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Clinical Data
Clinical data about INVEGA:
- Clinical Trials
- Adverse Reactions
- Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Subjects with Schizophrenia
- Adverse Events Occurring at an Incidence of 2% or More Among INVEGA Treated Patients with Schizophrenia and More Frequent on Drug than Placebo
- Table 1. Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials in Adult Subjects With Schizophrenia
- Dose-Related Adverse Events
- Common and Drug-Related Adverse Events
- Extrapyramidal Symptoms (EPS)
- Adverse Events Associated with Discontinuation of Treatment
- Demographic Differences in Adverse Reactions
- Laboratory Test Abnormalities
- Weight Gain
- Adverse Events Reported With Risperidone
The short-term efficacy of INVEGA (3 to 15 mg once daily) was established in three placebo-controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in non-elderly adult subjects (mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were carried out in North America, Eastern Europe, Western Europe, and Asia. The doses studied among these three trials included 3, 6, 9, 12, and 15 mg/day. Dosing was in the morning without regard to meals.
Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacy was also evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in the domains of socially useful activities (e.g. work and study), personal and social relationships, self care, and disturbing and aggressive behaviors.
In all 3 studies (n = 1665), INVEGA was superior to placebo on the PANSS at all doses. Mean effects at all doses were fairly similar, although the higher doses in all studies were numerically superior. INVEGA was also superior to placebo on the PSP in these trials.
An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age (there were few patients over 65), or geographic regions. There were insufficient data to explore differential effects based on race.
In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had clinically responded (defined as PANSS score < 70 or < 4 on pre-defined PANSS subscales, as well as having been on a stable fixed dose of INVEGA® for the last two weeks of an 8-week run-in phase) were entered into a 6-week open-label stabilization phase where they received INVEGA® (doses ranging from 3 to 15 mg once daily). After the stabilization phase, patients were randomized in a double-blind manner to either continue on INVEGA® at their achieved stable dose, or to placebo, until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as significant increase in PANSS (or pre-defined PANSS subscales), hospitalization, clinically significant suicidal or homicidal ideation, or deliberate injury to self or others. An interim analysis of the data showed a significantly longer time to relapse in patients treated with INVEGA® compared to placebo, and the trial was stopped early because maintenance of efficacy was demonstrated.
The information below is derived from a clinical trial database for INVEGA consisting of 2720 patients and/or normal subjects exposed to one or more doses of INVEGA for the treatment of schizophrenia.
Of these 2720 patients, 2054 were patients who received INVEGA while participating in multiple dose, effectiveness trials. The conditions and duration of treatment with INVEGA varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure. Adverse events were assessed by collecting adverse events and performing physical examinations, vital signs, weights, laboratory analyses and ECGs.
Adverse events during exposure were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
The stated frequencies of adverse events represent the proportions of individuals who experienced a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
The information presented in these sections were derived from pooled data from the three placebo-controlled, 6-week, fixed-dose studies based on subjects with schizophrenia who received INVEGA at daily doses within the recommended range of 3 to 12 mg (n = 850).
Table 1 enumerates the pooled incidences of treatment-emergent adverse events that were spontaneously reported in the three placebo-controlled, 6-week, fixed-dose studies, listing those events that occurred in 2% or more of subjects treated with INVEGA in any of the dose groups, and for which the incidence in INVEGA - treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.
