event by < 1% (1/506) of subjects treated with the 1-month paliperidone palmitate extended-release injectable suspension and < 1% (1/379) of subjects after receiving a single-dose of INVEGA TRINZA during the open-label phase; there were no cases reported during the double-blind phase in either treatment group.

INVEGA TRINZA 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.

Injection site toxicity was assessed in minipigs injected intramuscularly with the 3-month paliperidone palmitate extended-release injectable suspension at doses up to 819 mg, which is equal to the MRHD. Injection site inflammatory reactions were greater and more advanced than reactions to the 1-month paliperidone palmitate extended-release injectable suspension. Reversibility of these findings was not examined.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA TRINZA 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.

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

273 mg

Each single-dose prefilled syringe contains

273 mg (0.88 mL) paliperidone palmitate.

NDC 50458-606-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®273 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

410 mg

Each single-dose prefilled syringe contains

410 mg (1.32 mL) paliperidone palmitate.

NDC 50458-607-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®410 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

546 mg

Each single-dose prefilled syringe contains

546 mg (1.75 mL) paliperidone palmitate.

NDC 50458-608-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®546 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

3

MONTHS

Administer

every

3 months

Shake syringe

vigorously for at

least 15 seconds

819 mg

Each single-dose prefilled syringe contains

819 mg (2.63 mL) paliperidone palmitate.

NDC 50458-609-01

Single-dose prefilled syringe. Use entire contents of syringe.

INVEGA TRINZA ^®819 mg

paliperidone palmitate

extended-release injectable suspension

FOR INTRAMUSCULAR INJECTION ONLY

Each injection must be administered only by

a health care professional.

Shake before using

CONTENTS: 1 single-dose prefilled syringe and 2 needles

(a 22G, 1-inch thin wall safety needle and a 22G,

1½-inch thin wall safety needle)

For recommended dosing instructions, please see

accompanying full Package Insert.

Rx only

Store at room temperature

20°C to 25°C; (68°F to 77°F);

excursions between 15°C to 30°C

(59°F to 86°F) are permitted.

janssen

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

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

Since paliperidone is the major active metabolite of risperidone, caution should be exercised when INVEGA TRINZA is coadministered with risperidone or oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA TRINZA with other antipsychotics is limited.

For intramuscular injection only. Do not administer by any other route.

Important

INVEGA TRINZA should be administered by a healthcare professional as a single injection. DO NOT divide dose into multiple injections.

INVEGA TRINZA is intended for intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel.

Read complete instructions prior to use.

Dosing

This medication should be administered once every 3 months.

Preparation

Peel off tab label from the syringe and place in patient record.

INVEGA TRINZA requires longer and more vigorous shaking than INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension). Shake the syringe vigorously, with the syringe tip pointing up, for at least 15 seconds within 5 minutes prior to administration (see Step 2).

Thin Wall Safety Needle Selection

Thin wall safety needles are designed to be used with INVEGA TRINZA. Therefore, it is important to only use the needles provided in the INVEGA TRINZA kit.

Dose pack contents

1 Select needle

Needle selection is determined by injection area and patient weight.

2 Prepare for injection

Check suspension

After shaking the syringe for at least 15 seconds, check the liquid in the viewing window.

The suspension should appear uniform and milky white in color.

It is also normal to see small air bubbles.

Open needle pouch and remove cap

First, open needle pouch by peeling the cover back half way. Place on a clean surface.

Then, holding the syringe upright, twist and pull the rubber cap to remove.

Grasp needle pouch

Fold back needle cover and plastic tray. Then, firmly grasp the needle sheath through the pouch, as shown.

Attach needle

Hold the syringe pointing up. Attach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leakage prior to administration.

Remove needle sheath

Pull the needle sheath away from the needle in a straight motion.

Do not twist the sheath, as this may loosen the needle from the syringe.

Remove air bubbles

Hold the syringe upright and tap gently to make any air bubbles rise to the top.

Remove air by pressing the plunger rod upward carefully until a drop of liquid comes out of the needle tip.

3 Inject

Inject dose

Slowly inject the entire contents of the syringe intramuscularly, deep into the selected deltoid or gluteal muscle.

Do not administer by any other route.

4 After injection

Secure needle

After the injection is complete, use your thumb or a flat surface to secure the needle in the safety device. The needle is secure when a "click" sound is heard.

Dispose properly

Dispose of the syringe and unused needle in an approved sharps container.

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA TRINZA. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

INVEGA TRINZA has not been systematically studied in patients with renal impairment [see Clinical Pharmacology (12.3)] . For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), adjust dosage and stabilize the patient using the 1-month paliperidone palmitate extended-release injectable suspension, then transition to INVEGA TRINZA (see Table 1) [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]. Refer to the Prescribing Information of the 1-month paliperidone palmitate extended-release injectable suspension product for the recommended dosage in patients with mild renal impairment.

INVEGA TRINZA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)] .

Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)] , results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. In addition, consider the 3-month dosing interval and long half-life of INVEGA TRINZA [see Dosage and Administration (2.1)and Clinical Pharmacology (12.3)] .

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA TRINZA is required when administered concomitantly with valproate [see Clinical Pharmacology (12.3)]. Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA TRINZA [see Clinical Pharmacology (12.3)] .

Pharmacokinetic interaction between lithium and INVEGA TRINZA is unlikely.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely. [See Clinical Pharmacology (12.3)]

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 TRINZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)] .

For switching from INVEGA TRINZA to oral paliperidone extended-release tablets, the daily dosing of the paliperidone extended-release tablets should be started 3 months after the last INVEGA TRINZA dose and transitioned over the next several months following the last INVEGA TRINZA dose as described in Table 4. Table 4 provides dose conversion regimens to allow patients previously stabilized on different doses of INVEGA TRINZA to attain similar paliperidone exposure with once daily paliperidone extended-release tablets.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA TRINZA is not approved for use in patients with dementia-related psychosis. [see Warnings and Precautions (5.1)] .

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, or INVEGA TRINZA 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)] .

For switching from INVEGA TRINZA to INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension), the 1-month paliperidone palmitate extended-release injectable suspension should be started 3 months after the last INVEGA TRINZA dose, using the equivalent 3.5-fold lower dose as shown in Table 3. The 1-month paliperidone palmitate extended-release injectable suspension should then continue, dosed at monthly intervals.