Save up to 80% by drug discount in your pharmacy with "Pharmacy Near Me - National Drug Discount Card"
You can scan QR Code(just open camera on your phone/scan by application) from the image on prescription drug discount card to save it to your mobile phone. Or just click on image if you're on mobile phone.
| Product NDC Code | 50458-606 | ||||
|---|---|---|---|---|---|
| Drug Name | Invega trinza |
||||
| Type | Brand | ||||
| Pharm Class | Atypical Antipsychotic [EPC] | ||||
| Active Ingredients |
|
||||
| Route | INTRAMUSCULAR | ||||
| Dosage Form | INJECTION, SUSPENSION, EXTENDED RELEASE | ||||
| RxCUI drug identifier | 1650966, 1650968, 1650971, 1650972, 1650973, 1650974, 1650975, 1650976 |
||||
| Application Number | NDA207946 | ||||
| Labeler Name | Janssen Pharmaceuticals, Inc | ||||
| Packages |
|
||||
| Check if available Online | Get Medication Prices online with Discount |
Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse Paliperidone has not been systematically studied in animals or humans for its potential for abuse.
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance INVEGA TRINZA (paliperidone) is not a controlled substance.
Dependence
Information about characteristic effects resulting from both psychological and physical dependence that occur with the drug, the quantity of drug over a period of time that may lead to tolerance or dependence, details of adverse effects related to chronic abuse and the effects of abrupt withdrawl, procedures necessary to diagnose the dependent state, and principles of treating the effects of abrupt withdrawal.9.3 Dependence Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance INVEGA TRINZA (paliperidone) is not a controlled substance. 9.2 Abuse Paliperidone has not been systematically studied in animals or humans for its potential for abuse. 9.3 Dependence Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
Overdosage of INVEGA TRINZA
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE 10.1 Human Experience 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. 10.2 Management of Overdosage 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.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ] QT prolongation [see Warnings and Precautions (5.4) ] Tardive dyskinesia [see Warnings and Precautions (5.5) ] Metabolic changes [see Warnings and Precautions (5.6) ] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9) ] Hyperprolactinemia [see Warnings and Precautions (5.10) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.11) ] Seizures [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Disruption of body temperature regulation [see Warnings and Precautions (5.15) ] The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Patient Exposure The data described in this section include data from two clinical trials. One is a long-term maintenance trial, in which 506 subjects with schizophrenia received several doses of the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase, of which 379 subjects continued to receive a single injection of INVEGA TRINZA during the open-label phase, and 160 subjects were subsequently randomized to receive at least one dose of INVEGA TRINZA and 145 subjects received placebo during the double-blind placebo-controlled phase. The mean (SD) duration of exposure during the double-blind phase was 150 (79) days in the placebo group and 175 (90) days in the INVEGA TRINZA group. The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of INVEGA TRINZA concomitantly with other oral antipsychotics. Adverse Reactions in a Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the open-label phase, or in the INVEGA TRINZA group and at least twice the incidence in the placebo group during the double-blind phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism. Discontinuation of Treatment Due to Adverse Events: The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the open-label phase. During the double-blind phase, no INVEGA TRINZA-treated subject and one placebo-treated subject discontinued due to adverse events. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA TRINZA - Treated Patients: The safety profile of INVEGA TRINZA was similar to that seen with the 1-month paliperidone extended-release injectable suspension. Table 8 lists the adverse reactions reported in a long-term maintenance trial in subjects with schizophrenia. Table 8. Incidences of Adverse Reactions 2% or More of INVEGA TRINZA-Treated Patients (and Greater than Placebo) for the Open-Label and Double-Blind Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia --- Open Label----- ------------ Double Blind ------------- Paliperidone Palmitate During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA prior to randomization to either placebo or INVEGA TRINZA in the subsequent double-blind phase [see Clinical Studies (14)]. Placebo INVEGA TRINZA System Organ Class (N=506) (N=145) (N=160) Adverse Reaction The following terms were combined: Injection site reaction includes Injection site reaction, Injection site erythema, Injection site extravasation, Injection site induration, Injection site inflammation, Injection site mass, Injection site nodule, Injection site pain, Injection site swelling. Weight increased includes Weight increased, Waist circumference increased. Upper respiratory tract infection includes Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis. Akathisia includes Akathisia, Restlessness. Parkinsonism includes Parkinsonism, Cogwheel rigidity, Drooling, Extrapyramidal disorder, Hypokinesia, Muscle rigidity, Muscle tightness, Musculoskeletal stiffness, Salivary hypersecretion. % Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events. % % Table includes adverse reactions that were reported in 2% or more of subjects in the INVEGA TRINZA group during the double-blind phase and which occurred at greater incidence than in the placebo group. General disorders and administration site conditions Injection site reaction 12 0 3 Infections and infestations Upper respiratory tract infection 5 4 10 Urinary tract infection <1 1 3 Metabolism and nutrition disorders Weight increased 10 3 9 Nervous system disorders Akathisia 5 2 5 Headache 7 4 9 Parkinsonism 5 0 4 Demographic Differences An examination of population subgroups in the long-term maintenance trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older. Extrapyramidal Symptoms (EPS) Data from the long-term maintenance trial provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 9), and (5) incidence of spontaneous reports of EPS (Table 10). Table 9. Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication Percentage of Subjects Open-label Phase Double-blind Phase Paliperidone Palmitate During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA [see Clinical Studies (14)] . Placebo INVEGA TRINZA Scale (N=506) % (N=145) % (N=160) % Parkinsonism For Parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at any time (Global score defined as total sum of items score divided by the number of items) 6 3 6 Akathisia For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at any time 3 1 4 Dyskinesia For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at any time 1 3 3 Use of Anticholinergic Medications Percent of subjects who received anticholinergic medications to treat EPS 11 9 11 Table 10. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Percentage of Subjects Open-label Phase Double-blind Phase Paliperidone Palmitate During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA [see Clinical Studies (14)] . Placebo INVEGA TRINZA EPS Group (N=506) % (N=145) % (N=160) % Parkinsonism group includes: Cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonism Hyperkinesia group includes: Akathisia, restlessness Dystonia group includes: Blepharospasm, dystonia, muscle spasms Overall percentage of subjects with EPS-related adverse events 10 3 8 Parkinsonism 4 0 4 Hyperkinesia 5 2 5 Tremor 2 0 1 Dyskinesia <1 1 1 Dystonia 1 0 1 After injection of INVEGA TRINZA in the open-label phase, 12 (3.2%) subjects had EPS that were new or worsened in severity, with events under the groupings of hyperkinesia (1.6%) and parkinsonism (1.3%) being the most common. After injection of INVEGA TRINZA in the open-label or double-blind phases, one subject discontinued from the open-label phase due to restlessness. An examination of the time to EPS during the double-blind phase showed no clustering of these events at visits that would be expected to correspond to median peak plasma concentrations of paliperidone for subjects randomized to INVEGA TRINZA. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Pain Assessment and Local Injection Site Reactions Investigator ratings of injection site. Redness and swelling were observed in 2% or less of subjects in the INVEGA TRINZA and placebo groups during the double-blind phase of the long-term maintenance study, and were rated mild based on investigator ratings using a 4-point scale (0=absent; 1=mild; 2=moderate; 3=severe). There were no reports of induration in either group during the double-blind phase, and no subjects discontinued due to INVEGA TRINZA injection. Subject ratings of injection site pain. Subject evaluations of injection pain during the double-blind phase also were similar for placebo and INVEGA TRINZA. Subject ratings of injection site pain in the single-dose Phase 1 study allowed for assessment of the temporal course of injection site pain. Residual injection pain peaked 1 or 6 hours after injection, and trended downward 3 days after the injection. Deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale. Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA TRINZA The following additional adverse reactions were identified in the long-term maintenance trial. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) occurred at an incidence lower than that of placebo-treated patients. Cardiac disorders: tachycardia Gastrointestinal disorders: nausea, vomiting Metabolism and nutrition disorders: hyperinsulinemia Psychiatric disorders: anxiety Additional Adverse Reactions Reported in Clinical Trials with the 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month paliperidone palmitate extended-release injectable suspension: Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome Ear and labyrinth disorders: vertigo Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache General disorders and administration site conditions : asthenia, fatigue Immune system disorders: hypersensitivity Investigations: electrocardiogram abnormal Metabolism and nutrition disorders: decreased appetite, increased appetite Musculoskeletal and connective tissue disorders: back pain, myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia, psychomotor hyperactivity, syncope Psychiatric disorders: agitation, nightmare Reproductive system and breast disorders: breast discharge, erectile dysfunction, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction Respiratory, thoracic and mediastinal disorders: cough Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria Vascular disorders : hypertension Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone: Cardiac disorders : bundle branch block left, sinus arrhythmia Gastrointestinal disorders : abdominal pain, constipation, flatulence, small intestinal obstruction General disorders and administration site conditions : edema, edema peripheral Immune system disorders : anaphylactic reaction Musculoskeletal and connective tissue disorders : arthralgia, musculoskeletal pain, torticollis, trismus Nervous system disorders : grand mal convulsion, parkinsonian gait, transient ischemic attack Psychiatric disorders: sleep disorder Reproductive system and breast disorders : breast engorgement, breast tenderness/breast pain, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders: rash papular Vascular disorders : hypotension, ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention. Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone. Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6) sections of the package inserts for those products.
