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Proven Safety and Tolerability
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:
- At the recommended 6 mg dose, incidence of weight gain was similar to that for placebo
- Discontinuation rates for INVEGA due to adverse events are similar to those for placebo across all doses
- INVEGA was shown to be safe and tolerable with low weight gain and EPS rates comparable with placebo at the recommended 6-mg dose
- The proportion of subjects having a weight gain of >7% body weight were comparable with placebo (5%) for 3 mg (7%) and 6 mg (6%). a higher incidence was seen for 9 mg (9%) and 12 mg (9%)
- No difference between INVEGA and placebo in the number of patients experiencing changes in lipids or fasting glucose*
Please see Hyperglycemia and Diabetes warning below.
*Data on file. Pooled results from three 6-week pivotal trials. The proportion of patients gaining >7% of body weight with INVEGA 3 mg, 9 mg, and 12 mg was 7%, 9%, and 9%, respectively.
Adverse Reactions
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.
Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Subjects with Schizophrenia
The information presented in these sections was 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).
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 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. | |||||
In the trials cited above, what were the effects on:
- Weight gain?
- Lipid levels and fasting glucose?
- Hepatic impairment?
- Prolactin Levels?
- EPS?
- Discontinuation?
What was the incidence or risk of:
What were the rates of:
Incidence of weight gain >7% similar to that for placebo.
*Adapted from Kramer et al and data on file.
†Pooled results from three 6-week pivotal trials.
‡The proportion of patients gaining > 7% of body weight with INVEGA was 7% (3 mg), 6% (6 mg), 9% (9 mg), and 9% (12 mg) in 6-week trials, and 20% (average 10.8 mg) in a longer-term, flexible-dose trial.
§Results from a longer-term trial of up to 11 months (average 24 weeks). The average dose of INVEGA was 10.8 mg.
†Pooled results from three 6-week pivotal trials.
‡The proportion of patients gaining > 7% of body weight with INVEGA was 7% (3 mg), 6% (6 mg), 9% (9 mg), and 9% (12 mg) in 6-week trials, and 20% (average 10.8 mg) in a longer-term, flexible-dose trial.
§Results from a longer-term trial of up to 11 months (average 24 weeks). The average dose of INVEGA was 10.8 mg.
Lipid levels and Fasting Glucose
No difference between INVEGA and placebo in the number of patients experiencing changes in lipids or fasting glucose.
No difference between INVEGA and placebo in the number of patients experiencing changes in lipids or fasting glucose.
Please see Hyperglycemia and Diabetes warning below.
Please see full Prescribing Information for INVEGA
*Data on file. Pooled results from three 6-week pivotal trials. No difference between INVEGA (3 mg, 6mg, 9mg, 12mg) and placebo in the number of patients experiencing changes in lipids or fasting glucose.
*Laboratory Test Abnormalties. Full Prescribing Information.
Please see Hyperglycemia and Diabetes warning below.
Please see full Prescribing Information for INVEGA.
In a study in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment is unknown.
Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with RISPERDAL® (risperidone), a drug that is associated with higher levels of prolactin than other antipsychotic drugs.
Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility). Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.
Please see full Prescribing Information for INVEGA and RISPERDAL.
- EPS rates were similar to those for placebo at the recommended 6-mg dose
- INVEGA 3-mg and 6-mg doses were comparable with placebo across EPS scales and rates of adverse events
- Total EPS-related adverse events in the higher 9-mg and 12-mg treatment groups were 25% and 26%, respectively, versus 11% for the placebo group
*Pooled results from three 6-week pivotal trials.
†Not otherwise specified.
‡Dyskinesia group includes: dyskinesia, muscle twitching, tardive dyskinesia.
INVEGA delivered discontinuation rates due to adverse events that are similar to those for placebo across all doses.
*Data on file. Pooled results from three 6-week pivotal trials.
Please see full Prescribing Information for INVEGA.
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 is contraindicated in patients with a known hypersensitivity to paliperidone, to risperidone, or to any components in the INVEGA formulation.
For warnings, including Boxed Warning on Increased Mortality in Elderly Patients with Dementia-Related Psychosis, see the full US Prescribing Information under WARNINGS.
For more on Safety, please see the full US Prescribing Information under PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE.
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