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Estimated Savings Of Over $1,003,096

Always pay a fair price for your medication!

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INVEGA prescribing information
This information is not for clinical use. These highlights do not include all the information needed to use Invega safely and effectively.
Before taking Invega please consult with your doctor. See full prescribing information for Invega.
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 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) Extended-Release Tablets is not approved for the treatment of patients with dementia-related psychosis. [see Warnings and Precautions (5.1)] WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA® is not approved for use in patients with dementia-related psychosis. (5.1)
1 INDICATIONS AND USAGE INVEGA® is an atypical antipsychotic agent indicated for Treatment of schizophrenia (1.1) Adults: Efficacy was established in three 6-week trials and one maintenance trial. (14.1) Adolescents (ages 12–17): Efficacy was established in one 6-week trial. (14.1) Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants. (1.2) Efficacy was established in two 6-week trials in adult patients. (14.2) 1.1 Schizophrenia INVEGA® (paliperidone) Extended-Release Tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14.1)]. The efficacy of INVEGA® in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults. 1.2 Schizoaffective Disorder INVEGA® (paliperidone) Extended-Release Tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2)]. The efficacy of INVEGA® in schizoaffective disorder was established in two 6-week trials in adults.
Initial Dose Recommended Dose Maximum Dose
Schizophrenia - adults (2.1) 6 mg/day 3 – 12 mg/day 12 mg/day
Schizophrenia-adolescents (2.1) Weight < 51kg 3 mg/day 3 – 6 mg/day 6 mg/day
Weight ≥ 51kg 3 mg/day 3 – 12 mg/day 12 mg/day
Schizoaffective disorder - adults (2.2) 6 mg/day 3 – 12 mg/day 12 mg/day
3 DOSAGE FORMS AND STRENGTHS INVEGA® Extended-Release Tablets are available in the following strengths and colors: 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink). All tablets are capsule shaped and are imprinted with either "PAL 1.5", "PAL 3", "PAL 6", or "PAL 9". Tablets: 1.5 mg, 3 mg, 6 mg, and 9 mg (3)
4 CONTRAINDICATIONS INVEGA® is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA® formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone. Known hypersensitivity to paliperidone, risperidone, or to any excipients in INVEGA®. (4)
5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack, including fatalities) has been seen in elderly patients with dementia- related psychoses treated with atypical antipsychotics. (5.2) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. (5.3) QT Prolongation: Increase in QT interval, 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, dyslipidemia, and weight gain. (5.6) Hyperglycemia and Diabetes Mellitus: Monitor patients 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 in patients treated with atypical antipsychotics. (5.6) Weight Gain: Significant weight gain has been reported. Monitor weight gain. (5.6) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.7) Gastrointestinal Narrowing: Obstructive symptoms may result in patients with gastrointestinal disease. (5.8) Orthostatic Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease and patients predisposed to hypotension. (5.9) Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including INVEGA®. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of INVEGA® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (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) Suicide: Closely supervise high-risk patients. (5.14) 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. INVEGA® (paliperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning]. 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. INVEGA® was not marketed at the time these studies were performed. INVEGA® is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)]. 5.3 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of 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. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient appears to require antipsychotic drug treatment after recovery from NMS, reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been reported. 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 torsade 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 QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia. In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended 12 mg dose of INVEGA® (Cmax ss = 113 ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study. For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the INVEGA® 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving INVEGA® had a QTcLD exceeding 500 msec at any time in any of these three studies. 5.5 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon. There is no known treatment for established tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown. Given these considerations, INVEGA® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA® despite the presence of the syndrome. 5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with INVEGA®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because INVEGA® was not marketed at the time these studies were performed, it is not known if INVEGA® is associated with this increased risk. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a. Table 1a. Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia INVEGA® Placebo 3 mg/day 6 mg/day 9 mg/day 12 mg/day Mean change from baseline (mg/dL) n=322 n=122 n=212 n=234 n=218 Serum Glucose Change from baseline 0.8 -0.7 0.4 2.3 4.3 Proportion of Patients with Shifts Serum Glucose Normal to High 5.1% 3.2% 4.5% 4.8% 3.8% (<100 mg/dL to ≥126 mg/dL) (12/236) (3/93) (7/156) (9/187) (6/157) In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a mean change in glucose of +3.3 mg/dL at Week 24 (n=570) and +4.6 mg/dL at Week 52 (n=314). Data from the placebo-controlled 6-week study in adolescent subjects (12–17 years of age) with schizophrenia are presented in Table 1b. Table 1b. Change in Fasting Glucose from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12–17 years of age) with Schizophrenia INVEGA® Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day Mean change from baseline (mg/dL) n=41 n=44 n=11 n=28 n=32 Serum Glucose Change from baseline 0.8 -1.4 -1.8 -0.1 5.2 Proportion of Patients with Shifts Serum Glucose Normal to High 3% 0% 0% 0% 11% (<100 mg/dL to ≥126 mg/dL) (1/32) (0/34) (0/9) (0/20) (3/27) Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 2a. Table 2a. Change in Fasting Lipids from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia INVEGA® Placebo 3 mg/day 6 mg/day 9 mg/day 12 mg/day Mean change from baseline (mg/dL) Cholesterol n=331 n=120 n=216 n=236 n=231 Change from baseline -6.3 -4.4 -2.4 -5.3 -4.0 LDL n=322 n=116 n=210 n=231 n=225 Change from baseline -3.2 0.5 -0.8 -3.9 -2.0 HDL n=331 n=119 n=216 n=234 n=230 Change from baseline 0.3 -0.4 0.5 0.8 1.2 Triglycerides n=331 n=120 n=216 n=236 n=231 Change from baseline -22.3 -18.3 -12.6 -10.6 -15.4 Proportion of Patients with Shifts Cholesterol Normal to High 2.6% 2.8% 5.6% 4.1% 3.1% (<200 mg/dL to ≥240 mg/dL) (5/194) (2/71) (7/125) (6/147) (4/130) LDL Normal to High 1.9% 0.0% 5.0% 3.7% 0.0% (<100 mg/dL to ≥160 mg/dL) (2/105) (0/44) (3/60) (3/81) (0/69) HDL Normal to Low 22.0% 16.3% 29.1% 23.4% 20.0% ( ≥40 mg/dL to <40 mg/dL) (44/200) (13/80) (39/134) (32/137) (27/135) Triglycerides Normal to High 5.3% 11.0% 8.8% 8.7% 4.3% (<150 mg/dL to ≥200 mg/dL) (11/208) (9/82) (12/136) (13/150) (6/139) In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b) triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52 (n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and (d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52 (n=302). Data from the placebo-controlled 6-week study in adolescent subjects (12–17 years of age) with schizophrenia are presented in Table 2b. Table 2b. Change in Fasting Lipids from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12–17 years of age) with Schizophrenia INVEGA® Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day Mean change from baseline (mg/dL) Cholesterol n=39 n=45 n=11 n=28 n=32 Change from baseline -7.8 -3.3 12.7 3.0 -1.5 LDL n=37 n=40 n=9 n=27 n=31 Change from baseline -4.1 -3.1 7.2 2.4 0.6 HDL n=37 n=41 n=9 n=27 n=31 Change from baseline -1.9 0.0 1.3 1.4 0.0 Triglycerides n=39 n=44 n=11 n=28 n=32 Change from baseline -8.9 3.2 17.6 -5.4 3.9 Proportion of Patients with Shifts Cholesterol Normal to High 7% 4% 0% 6% 11% (<170 mg/dL to ≥200 mg/dL) (2/27) (1/26) (0/6) (1/18) (2/19) LDL Normal to High 3% 4% 14% 0% 9% (<110 mg/dL to ≥130 mg/dL) (1/32) (1/25) (1/7) (0/22) (2/22) HDL Normal to Low 14% 7% 29% 13% 23% ( ≥40 mg/dL to <40 mg/dL) (4/28) (2/30) (2/7) (3/23) (5/22) Triglycerides Normal to High 3% 5% 13% 8% 7% (<150 mg/dL to ≥200 mg/dL) (1/34) (2/38) (1/8) (2/26) (2/28) Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Schizophrenia Trials Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects are presented in Table 3a. Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia INVEGA® Placebo 3 mg/day 6 mg/day 9 mg/day 12 mg/day n=323 n=112 n=215 n=235 n=218 Weight (kg) Change from baseline -0.4 0.6 0.6 1.0 1.1 Weight Gain ≥ 7% increase from baseline 5% 7% 6% 9% 9% In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a mean change in weight of +1.4 kg at Week 24 (n=63) and +2.6 kg at Week 52 (n=302). Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind, placebo-controlled study and an open-label extension with a median duration of exposure to INVEGA® of 182 days. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight [see Clinical Studies (14.1)] from the placebo-controlled 6-week study in adolescent subjects (12–17 years of age) are presented in Table 3b. Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12–17 years of age) with Schizophrenia INVEGA® Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day n=51 n=54 n=16 n=45 n=34 Weight (kg) Change from baseline 0.0 0.3 0.8 1.2 1.5 Weight Gain ≥ 7% increase from baseline 2% 6% 19% 7% 18% In the open-label long-term study the proportion of total subjects treated with INVEGA® with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with INVEGA®, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to INVEGA® in the open-label study (182 days) along with expected normal growth in this population based on age and gender, an assessment of standardized scores relative to normative data provides a more clinically relevant measure of changes in weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant. Schizoaffective Disorder Trials In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, a higher percentage of INVEGA®-treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥ 7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group. 