| --- Open Label----- | ------------ Double Blind ------------- | ||
|---|---|---|---|
| Paliperidone Palmitate | Placebo | INVEGA TRINZA | |
| System Organ Class | (N=506) | (N=145) | (N=160) |
| Adverse Reaction | % | % | % |
| Table includes adverse reactions that were reported in 2% or more of subjects in the INVEGA TRINZA group during the double-blind phase and which occurred at greater incidence than in the placebo group. | |||
| Injection site reaction | 12 | 0 | 3 |
| Upper respiratory tract infection | 5 | 4 | 10 |
| Urinary tract infection | <1 | 1 | 3 |
| Weight increased | 10 | 3 | 9 |
| Akathisia | 5 | 2 | 5 |
| Headache | 7 | 4 | 9 |
| Parkinsonism | 5 | 0 | 4 |
| Percentage of Subjects | |||
|---|---|---|---|
| Open-label Phase | Double-blind Phase | ||
| Paliperidone Palmitate | Placebo | INVEGA TRINZA | |
| Scale | (N=506) % | (N=145) % | (N=160) % |
| Parkinsonism | 6 | 3 | 6 |
| Akathisia | 3 | 1 | 4 |
| Dyskinesia | 1 | 3 | 3 |
| Use of Anticholinergic Medications | 11 | 9 | 11 |
| Percentage of Subjects | |||
|---|---|---|---|
| Open-label Phase | Double-blind Phase | ||
| Paliperidone Palmitate | Placebo | INVEGA TRINZA | |
| EPS Group | (N=506) % | (N=145) % | (N=160) % |
| Parkinsonism group includes: Cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonism | |||
| Hyperkinesia group includes: Akathisia, restlessness | |||
| Dystonia group includes: Blepharospasm, dystonia, muscle spasms | |||
| Overall percentage of subjects with EPS-related adverse events | 10 | 3 | 8 |
| Parkinsonism | 4 | 0 | 4 |
| Hyperkinesia | 5 | 2 | 5 |
| Tremor | 2 | 0 | 1 |
| Dyskinesia | <1 | 1 | 1 |
| Dystonia | 1 | 0 | 1 |
INVEGA TRINZA Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS 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 ) 7.1 Drugs Having Clinically Important Interactions with INVEGA TRINZA 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) ] . Table 11. Clinically Important Drug Interactions with INVEGA TRINZA Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Centrally Acting Drugs and Alcohol Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of INVEGA TRINZA. INVEGA TRINZA should be used with caution in combination with other centrally acting drugs and alcohol [see Adverse Reactions (6.1 , 6.2) ] . Drugs with Potential for Inducing Orthostatic Hypotension Because INVEGA TRINZA has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA TRINZA is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.7) ] . Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7) ] . Strong Inducers of CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St. John's Wort) The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3) ] . Avoid using CYP3A4 and/or P-gp inducers with INVEGA TRINZA during the 3-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Dosage and Administration (2.7) ] . Levodopa and Other Dopamine Agonists Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Monitor and manage patient as clinically appropriate. 7.2 Drugs Having No Clinically Important Interactions with INVEGA TRINZA 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) ]
| Concomitant Drug Name or Drug Class | Clinical Rationale | Clinical Recommendation |
|---|---|---|
| Centrally Acting Drugs and Alcohol | Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of INVEGA TRINZA. | INVEGA TRINZA should be used with caution in combination with other centrally acting drugs and alcohol |
| Drugs with Potential for Inducing Orthostatic Hypotension | Because INVEGA TRINZA has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA TRINZA is administered with other therapeutic agents that have this potential | Monitor orthostatic vital signs in patients who are vulnerable to hypotension |
| Strong Inducers of CYP3A4 and P-gp (e.g., carbamazepine, rifampin, or St. John's Wort) | The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone | Avoid using CYP3A4 and/or P-gp inducers with INVEGA TRINZA during the 3-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets |
| Levodopa and Other Dopamine Agonists | Paliperidone may antagonize the effect of levodopa and other dopamine agonists. | Monitor and manage patient as clinically appropriate. |
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics 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. 12.3 Pharmacokinetics Absorption and Distribution Due to its extremely low water solubility, the 3-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and lasts for as long as 18 months. Following a single intramuscular dose of INVEGA TRINZA, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median T max of 30–33 days. Following intramuscular injection of INVEGA TRINZA at doses of 273–819 mg in the deltoid muscle, on average, an 11–12% higher C max was observed compared with injection in the gluteal muscle. The release profile and dosing regimen of INVEGA TRINZA results in sustained therapeutic concentrations over 3 months. The total and peak exposure of paliperidone following INVEGA TRINZA administration was dose-proportional over a 273–819 mg dose range. The mean steady-state peak:trough ratio for a INVEGA TRINZA dose was 1.6 following gluteal administration and 1.7 following deltoid administration. Following administration of INVEGA TRINZA, the apparent volume of distribution of paliperidone is 1960 L. The plasma protein binding of racemic paliperidone is 74%. Following administration of INVEGA TRINZA, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.7–1.8. Metabolism and Elimination In a study with oral immediate-release 14 C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14 C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo , none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates. The median apparent half-life of paliperidone following INVEGA TRINZA administration over the dose range of 273–819 mg ranged from 84–95 days following deltoid injections and 118–139 days following gluteal injections. The concentration of paliperidone remaining in the circulation 18 months after dosing of 819 mg INVEGA TRINZA is stopped is estimated to be 3% (following deltoid injection) or 7% (following gluteal injection) of the average steady-state levels. Long-acting 3-month paliperidone palmitate injection versus other paliperidone formulations INVEGA TRINZA is designed to deliver paliperidone over a 3-month period, while 1-month paliperidone palmitate injection is administered on a monthly basis. INVEGA TRINZA, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-month paliperidone palmitate injection, results in paliperidone exposures similar to those obtained with corresponding monthly doses of 1-month paliperidone palmitate injection and corresponding once daily doses of paliperidone extended-release tablets. The exposure range for INVEGA TRINZA is encompassed within the exposure range for the approved dose strengths of paliperidone extended-release tablets. The between-subject variability for paliperidone pharmacokinetics following delivery from INVEGA TRINZA was similar to the variability for paliperidone extended-release tablets. Because of the difference in median pharmacokinetic profiles among the three formulations, caution should be exercised when making a direct comparison of their pharmacokinetic properties. Drug Interaction Studies No specific drug interaction studies have been performed with INVEGA TRINZA. The information below is obtained from studies with oral paliperidone. Effects of other drugs on the exposures of INVEGA TRINZA are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C max and AUC values at steady-state was observed (see Figure 1 ). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, a decrease in mean C max and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1) ] . This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. Figure 1: The effects of other drugs on INVEGA TRINZA pharmacokinetics. 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; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2) ] . In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown. The effects of INVEGA TRINZA on the exposures of other drugs are summarized in Figure 2. After oral administration of paliperidone, the steady-state C max and AUC of valproate were not affected in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3–15 mg/day was added to their existing valproate treatment [see Drug Interactions (7.1) ] . Figure 2: The effects of INVEGA TRINZA on pharmacokinetics of other drugs. Figure 1 Figure 2 Studies in Specific Populations No specific pharmacokinetic studies have been performed with INVEGA TRINZA in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA TRINZA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 3 [see Dosage and Administration (2.5) and Use in Specific Populations (8.6) ] . After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ] . After oral administration of paliperidone in elderly subjects, the C max and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5) ] . Figure 3: Effects of intrinsic factors on paliperidone pharmacokinetics. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with INVEGA TRINZA, the trough concentrations were similar between males and females. Lower C max was observed in overweight and obese subjects. At apparent steady-state with INVEGA TRINZA, the trough concentrations were similar among normal, overweight, and obese subjects. Figure 3
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action 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.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics 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.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption and Distribution Due to its extremely low water solubility, the 3-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and lasts for as long as 18 months. Following a single intramuscular dose of INVEGA TRINZA, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median T max of 30–33 days. Following intramuscular injection of INVEGA TRINZA at doses of 273–819 mg in the deltoid muscle, on average, an 11–12% higher C max was observed compared with injection in the gluteal muscle. The release profile and dosing regimen of INVEGA TRINZA results in sustained therapeutic concentrations over 3 months. The total and peak exposure of paliperidone following INVEGA TRINZA administration was dose-proportional over a 273–819 mg dose range. The mean steady-state peak:trough ratio for a INVEGA TRINZA dose was 1.6 following gluteal administration and 1.7 following deltoid administration. Following administration of INVEGA TRINZA, the apparent volume of distribution of paliperidone is 1960 L. The plasma protein binding of racemic paliperidone is 74%. Following administration of INVEGA TRINZA, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.7–1.8. Metabolism and Elimination In a study with oral immediate-release 14 C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14 C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo , none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates. The median apparent half-life of paliperidone following INVEGA TRINZA administration over the dose range of 273–819 mg ranged from 84–95 days following deltoid injections and 118–139 days following gluteal injections. The concentration of paliperidone remaining in the circulation 18 months after dosing of 819 mg INVEGA TRINZA is stopped is estimated to be 3% (following deltoid injection) or 7% (following gluteal injection) of the average steady-state levels. Long-acting 3-month paliperidone palmitate injection versus other paliperidone formulations INVEGA TRINZA is designed to deliver paliperidone over a 3-month period, while 1-month paliperidone palmitate injection is administered on a monthly basis. INVEGA TRINZA, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-month paliperidone palmitate injection, results in paliperidone exposures similar to those obtained with corresponding monthly doses of 1-month paliperidone palmitate injection and corresponding once daily doses of paliperidone extended-release tablets. The exposure range for INVEGA TRINZA is encompassed within the exposure range for the approved dose strengths of paliperidone extended-release tablets. The between-subject variability for paliperidone pharmacokinetics following delivery from INVEGA TRINZA was similar to the variability for paliperidone extended-release tablets. Because of the difference in median pharmacokinetic profiles among the three formulations, caution should be exercised when making a direct comparison of their pharmacokinetic properties. Drug Interaction Studies No specific drug interaction studies have been performed with INVEGA TRINZA. The information below is obtained from studies with oral paliperidone. Effects of other drugs on the exposures of INVEGA TRINZA are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C max and AUC values at steady-state was observed (see Figure 1 ). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, a decrease in mean C max and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1) ] . This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. Figure 1: The effects of other drugs on INVEGA TRINZA pharmacokinetics. 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; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2) ] . In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown. The effects of INVEGA TRINZA on the exposures of other drugs are summarized in Figure 2. After oral administration of paliperidone, the steady-state C max and AUC of valproate were not affected in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3–15 mg/day was added to their existing valproate treatment [see Drug Interactions (7.1) ] . Figure 2: The effects of INVEGA TRINZA on pharmacokinetics of other drugs. Figure 1 Figure 2 Studies in Specific Populations No specific pharmacokinetic studies have been performed with INVEGA TRINZA in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA TRINZA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 3 [see Dosage and Administration (2.5) and Use in Specific Populations (8.6) ] . After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ] . After oral administration of paliperidone in elderly subjects, the C max and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5) ] . Figure 3: Effects of intrinsic factors on paliperidone pharmacokinetics. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with INVEGA TRINZA, the trough concentrations were similar between males and females. Lower C max was observed in overweight and obese subjects. At apparent steady-state with INVEGA TRINZA, the trough concentrations were similar among normal, overweight, and obese subjects. Figure 3