| Percentage of Patients Reporting Event | |||||
| INVEGA | |||||
| Placebo | 3 mg once daily |
6 mg once daily |
9 mg once daily |
12 mg once daily |
|
| Body System or Organ Class | (N=355) | (N=127) | (N=235) | (N=246) | (N=242) |
| Dictionary-Derived Term | |||||
| Percentage of subjects with adverse events |
66 | 72 | 66 | 70 | 76 |
| Cardiac disorders | |||||
| Atrioventricular block first degree | 1 | 2 | 0 | 2 | 1 |
| Bundle branch block | 2 | 3 | 1 | 3 | <1 |
| Sinus arrhythmia | 0 | 2 | 1 | 1 | <1 |
| Tachycardia | 7 | 14 | 12 | 12 | 14 |
| Eye disorders | |||||
| Vision blurred | 1 | 1 | <1 | 0 | 2 |
| Gastrointestinal disorders | |||||
| Abdominal pain upper | 1 | 1 | 3 | 2 | 2 |
| Dry mouth | 1 | 2 | 3 | 1 | 3 |
| Dyspepsia | 4 | 2 | 3 | 2 | 5 |
| Nausea | 5 | 6 | 4 | 4 | 4 |
| Salivary hypersecretion | <1 | 0 | <1 | 1 | 4 |
| General disorders | |||||
| Asthenia | 1 | 1 | <1 | 2 | 2 |
| Fatigue | 1 | 2 | 1 | 2 | 2 |
| Pyrexia | 1 | 1 | <1 | 2 | 2 |
| Investigations | |||||
| Blood insulin increased | 1 | 2 | 1 | 1 | <1 |
| Blood pressure increased | 1 | 2 | <1 | <1 | 1 |
| Electrocardiogram QT corrected interval progonged | 3 | 3 | 4 | 3 | 5 |
| Electrocardiogram T wave abnormal | 1 | 2 | 1 | 2 | 1 |
| Musculoskeletal and connective tissue disorders | |||||
| Back pain | 1 | 1 | 1 | 1 | 2 |
| Pain in extremity | 1 | 0 | 1 | 0 | 2 |
| Nervous system disorders | |||||
| Akathisia | 4 | 4 | 3 | 8 | 10 |
| Dizziness | 4 | 6 | 5 | 4 | 5 |
| Dystonia | 1 | 1 | 1 | 5 | 4 |
| Extrapyramidal disorder | 2 | 5 | 2 | 7 | 7 |
| Headache | 12 | 11 | 12 | 14 | 14 |
| Hypertonia | 1 | 2 | 1 | 4 | 3 |
| Parkinsonism | 0 | 0 | <1 | 2 | 1 |
| Somnolence | 7 | 6 | 9 | 10 | 11 |
| Tremor | 3 | 3 | 3 | 4 | 3 |
| Psychiatric disorders | |||||
| Anxiety | 8 | 9 | 7 | 6 | 5 |
| Respiratory, thoracic and mediastinal disorders | |||||
| Cough | 1 | 3 | 2 | 3 | 2 |
| Vascular disorders | |||||
| Orthostatic hypotension | 1 | 2 | 1 | 2 | 4 |
| * Table includes adverse events that were reported in 2% or more of subjects in any of the INVEGA® dose groups and which occurred at greaer incidence than in the placebo group. Data are pooled from three studies: one study included once-daily INVEGA® doses of 3 and 9 mg; the second study included 6,9, and 12 mg; and the third study included 6 and 12 mg (see CLINICAL PHARMACOLOGY: Clinical Trials). Events for which the INVEGA® incidence was equal to or less than placebo are not listed in the table, but included the following: constipation, diarrhea, vomiting, nasopharyngitis, agitation, and insomnia. | |||||
Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, adverse events that occurred with a greater than 2% incidence in the subjects treated with INVEGA, the incidences of the following adverse events increased with dose: somnolence, orthostatic hypotension 9-mg, salivary hypersecretion, akathisia, dystonia, extrapyramidal disorder, hypertonia and Parkinsonism. For most of these, the increased incidence was seen primarily at the 12 mg, and in some cases the 9-mg dose.
Adverse events reported in 5% or more of subjects treated with INVEGA and at least twice the placebo rate for at least one dose included: akathisia and extrapyramidal disorder.
Pooled data from the three placebo-controlled, 6-week, fixed-dose studies provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS, and (4) incidence of spontaneous reports of EPS. For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and INVEGA 3 mg and 6 mg doses for any of these EPS measures.