5.7 Hyperprolactinemia 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 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 Nonclinical Toxicology (13.1)]. 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. 5.8 Potential for Gastrointestinal Obstruction Because the INVEGA® tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, INVEGA® should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable controlled-release formulations. Because of the controlled-release design of the tablet, INVEGA® should only be used in patients who are able to swallow the tablet whole [see Dosage and Administration (2.3) and Patient Counseling Information (17.8)]. A decrease in transit time, e.g., as seen with diarrhea, would be expected to decrease bioavailability and an increase in transit time, e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These changes in bioavailability are more likely when the changes in transit time occur in the upper GI tract. 5.9 Orthostatic Hypotension and Syncope Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose trials in subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with INVEGA® (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo. INVEGA® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension. 5.10 Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including INVEGA®. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of INVEGA® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. 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. 5.11 Potential for Cognitive and Motor Impairment Somnolence was reported in subjects treated with INVEGA® [see Adverse Reactions (6.1, 6.2)]. Antipsychotics, including INVEGA®, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them. 5.12 Seizures During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled, 6-week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in 0.22% of subjects treated with INVEGA® (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, INVEGA® should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older. 5.13 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. INVEGA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. 5.14 Suicide The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for INVEGA® should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose. 5.15 Priapism Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with INVEGA® during postmarketing surveillance. Severe priapism may require surgical intervention. 5.16 Thrombotic Thrombocytopenic Purpura (TTP) No cases of TTP were observed during clinical studies with paliperidone. Although cases of TTP have been reported in association with risperidone administration, the relationship to risperidone therapy is unknown. 5.17 Body Temperature Regulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA® to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration. 5.18 Antiemetic Effect An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumor. 5.19 Use in Patients with Concomitant Illness Clinical experience with INVEGA® in patients with certain concomitant illnesses is limited [see Clinical Pharmacology (12.3)]. Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome. INVEGA® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with INVEGA®, caution should be observed in patients with known cardiovascular disease [see Warnings and Precautions (5.9)]. 5.20 Monitoring: Laboratory Tests No specific laboratory tests are recommended.
6 ADVERSE REACTIONS Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were (6) Adults with schizophrenia: extrapyramidal symptoms, tachycardia, and akathisia. Adolescents with schizophrenia: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increased, and tachycardia. Adults with schizoaffective disorder: extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Overall Adverse Reaction Profile The following adverse reactions 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)] Hyperprolactinemia [see Warnings and Precautions (5.7)] Potential for gastrointestinal obstruction [see Warnings and Precautions (5.8)] Orthostatic hypotension and syncope [see Warnings and Precautions (5.9)] Leukopenia, neutropenia, and agranulocytosis [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)] Suicide [see Warnings and Precautions (5.14)] Priapism [see Warnings and Precautions (5.15)] Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.16)] Disruption of body temperature regulation [see Warnings and Precautions (5.17)] Antiemetic effect [see Warnings and Precautions (5.18)] Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.19)] Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.19)] The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of INVEGA®-treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of INVEGA®-treated subjects. [See Adverse Reactions (6.4)]. The safety of INVEGA® was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA® at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received INVEGA® at daily doses within the range of 3 mg to 15 mg (n=104), is also included. The safety of INVEGA® was evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received INVEGA® in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. The safety of INVEGA® was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of INVEGA®: 6 mg with the option to reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. In the other study, 214 subjects received flexible doses of INVEGA® (3–12 mg once daily). Both studies included subjects who received INVEGA® either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment 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. Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of INVEGA® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for INVEGA® often cannot be reliably established in individual cases. Further, 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. 6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia in Adults and Adolescents Adult Patients with Schizophrenia Table 4 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those 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. Table 4. Adverse Reactions Reported by ≥ 2% of INVEGA®-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials Table includes adverse reactions that were reported in 2% or more of subjects in any of the INVEGA® dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily INVEGA® doses of 3 mg and 9 mg, the second study included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg [see Clinical Studies (14)]. Extrapyramidal symptoms includes the terms dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity, oculogyration, parkinsonism, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Adverse reactions for which the INVEGA® incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting. Percentage of Patients 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 Total percentage of subjects with adverse reactions 37 48 47 53 59 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 Gastrointestinal disorders Abdominal pain upper 1 1 3 2 2 Dry mouth 1 2 3 1 3 Salivary hypersecretion <1 0 <1 1 4 General disorders Asthenia 1 2 <1 2 2 Fatigue 1 2 1 2 2 Nervous system disorders Akathisia 4 4 3 8 10 Dizziness 4 6 5 4 5 Extrapyramidal symptoms 8 10 7 20 18 Headache 12 11 12 14 14 Somnolence 7 6 9 10 11 Vascular disorders Orthostatic hypotension 1 2 1 2 4 Adolescent Patients with Schizophrenia Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12–17 years of age with schizophrenia, listing those 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. Table 5. Adverse Reactions Reported by ≥ 2% of INVEGA®-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial Table includes adverse reactions that were reported in 2% or more of subjects in any of the INVEGA® dose groups and which occurred at greater incidence than in the placebo group. Extrapyramidal symptoms includes the terms oculogyric crisis, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus, bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, muscle contractions involuntary, parkinsonian gait, parkinsonism, tremor, and restlessness. Somnolence includes the terms somnolence, sedation, and hypersomnia. Insomnia includes the terms insomnia and initial insomnia. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Hypertension includes the terms hypertension and blood pressure increased. Gynecomastia includes the terms gynecomastia and breast swelling. Percentage of Patients INVEGA® Placebo 1.5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily Body System or Organ Class (N=51) (N=54) (N=16) (N=45) (N=35) Dictionary-Derived Term Total percentage of subjects with adverse reactions 43 37 50 58 74 Cardiac disorders Tachycardia 0 0 6 9 6 Eye disorders Vision blurred 0 0 0 0 3 Gastrointestinal disorders Dry mouth 2 0 0 0 3 Salivary hypersecretion 0 2 6 2 0 Swollen tongue 0 0 0 0 3 Vomiting 10 0 6 11 3 General disorders Asthenia 0 0 0 2 3 Fatigue 0 4 0 2 3 Infections and infestations Nasopharyngitis 2 4 0 4 0 Investigations Weight increased 0 7 6 2 3 Nervous system disorders Akathisia 0 4 6 11 17 Dizziness 0 2 6 2 3 Extrapyramidal symptoms 0 4 19 18 23 Headache 4 9 6 4 14 Lethargy 0 0 0 0 3 Somnolence 4 9 13 20 26 Tongue paralysis 0 0 0 0 3 Psychiatric disorders Anxiety 4 0 0 2 9 Reproductive system and breast disorders Amenorrhea 0 0 6 0 0 Galactorrhea 0 0 0 4 0 Gynecomastia 0 0 0 0 3 Respiratory, thoracic and mediastinal disorders Epistaxis 0 0 0 2 0 6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder in Adults Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with INVEGA® and for which the incidence in INVEGA®-treated subjects was greater than the incidence in subjects treated with placebo. Table 6. Adverse Drug Reactions Reported by ≥ 2% of INVEGA®-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials Table includes adverse reactions that were reported in 2% or more of subjects in any of the INVEGA® dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily INVEGA® doses of 6 mg (with the option to reduce to 3 mg) and 12 mg (with the option to reduce to 9 mg). The second study included flexible once-daily doses of 3 to 12 mg. Among the 420 subjects treated with INVEGA®, 230 (55%) received INVEGA® as monotherapy and 190 (45%) received INVEGA® as an adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia, drooling, dyskinesia, dystonia, hypertonia, muscle rigidity, muscle twitching, oculogyration, parkinsonian gait, parkinsonism, restlessness, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Percentage of Patients INVEGA® INVEGA® INVEGA® Placebo 3–6 mg once-daily fixed-dose range 9–12 mg once-daily fixed-dose range 3–12 mg once-daily flexible dose Body System or Organ Class (N=202) (N=108) (N=98) (N=214) Dictionary-Derived Term Total percentage of subjects with adverse reactions 32 48 50 43 Cardiac disorders Tachycardia 2 3 1 2 Gastrointestinal disorders Abdominal discomfort/Abdominal pain upper 1 1 0 3 Constipation 2 4 5 4 Dyspepsia 2 5 6 