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS 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. Known hypersensitivity to paliperidone, risperidone, or to any excipients in INVEGA TRINZA. ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION 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 39 H 57 FN 4 O 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. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION 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 ) 2.1 Administration Instructions 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. 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. Gluteal Injection Regardless of patient weight, the recommended needle size for administration of INVEGA TRINZA into the gluteal muscle is the 1½-inch, 22 gauge thin wall needle. Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles. Incomplete Administration To avoid an incomplete administration of INVEGA TRINZA, ensure that the prefilled syringe is shaken vigorously for at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension and ensure the needle does not get clogged during injection [see Dosage and Administration (2.8) ] . However, in the event of an incompletely administered dose, do not re-inject the dose remaining in the syringe and do not administer another dose of INVEGA TRINZA. Closely monitor and treat the patient with oral supplementation as clinically appropriate until the next scheduled 3-month injection of INVEGA TRINZA. 2.2 Schizophrenia Adults INVEGA TRINZA is to be used only after INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension) has been established as adequate treatment for at least four months. In order to establish a consistent maintenance dose, it is recommended that the last two doses of INVEGA SUSTENNA be the same dosage strength before starting INVEGA TRINZA. 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, using the equivalent 3.5-fold higher dose as shown in Table 1. INVEGA TRINZA may be administered up to 7 days before or after the monthly time point of the next scheduled paliperidone palmitate 1-month dose. Table 1. 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: Conversion from the INVEGA SUSTENNA 39 mg dose was not studied. 78 mg 273 mg 117 mg 410 mg 156 mg 546 mg 234 mg 819 mg Following the initial INVEGA TRINZA dose, INVEGA TRINZA should be administered every 3 months. If needed, dose adjustment can be made every 3 months in increments within the range of 273 mg to 819 mg based on individual patient tolerability and/or efficacy. Due to the long-acting nature of INVEGA TRINZA, the patient's response to an adjusted dose may not be apparent for several months [see Clinical Pharmacology (12.3) ] . 2.3 Missed Doses Dosing Window Missing doses of INVEGA TRINZA should be avoided. If necessary, patients may be given the injection up to 2 weeks before or after the 3-month time point. Missed Dose 3½ Months to 4 Months Since Last Injection If more than 3½ months (up to but less than 4 months) have elapsed since the last injection of INVEGA TRINZA, the previously administered INVEGA TRINZA dose should be administered as soon as possible, then continue with the 3-month injections following this dose. Missed Dose 4 Months to 9 Months Since Last Injection If 4 months up to and including 9 months have elapsed since the last injection of INVEGA TRINZA, do NOT administer the next dose of INVEGA TRINZA. Instead, use the re-initiation regimen shown in Table 2. Table 2. Re-initiation Regimen After Missing 4 Months to 9 Months of INVEGA TRINZA If the Last Dose of INVEGA TRINZA was: Administer INVEGA SUSTENNA, two doses one week apart (into deltoid muscle) Then administer INVEGA TRINZA (into deltoid See Instructions for Use for deltoid injection needle selection based on body weight. or gluteal muscle) Day 1 Day 8 1 month after Day 8 273 mg 78 mg 78 mg 273 mg 410 mg 117 mg 117 mg 410 mg 546 mg 156 mg 156 mg 546 mg 819 mg 156 mg 156 mg 819 mg Missed Dose Longer than 9 Months Since Last Injection If more than 9 months have elapsed since the last injection of INVEGA TRINZA, re-initiate treatment with the 1-month paliperidone palmitate extended-release injectable suspension as described in the prescribing information for that product. INVEGA TRINZA can then be resumed after the patient has been adequately treated with the 1-month paliperidone palmitate extended-release injectable suspension for at least 4 months. 2.4 Use with Risperidone or with Oral Paliperidone 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. 2.5 Dosage Recommendations in Patients with Renal Impairment 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) ] . 2.6 Switching from INVEGA TRINZA to the 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension 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. Table 3. Conversion from INVEGA TRINZA to INVEGA SUSTENNA If the Last Dose of INVEGA TRINZA is: Initiate The initiation dosing as described in the prescribing information for INVEGA SUSTENNA is not required. INVEGA SUSTENNA 3 Months Later at the Following Dose: 273 mg 78 mg 410 mg 117 mg 546 mg 156 mg 819 mg 234 mg 2.7 Switching from INVEGA TRINZA to Oral Paliperidone Extended-Release Tablets 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. Table 4. INVEGA TRINZA Doses and Once-Daily Paliperidone Extended-Release Conversion Regimens Needed to Attain Similar Paliperidone Exposures Weeks Since Last INVEGA TRINZA Dose 3 months to 18 weeks Longer than 18 weeks to 24 weeks Longer than 24 weeks Last INVEGA TRINZA Dose Doses of oral paliperidone extended-release tablets 273 mg 3 mg 3 mg 3 mg 410 mg 3 mg 3 mg 6 mg 546 mg 3 mg 6 mg 9 mg 819 mg 6 mg 9 mg 12 mg 2.8 Instructions for Preparation and Administration Administer every 3 months Shake syringe vigorously for at least 15 seconds 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 Prefilled Syringe Thin Wall Safety Needles 1 Select needle Needle selection is determined by injection area and patient weight. If administering a Deltoid injection If patient weighs: Less than 90 kg pink hub If administering a Gluteal injection If patient weighs: Less than 90 kg yellow hub 90 kg or more yellow hub 90 kg or more yellow hub 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. Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image
| 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 |
| If the Last Dose of INVEGA SUSTENNA is: | Initiate INVEGA TRINZA at the Following Dose: |
|---|---|
| Conversion from the INVEGA SUSTENNA 39 mg dose was not studied. | |
| 78 mg | 273 mg |
| 117 mg | 410 mg |
| 156 mg | 546 mg |
| 234 mg | 819 mg |
| If the Last Dose of INVEGA TRINZA was: | Administer INVEGA SUSTENNA, two doses one week apart (into deltoid muscle) | Then administer INVEGA TRINZA (into deltoid | |
|---|---|---|---|
| Day 1 | Day 8 | 1 month after Day 8 | |
| 273 mg | 78 mg | 78 mg | 273 mg |
| 410 mg | 117 mg | 117 mg | 410 mg |
| 546 mg | 156 mg | 156 mg | 546 mg |
| 819 mg | 156 mg | 156 mg | 819 mg |
| If the Last Dose of INVEGA TRINZA is: | Initiate |
|---|---|
| 273 mg | 78 mg |
| 410 mg | 117 mg |
| 546 mg | 156 mg |
| 819 mg | 234 mg |
| Weeks Since Last INVEGA TRINZA Dose | |||
|---|---|---|---|
| 3 months to 18 weeks | Longer than 18 weeks to 24 weeks | Longer than 24 weeks | |
| Last INVEGA TRINZA Dose | Doses of oral paliperidone extended-release tablets | ||
| 273 mg | 3 mg | 3 mg | 3 mg |
| 410 mg | 3 mg | 3 mg | 6 mg |
| 546 mg | 3 mg | 6 mg | 9 mg |
| 819 mg | 6 mg | 9 mg | 12 mg |
| Administer every 3 months | |
| Shake syringe vigorously for at least 15 seconds |
| Prefilled Syringe | Thin Wall Safety Needles | ||||
|---|---|---|---|---|---|
