Invega Trinza
paliperidone palmitate · Injection, Suspension, Extended Release · Intramuscular
Uses
(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 )
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.
Dosage forms and strengths
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 )
Contraindications
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 )
Warnings and precautions
Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack, including fatalities). INVEGA TRINZA is not approved for use in patients with dementia-related psychosis ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring ( 5.3 ) QT Prolongation: Avoid use with drugs that also increase QT interval and in patients with risk factors for prolonged QT interval ( 5.4 ) Tardive Dyskinesia: Discontinue drug if clinically appropriate ( 5.5 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include: Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.6 ) Dyslipidemia: Undesirable alterations have been observed. ( 5.6 ) Weight Gain: Significant weight gain has been reported. Monitor weight gain. ( 5.6 ) Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Monitor complete blood count in patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors ( 5.9 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration ( 5.10 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery ( 5.11 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.12 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA TRINZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2) ] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, the 1-month paliperidone palmitate extended-release injectable suspension, or INVEGA TRINZA in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] . 5.3 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue INVEGA TRINZA and provide symptomatic treatment and monitoring. 5.4 QT Prolongation Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter Thorough QT study with oral paliperidone in adult patients, and in four fixed-dose efficacy studies and one maintenance study of the 1-month paliperidone palmitate injectable product.
Side effects
The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ] Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ] QT prolongation [see Warnings and Precautions (5.4) ] Tardive dyskinesia [see Warnings and Precautions (5.5) ] Metabolic changes [see Warnings and Precautions (5.6) ] Orthostatic hypotension and syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9) ] Hyperprolactinemia [see Warnings and Precautions (5.10) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.11) ] Seizures [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Disruption of body temperature regulation [see Warnings and Precautions (5.15) ] The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Patient Exposure The data described in this section include data from two clinical trials. One is a long-term maintenance trial, in which 506 subjects with schizophrenia received several doses of the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase, of which 379 subjects continued to receive a single injection of INVEGA TRINZA during the open-label phase, and 160 subjects were subsequently randomized to receive at least one dose of INVEGA TRINZA and 145 subjects received placebo during the double-blind placebo-controlled phase. The mean (SD) duration of exposure during the double-blind phase was 150 (79) days in the placebo group and 175 (90) days in the INVEGA TRINZA group. The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of INVEGA TRINZA concomitantly with other oral antipsychotics. Adverse Reactions in a Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the open-label phase, or in the INVEGA TRINZA group and at least twice the incidence in the placebo group during the double-blind phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism. Discontinuation of Treatment Due to Adverse Events: The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the open-label phase. During the double-blind phase, no INVEGA TRINZA-treated subject and one placebo-treated subject discontinued due to adverse events. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA TRINZA - Treated Patients: The safety profile of INVEGA TRINZA was similar to that seen with the 1-month paliperidone extended-release injectable suspension. Table 8 lists the adverse reactions reported in a long-term maintenance trial in subjects with schizophrenia. Table 8. Incidences of Adverse Reactions 2% or More of INVEGA TRINZA-Treated Patients (and Greater than Placebo) for the Open-Label and Double-Blind Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia --- Open Label----- ------------ Double Blind ------------- Paliperidone Palmitate During the open-label phase, subjects received several doses of the 1-month paliperidone palmitate extended-release injectable suspension followed by a single dose of INVEGA TRINZA prior to randomization to either placebo or INVEGA TRINZA in the subsequent double-blind phase [see Clinical Studies (14)] . Placebo INVEGA TRINZA System Organ Class (N=506) (N=145) (N=160) Adverse Reaction The following terms were combined: Injection site reaction includes Injection site reaction, Injection site erythema, Injection site extravasation, Injection site induration, Injection site inflammation, Injection site mass, Injection site nodule, Injection site pain, Injection site swelling. Weight increased includes Weight increased, Waist circumference increased. Upper respiratory tract infection includes Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis. Akathisia includes Akathisia, Restlessness. Parkinsonism includes Parkinsonism, Cogwheel rigidity, Drooling, Extrapyramidal disorder, Hypokinesia, Muscle rigidity, Muscle tightness, Musculoskeletal stiffness, Salivary hypersecretion. % Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events. % % Table includes adverse reactions that were reported in 2% or more of subjects in the INVEGA TRINZA group during the double-blind phase and which occurred at greater incidence than in the placebo group.
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) ]
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.
Pregnancy
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.
Pediatric use
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.
Geriatric use
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) ].
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.
Description
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
Mechanism of action
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.
How supplied
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
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.
Patient 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.
Label text from the FDA structured product label by Janssen Pharmaceuticals, Inc (revised Feb 14, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Paliperidone Palmitate in 4 products
Invega Trinza NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 50458-606 | Paliperidone Palmitate 273 mg/.88mL Injection, Suspension, Extended Release | Janssen Pharmaceuticals, Inc | NDA |
| 50458-607 | Paliperidone Palmitate 410 mg/1.32mL Injection, Suspension, Extended Release | Janssen Pharmaceuticals, Inc | NDA |
| 50458-608 | Paliperidone Palmitate 546 mg/1.75mL Injection, Suspension, Extended Release | Janssen Pharmaceuticals, Inc | NDA |
| 50458-609 | Paliperidone Palmitate 819 mg/2.63mL Injection, Suspension, Extended Release | Janssen Pharmaceuticals, Inc | NDA |
Frequently asked questions
What is Invega Trinza used for?
(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…
What are the side effects of Invega Trinza?
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… See the full label for the complete list.
Who makes Invega Trinza?
Invega Trinza is listed by 1 labeler in the FDA NDC directory, including Janssen Pharmaceuticals, Inc.