Dyskinesia group includes: Dyskinesia, Extrapyramidal disorder, Muscle twitching, Tardive dyskinesia
Dystonia group includes: Dystonia, Muscle spasms, Oculogyration, Trismus
Hyperkinesia group includes: Akathisia, Hyperkinesia
Parkinsonism group includes: Bradykinesia, Cogwheel rigidity, Drooling, Hypertonia, Hypokinesia, Muscle rigidity, Musculoskeletal stiffness, Parkinsonism
Tremor group includes: Tremor1
Overall, there was no difference in the incidence of discontinuation due to adverse events between INVEGA-treated (5%) and placebo-treated (5%) subjects. The types of adverse events that led to discontinuation were similar for the INVEGA and placebo-treated subjects, except for Nervous System Disorders events which were more common among INVEGA-treated subjects than placebo-treated subjects (2% and 0%, respectively), and Psychiatric Disorders events which were more common among placebo-treated subjects than subjects treated with INVEGA (3% and 1%, respectively).
An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race. (see PRECAUTIONS: Geriatric Use).
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, between-group comparisons revealed no medically important differences between INVEGA and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements, parameters. Similarly, there were no differences between INVEGA and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry. However, INVEGA was associated with increases in serum prolactin (see the full US Prescribing Information under PRECAUTIONS: General: Hyperprolactinemia).
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, the proportions of subjects having a weight gain of < 7% of body weight were similar for INVEGA 3 mg and 6 mg (7% and 6%, respectively) and placebo (5%), but there was a higher incidence of weight gain for INVEGA 9 mg and 12 mg (9% and 9%, respectively).
Paliperidone is the major active metabolite of risperidone. Adverse events reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.
Please see the full US Prescribing Information.
For additional medical or clinical information, please call our Customer Communications Center at
1-800-JANSSEN (1-800-526-7736), 9 AM - 5 PM (ET), Monday through Friday.
INVEGA® (paliperidone) extended-release tablets are indicated for the acute and maintenance treatment of schizophrenia and for the acute treatment of schizoaffective disorder.
IMPORTANT SAFETY INFORMATION FOR INVEGA® (paliperidone)
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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the 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® is not approved for the treatment of patients with dementia-related psychosis.
Contraindications: Paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any of the components in the formulation.
Cerebrovascular Adverse Events (CAEs): CAEs (e.g., stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone, aripiprazole, and olanzapine. The incidence of CAEs was significantly higher than with placebo. INVEGA® is not approved for the treatment of patients with dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including paliperidone. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems.
QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QT interval and in patients with risk factors for prolonged QT 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 torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.
Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly women patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics (APS), including INVEGA®. Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, INVEGA® elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.
Gastrointestinal: INVEGA® should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing. Rare instances of obstructive symptoms have been reported in patients with known strictures taking non-deformable formulations. INVEGA® should only be used in patients who are able to swallow the tablet whole.
Orthostatic Hypotension and Syncope: INVEGA® may induce orthostatic hypotension in some patients due to its alpha-blocking activity. INVEGA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of MI or ischemia, conduction abnormalities), cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with anti-hypertensive medications). Monitoring should be considered in patients who are vulnerable to hypotension.
Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including paliperidone. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of INVEGA® should be considered. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue INVEGA® and have their WBC followed until recovery.
Potential for Cognitive and Motor Impairment: Somnolence was reported in subjects treated with INVEGA®. INVEGA® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA® does not adversely affect them.
Seizures: INVEGA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.
Suicide: The possibility of suicide attempt is inherent in psychotic illnesses. Close supervision of high-risk patients should accompany drug therapy. Prescriptions should be written for the smallest quantity of tablets to reduce the risk of overdose.
Commonly Observed Adverse Reactions: The most commonly observed adverse reactions in clinical trials occurring at an incidence of ≥5% and at least 2 times placebo were: schizophrenia ? extrapyramidal symptoms, tachycardia, and akathisia; schizoaffective disorder ? extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.
01JN10007
Please see the full US Prescribing Information.
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This page was last modified on: Jan 10 2008 at 16:39:57 EST