| If administering a | If administering a |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS 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. Extended-release injectable suspension: 273 mg/0.88 mL, 410 mg/1.32 mL, 546 mg/1.75 mL, or 819 mg/2.63 mL ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE INVEGA TRINZA (paliperidone palmitate), a 3-month injection, is indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension) for at least four months [see Dosage and Administration (2.2) and Clinical Studies (14) ] . INVEGA TRINZA, a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA (1-month paliperidone palmitate extended-release injectable suspension) for at least four months. ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.INVEGA TRINZA paliperidone palmitate POLYSORBATE 20 POLYETHYLENE GLYCOL 4000 CITRIC ACID MONOHYDRATE SODIUM HYDROXIDE WATER PALIPERIDONE PALMITATE PALIPERIDONE INVEGA TRINZA paliperidone palmitate POLYSORBATE 20 POLYETHYLENE GLYCOL 4000 CITRIC ACID MONOHYDRATE SODIUM HYDROXIDE WATER PALIPERIDONE PALMITATE PALIPERIDONE INVEGA TRINZA paliperidone palmitate POLYSORBATE 20 POLYETHYLENE GLYCOL 4000 CITRIC ACID MONOHYDRATE SODIUM HYDROXIDE WATER PALIPERIDONE PALMITATE PALIPERIDONE INVEGA TRINZA paliperidone palmitate POLYSORBATE 20 POLYETHYLENE GLYCOL 4000 CITRIC ACID MONOHYDRATE SODIUM HYDROXIDE WATER PALIPERIDONE PALMITATE PALIPERIDONE
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology and/or Pharmacology 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.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. The carcinogenic potential of intramuscularly injected 1-month paliperidone palmitate extended-release injectable suspension was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which is 0.2, 0.6, and 1 times, respectively, the MRHD of 819 mg of INVEGA TRINZA based on mg/m 2 body surface area. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at 0.6 and 1 times the MRHD based on mg/m 2 body surface area. A carcinogenicity study in mice has not been conducted with paliperidone palmitate. Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the maximum recommended human dose of risperidone based on mg/m 2 body surface area (see risperidone package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.7) ]. Mutagenesis No mutagenesis studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay or the in vivo rat bone marrow micronucleus test. Impairment of Fertility No fertility studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. In an oral paliperidone study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the MRHD based on mg/m 2 body surface area. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, which is half of the MRHD based on mg/m 2 body surface area. The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the MRHD of 12 mg/day based on mg/m 2 body surface area, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg – 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m 2 body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. The carcinogenic potential of intramuscularly injected 1-month paliperidone palmitate extended-release injectable suspension was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which is 0.2, 0.6, and 1 times, respectively, the MRHD of 819 mg of INVEGA TRINZA based on mg/m 2 body surface area. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at 0.6 and 1 times the MRHD based on mg/m 2 body surface area. A carcinogenicity study in mice has not been conducted with paliperidone palmitate. Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the maximum recommended human dose of risperidone based on mg/m 2 body surface area (see risperidone package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.7) ]. Mutagenesis No mutagenesis studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay or the in vivo rat bone marrow micronucleus test. Impairment of Fertility No fertility studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. In an oral paliperidone study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the MRHD based on mg/m 2 body surface area. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, which is half of the MRHD based on mg/m 2 body surface area. The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the MRHD of 12 mg/day based on mg/m 2 body surface area, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg – 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m 2 body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued). 13.2 Animal Toxicology and/or Pharmacology 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 273 mg Syringe Carton 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 PRINCIPAL DISPLAY PANEL - 273 mg Syringe Carton
PRINCIPAL DISPLAY PANEL - 410 mg Syringe Carton 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 PRINCIPAL DISPLAY PANEL - 410 mg Syringe Carton
PRINCIPAL DISPLAY PANEL - 546 mg Syringe Carton 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 PRINCIPAL DISPLAY PANEL - 546 mg Syringe Carton
PRINCIPAL DISPLAY PANEL - 819 mg Syringe Carton 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 PRINCIPAL DISPLAY PANEL - 819 mg Syringe Carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Dosage and Administration ( 2.5 , 2.8 ) 9/2024
| Dosage and Administration ( | 9/2024 |
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.Product of Ireland Manufactured by: Janssen Pharmaceutica NV Beerse, Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2015 Janssen Pharmaceutical Companies
INVEGA TRINZA: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact their healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3) ]. Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5) ]. Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6) ]. Orthostatic Hypotension Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7) ] . Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while taking INVEGA TRINZA [see Warnings and Precautions (5.9) ] . Hyperprolactinemia Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of INVEGA TRINZA. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [See Warnings and Precautions (5.10) ] Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle until they are reasonably certain that INVEGA TRINZA therapy does not affect them adversely [see Warnings and Precautions (5.11) ] . Priapism Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [Warnings and Precautions (5.14)] . Heat Exposure and Dehydration Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.15) ] . Concomitant Medication Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter medications, because there is a potential for clinically significant interactions [see Drug Interactions (7) ] . Alcohol Advise patients to avoid alcohol during treatment with INVEGA TRINZA [see Drug Interactions (7.1) ] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with INVEGA TRINZA. Advise patients that INVEGA TRINZA may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to INVEGA TRINZA during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise breastfeeding women using INVEGA TRINZA to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2) ] . Infertility Advise females of reproductive potential that INVEGA TRINZA may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3) ]. INVEGA TRINZA (paliperidone palmitate) Extended-Release Injectable Suspension INVEGA SUSTENNA ® , RISPERDAL ® , and RISPERDAL CONSTA ® are trademarks of Janssen Pharmaceuticals, Inc.
