Summary

• The most common adverse reactions in the long-term maintenance trial (incidence at least 5% in the open-label [OL] phase, or in the INVEGA TRINZA^® (paliperidone palmitate) group and at least twice the incidence in the placebo group during the double-blind [DB] phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism.¹
• The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the OL phase. During the DB phase, no INVEGA TRINZA-treated subject and one placebo-treated subject discontinued due to adverse events.¹
• The safety profile of INVEGA TRINZA was similar to that seen with the 1-month paliperidone extended-release injectable suspension (PP1M).¹
• The long-term maintenance trial was not designed to assess dose-response with regard to safety and tolerability across the dose range of INVEGA TRINZA.²
• For questions regarding specific adverse events please contact Medical Information at 1-800-JANSSEN (1-800-526-7736).

PRODUCT LABELING.

Please refer to the following sections of the Full Prescribing Information¹ which are relevant to your inquiry: BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

BOXED WARNING

Increased Mortality in Elderly Patients with Dementia-Related Psychosis¹

-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.

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 observed in patients treated with risperidone and paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.¹

WARNINGS AND PRECAUTIONS

Please refer to the Full Prescribing Information for detailed information regarding the Boxed Warning and Warnings and Precautions for INVEGA TRINZA.

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients With Dementia-Related Psychosis
• Neuroleptic Malignant Syndrome
• QT Prolongation
• Tardive Dyskinesia
• Metabolic Changes
  • Hyperglycemia and Diabetes Mellitus
  • Dyslipidemia
  • Weight Gain
• Orthostatic Hypotension and Syncope
• Falls
• Leukopenia, Neutropenia, and Agranulocytosis
• Hyperprolactinemia
• Potential for Cognitive and Motor Impairment
• Seizures
• Dysphagia
• Priapism
• Disruption of Body Temperature Regulation

ADVERSE REACTIONS

Adverse Reactions in a DB, Placebo-Controlled (Long-Term Maintenance) Clinical Trial

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the OL phase, or in the INVEGA TRINZA group and at least twice the incidence in the placebo group during the DB phase) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia, and parkinsonism.¹

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 OL phase. During the DB phase, no INVEGA TRINZA-treated subject and one placebo-treated subject discontinued due to adverse events.¹

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. Please refer to the ADVERSE REACTIONS section of the Full Prescribing Information for the incidence of adverse reactions reported in a long-term maintenance trial in subjects with schizophrenia.¹

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.¹

Dose Response

The long-term maintenance trial was not designed to assess dose response with regard to safety and tolerability across the dose range of INVEGA TRINZA. All subjects were required to complete the OL transition phase on a specific dose of PP1M prior to converting to a corresponding dose of INVEGA TRINZA in the DB phase. Therefore, determining a differential effect of INVEGA TRINZA dose level may be confounded by the subjects' tolerability to a given dose of PP1M during the transition phase. However, post-hoc analyses of safety by optimized INVEGA TRINZA dose level in the DB phase did not suggest a dose effect on rates of EPS-related adverse events, changes in body weight or body mass index (BMI), or investigator or subject ratings of local injection site reactions.²

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 evaluate dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table: Extrapyramidal Symptoms [EPS] Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication), and (5) incidence of spontaneous reports of EPS (Table: Extrapyramidal Symptoms [EPS]-Related Events by MedDRA Preferred Term).¹

After injection of INVEGA TRINZA in the OL 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 OL or DB phases; one subject discontinued from the OL phase due to restlessness.¹

An examination of the time to EPS during the DB 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.¹

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.¹

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 DB 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 DB phase, and no subjects discontinued due to INVEGA TRINZA injection.¹

Subject ratings of injection-site pain: Subject evaluations of injection pain during the DB phase also were similar for placebo and INVEGA TRINZA.¹

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.¹

Additional Adverse Reactions

Please refer to the Full Prescribing Information for information regarding adverse reactions reported in clinical trials and postmarketing experience with PP1M and oral paliperidone.