Get treatment-related news and the latest information about INVEGA.
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.
RISPERDAL® (risperidone) is indicated for the treatment of schizophrenia in adults and children aged 13-17 years.
IMPORTANT SAFETY INFORMATION FOR INVEGA® AND RISPERDAL ®
Increased Mortality in Elderly Patients with Dementia-Related
Psychosis
Elderly patients with dementia-related psychosis treated with atypical 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® (paliperidone) and RISPERDAL® (risperidone) are not approved for the treatment of patients with dementia-related psychosis.
Elderly patients with dementia-related psychosis treated with atypical 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® (paliperidone) and RISPERDAL® (risperidone) are not approved for the treatment of patients with dementia-related psychosis.
Cerebrovascular Adverse Events (CAEs): CAEs, including fatalities, have been reported in elderly patients with dementia-related psychosis taking atypical antipsychotics in clinical trials. INVEGA® and RISPERDAL® are not approved for treating these patients.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including INVEGA® and RISPERDAL®. 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 medical monitoring, and treatment of any concomitant serious medical problems.
QT Prolongation: INVEGA® causes a modest increase in the corrected QT (QTc) interval. INVEGA® should be avoided in combination with other drugs that are known to prolong the QTc interval, in patients with congenital long QT syndrome or a history of cardiac arrhythmias. Certain circumstances may increase the risk of torsades 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. Elderly patients appeared to be at increased risk for TD. Prescribing should be consistent with the need to minimize the risk of TD. 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). Patients starting treatment with APS who have or are at risk for diabetes 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.
Hyperprolactinemia: As with other drugs that antagonize dopamine
Potential for Gastrointestinal Obstruction: 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 nondeformable formulations. INVEGA® should only be used in patients who are able to swallow the tablet whole.
Orthostatic Hypotension and Syncope: INVEGA® and RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. Monitoring should be considered in patients for whom this may be of concern. INVEGA® and RISPERDAL® should be used with caution in patients with known cardiovascular disease, and conditions that would predispose patients to hypotension.
Potential for Cognitive and Motor Impairment: INVEGA® and RISPERDAL® have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA® and RISPERDAL® do not affect them adversely.
Seizures: INVEGA® and RISPERDAL® should be used cautiously in patients with a history of seizures.
Suicide: The possibility of suicide attempt is inherent in psychotic illnesses and close supervision of high-risk patients should accompany drug therapy.
Maintenance Treatment: Physicians who elect to use INVEGA® and RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Drug Interactions: Co-administration of INVEGA® 6 mg once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. On initiation of discontinuation of carbamazepine, the dose of INVEGA® should be re-evaluated and adjusted if necessary. Given the primary CNS effects of INVEGA®, INVEGA® should be used with caution in combination with other centrally acting drugs and the use of alcohol should be avoided.
Extrapyramidal Symptoms (EPS): Total EPS-related adverse events with INVEGA® in the higher 9-mg and 12-mg treatment groups were 25% and 26%, respectively, versus 11% for the placebo group.
Weight Gain: The proportion of subjects having a weight gain of >7% body weight with INVEGA® were comparable to placebo (5%) for 3 mg (7%) and 6 mg (6%). A higher incidence was seen for 9 mg (9%) and 12 mg (9%).
Renal Impairment: Dosing must be individualized according to the patient's renal function status. The maximum recommended dose of INVEGA® is 6 mg for patients with mild renal impairment and 3 mg for patients with moderate to severe renal impairment (see Dosing for Special Populations).
Elderly: No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance (see Dosing for Special Populations).
Commonly observed adverse reactions for INVEGA®: The most commonly observed adverse reactions, occurring at an incidence of >5% and at least 2 times placebo, were akathisia and extrapyramidal disorder.
Commonly observed adverse reactions for RISPERDAL®: The most common adverse reactions from all clinical trials (>10%) were: somnolence, appetite increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia.
Use with Risperidone: Concomitant use of paliperidone with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is co-administered.
01JN777R1
Please see the full US Prescribing Information for INVEGA and RISPERDAL.
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2006-2009. All rights reserved.
Your use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy.
This site is published by Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. which is solely responsible for its contents. This information is intended for the use of our customers, patients and healthcare professionals in the United States only. Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. recognizes that the Internet is a global communications medium; however, laws, regulatory requirements and medical practices for pharmaceutical products vary from country to country. The Prescribing Information included here may not be appropriate for use outside the United States.
Capitalized product names are trademarks of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Some documents on this site are stored in Adobe PDF format and require the free Adobe® Reader to view.
This page was last modified on: Jan 10 2008 at 16:39:57 EST