Instructions for use
Information about safe handling and use of the drug product.2.8 Instructions for Preparation and Administration Administer every 3 months Shake syringe vigorously for at least 15 seconds 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 Prefilled Syringe Thin Wall Safety Needles 1 Select needle Needle selection is determined by injection area and patient weight. If administering a Deltoid injection If patient weighs: Less than 90 kg pink hub If administering a Gluteal injection If patient weighs: Less than 90 kg yellow hub 90 kg or more yellow hub 90 kg or more yellow hub 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. Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image
Instructions for Use INVEGA TRINZA ® paliperidone palmitate extended-release injectable suspension Administer every 3 months Shake syringe vigorously for at least 15 seconds 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 Prefilled Syringe Thin Wall Safety Needles 1 Select needle Needle selection is determined by injection area and patient weight. If administering a Deltoid injection If patient weighs: Less than 90 kg pink hub If administering a Gluteal injection If patient weighs: Less than 90 kg yellow hub 90 kg or more yellow hub 90 kg or more yellow hub 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 For patent information: www.janssenpatents.com © 2015 Janssen Pharmaceutical Companies This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 9/2024 Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image Image
| Administer every 3 months | |
| Shake syringe vigorously for at least 15 seconds |
| Prefilled Syringe | Thin Wall Safety Needles | ||||
|---|---|---|---|---|---|
| If administering a | If administering a |
| Prefilled Syringe | Thin Wall Safety Needles | ||||
|---|---|---|---|---|---|
| If administering a | If administering a |
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: September 2024 PATIENT INFORMATION INVEGA TRINZA ® (in-VAY-guh TRIN-zuh) (paliperidone palmitate) Extended-Release Injectable Suspension What is the most important information I should know about INVEGA TRINZA ? INVEGA TRINZA can cause serious side effects, including: Increased risk of death in elderly people who are confused, have memory loss and have lost touch with reality (dementia-related psychosis). INVEGA TRINZA is not for treating dementia-related psychosis. What is INVEGA TRINZA ? INVEGA TRINZA is a prescription medicine given by injection by a healthcare professional and used to treat schizophrenia. INVEGA TRINZA is used in people who have been treated with INVEGA SUSTENNA 1 time a month injections for at least 4 months. It is not known if INVEGA TRINZA is safe and effective in children under 18 years of age. Who should not receive INVEGA TRINZA ? Do not receive INVEGA TRINZA if you: are allergic to paliperidone palmitate, risperidone, or any of the ingredients in INVEGA TRINZA. See the end of this Patient Information leaflet for a complete list of ingredients in INVEGA TRINZA. What should I tell my healthcare provider before receiving INVEGA TRINZA ? Before you receive INVEGA TRINZA, tell your healthcare provider about all your medical conditions, including if you: have had Neuroleptic Malignant Syndrome (NMS) have or have had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome have or have had low levels of potassium or magnesium in your blood have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) have or have had kidney or liver problems have diabetes or have a family history of diabetes have had a low white blood cell count have had problems with dizziness or fainting or are being treated for high blood pressure have or have had seizures or epilepsy have any other medical conditions are pregnant or plan to become pregnant. It is not known if INVEGA TRINZA will harm your unborn baby. If you become pregnant while taking INVEGA TRINZA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Infants born to women who are treated with INVEGA TRINZA may experience symptoms such as tremors, irritability, excessive sleepiness, eye twitching, muscle spasms, decreased appetite, difficulty breathing, or abnormal movement of arms and legs. Let your healthcare provider know if these symptoms occur. are breastfeeding or plan to breastfeed. INVEGA TRINZA can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive INVEGA TRINZA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show to your healthcare provider or pharmacist when you get a new medicine. How will I receive INVEGA TRINZA ? Follow your INVEGA TRINZA treatment schedule exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much INVEGA TRINZA you will receive and when you will receive it. INVEGA TRINZA is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your buttocks, 1 time every 3 months. What should I avoid while receiving INVEGA TRINZA ? INVEGA TRINZA may affect your ability to make decisions, think clearly, or react quickly. Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA TRINZA affects you. Avoid getting overheated or dehydrated. What are the possible side effects of INVEGA TRINZA ? INVEGA TRINZA may cause serious side effects, including: See " What is the most important information I should know about INVEGA TRINZA? " stroke in elderly people (cerebrovascular problems) that can lead to death Neuroleptic Malignant Syndrome (NMS). NMS is a rare but very serious problem that can happen in people who receive INVEGA TRINZA. NMS can cause death and must be treated in a hospital. Call your healthcare provider right away if you become severely ill and have any of these symptoms: high fever severe muscle stiffness confusion loss of consciousness changes in your breathing, heartbeat and blood pressure problems with your heartbeat. These heart problems can cause death. Call your healthcare provider right away if you have any of these symptoms: passing out or feeling like you will pass out dizziness feeling as if your heart is pounding or missing beats uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia) metabolic changes. Metabolic changes may include high blood sugar (hyperglycemia), diabetes mellitus and changes in the fat levels in your blood (dyslipidemia), and weight gain. low blood pressure and fainting changes in your blood cell counts high level of prolactin in your blood (hyperprolactinemia). INVEGA TRINZA may cause a rise in the blood levels of a hormone called prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, leakage of milk from the breasts, development of breasts in men, or problems with erection. problems thinking clearly and moving your body seizures difficulty swallowing that can cause food or liquid to get into your lungs prolonged or painful erection lasting more than 4 hours. Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than 4 hours. problems with control of your body temperature especially when you exercise a lot or spend time doing things that make you warm. It is important for you to drink water to avoid dehydration. The most common side effects of INVEGA TRINZA include: injection site reactions, weight gain, headache, upper respiratory tract infections, feeling restlessness or difficulty sitting still, slow movements, tremors, stiffness and shuffling walk. Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of INVEGA TRINZA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of INVEGA TRINZA . Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use INVEGA TRINZA for a condition for which it was not prescribed. Do not give INVEGA TRINZA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about INVEGA TRINZA that is written for health professionals. This Patient Information leaflet summarizes the most important information about INVEGA TRINZA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for more information that is written for healthcare professionals. For more information, go to www.invegatrinzahcp.com or call 1-800-526-7736. What are the ingredients in INVEGA TRINZA ? Active ingredient : paliperidone palmitate Inactive ingredients: polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection Manufactured by: Janssen Pharmaceutica NV Beerse, Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2015 Janssen Pharmaceutical Companies
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: September 2024 |
| |
| |
| |
| |
| |
| |
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 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. a The 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. Figure 4
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use 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) ].
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use 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. Juvenile Animal Studies No juvenile animal studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2–3 times those in adolescents. Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. The long-term effects of INVEGA TRINZA on growth and sexual maturation have not been fully evaluated in children and adolescents.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA TRINZA, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA TRINZA during pregnancy (see Clinical Considerations ) . Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of INVEGA TRINZA [see Clinical Pharmacology (12.3) ] , and the clinical significance of INVEGA TRINZA administered before pregnancy or anytime during pregnancy is not known. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m 2 body surface area. There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m 2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data ). Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA TRINZA, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data No developmental toxicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 3 times the MRHD of 819 mg of the 3-month paliperidone palmitate extended-release injectable suspension based on mg/m 2 body surface area. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m 2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m 2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed. In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m 2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL package insert).
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA TRINZA, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA TRINZA during pregnancy (see Clinical Considerations ) . Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of INVEGA TRINZA [see Clinical Pharmacology (12.3) ] , and the clinical significance of INVEGA TRINZA administered before pregnancy or anytime during pregnancy is not known. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone based on mg/m 2 body surface area. There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m 2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data ). Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA TRINZA, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data No developmental toxicity studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 3 times the MRHD of 819 mg of the 3-month paliperidone palmitate extended-release injectable suspension based on mg/m 2 body surface area. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m 2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m 2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed. In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m 2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL package insert). 8.2 Lactation Risk Summary Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations ) . Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of INVEGA TRINZA, and the clinical significance on the breastfed infant is not known [see Clinical Pharmacology (12.3) ]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for INVEGA TRINZA and any potential adverse effects on the breastfed child from INVEGA TRINZA or from the mother's underlying condition. Clinical Considerations Infants exposed to INVEGA TRINZA through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). 8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of paliperidone (D 2 receptor antagonism), treatment with INVEGA TRINZA may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.10) ]. 8.4 Pediatric Use 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. Juvenile Animal Studies No juvenile animal studies were conducted with the 3-month paliperidone palmitate extended-release injectable suspension. In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2–3 times those in adolescents. Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. The long-term effects of INVEGA TRINZA on growth and sexual maturation have not been fully evaluated in children and adolescents. 8.5 Geriatric Use 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) ]. 8.6 Renal Impairment 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) ] . 8.7 Hepatic Impairment 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) ] . 8.8 Patients with Parkinson's Disease or Lewy Body Dementia 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.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 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) 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.
Storage and handling
Information about safe storage and handling of the drug product.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.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA TRINZA is not approved for use in patients with dementia-related psychosis. [see Warnings and Precautions (5.1) ] . WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA TRINZA is not approved for use in patients with dementia-related psychosis. ( 5.1 )
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API