6 Nausea 6 8 8 5 Stomach discomfort 1 0 1 2 General disorders Asthenia 1 3 4 <1 Infections and Infestations Nasopharyngitis 1 2 5 3 Rhinitis 0 1 3 1 Upper respiratory tract infection 1 2 2 2 Investigations Weight increased 1 5 4 4 Metabolism and nutrition disorders Decreased appetite <1 1 0 2 Increased appetite <1 3 2 2 Musculoskeletal and connective tissue disorders Back pain 1 1 1 3 Myalgia <1 2 4 1 Nervous system disorders Akathisia 4 4 6 6 Dysarthria 0 1 4 2 Extrapyramidal symptoms 8 20 17 12 Somnolence 5 12 12 8 Psychiatric disorders Sleep disorder <1 2 3 0 Respiratory, thoracic and mediastinal disorders Cough 1 1 3 1 Pharyngolaryngeal pain <1 0 2 1 Monotherapy versus Adjunctive Therapy The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received INVEGA® as monotherapy and 190 (45%) subjects received INVEGA® as an adjunct to mood stabilizers and/or antidepressants. When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving INVEGA® as monotherapy. 6.4 Discontinuations Due to Adverse Reactions Schizophrenia Trials The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in INVEGA®- and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in INVEGA®- and placebo-treated subjects, respectively). Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (<1% of INVEGA®-treated subjects). Schizoaffective Disorder Trials The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and <1% in INVEGA®- and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in INVEGA®- and placebo-treated subjects, respectively). 6.5 Dose-Related Adverse Reactions Schizophrenia Trials Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with INVEGA®, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose. In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the adverse reactions that occurred with >2% incidence in the subjects treated with INVEGA®, the incidences of the following adverse reactions increased with dose: tachycardia, akathisia, extrapyramidal symptoms, somnolence, and headache. Schizoaffective Disorder Trials In a placebo-controlled, 6-week, high- and low-dose study in adult subjects with schizoaffective disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of INVEGA® compared with subjects who received lower doses. 6.6 Demographic Differences An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on the basis of gender or race alone; there was also no difference on the basis of age [see Use in Specific Populations (8.5)]. 6.7 Extrapyramidal Symptoms (EPS) Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia 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 (Table 7), and (4) incidence of spontaneous reports of EPS (Table 8). 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. Table 7. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults Percentage of Patients INVEGA® Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily EPS Group (N=355) (N=127) (N=235) (N=246) (N=242) Parkinsonism For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of items score divided by the number of items) 9 11 3 15 14 AkathisiaFor Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2 6 6 4 7 9 Use of anticholinergic medicationsPercent of patients who received anticholinergic medications to treat emergent EPS 10 10 9 22 22 Table 8. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adults Percentage of Patients INVEGA® Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily EPS Group (N=355) (N=127) (N=235) (N=246) (N=242) 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: Tremor Overall percentage of patients with EPS-related AE 11 13 10 25 26 Dyskinesia 3 5 3 8 9 Dystonia 1 1 1 5 5 Hyperkinesia 4 4 3 8 10 Parkinsonism 2 3 3 7 6 Tremor 3 3 3 4 3 Compared to data from the studies in adults subjects with schizophrenia, pooled data from the two placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types and frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous reports of EPS-related adverse events. For subjects with schizoaffective disorder, there was no dose-related increase in EPS observed for parkinsonism with the Simpson-Angus scale or akathisia with the Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of anticholinergic medications. Table 9 shows the EPS data from the pooled schizoaffective disorder trials. Table 9. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizoaffective Disorder Studies in Adults Percentage of Patients INVEGA® Placebo 3–6 mg once-daily fixed-dose range 9–12 mg once-daily fixed-dose range 3–12 mg once-daily flexible dose EPS Group (N=202) (N=108) (N=98) (N=214) Dyskinesia group includes: Dyskinesia, muscle twitching Dystonia group includes: Dystonia, muscle spasms, oculogyration Hyperkinesia group includes: Akathisia, hyperkinesia, restlessness Parkinsonism group includes: Bradykinesia, drooling, hypertonia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonian gait, parkinsonism Tremor group includes: Tremor Overall percentage of patients with EPS-related AE 11 23 22 17 Dyskinesia 1 3 1 1 Dystonia 1 2 3 2 Hyperkinesia 5 5 8 7 Parkinsonism 3 14 7 7 Tremor 3 12 11 5 The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies (Table 10). Table 10. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adolescent Subjects Percentage of Patients INVEGA® Placebo 1.5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily EPS Group (N=51) (N=54) (N=16) (N=45) (N=35) Hyperkinesia group includes: Akathisia Dystonia group includes: Dystonia, muscle contracture, oculogyric crisis, tongue paralysis, torticollis Tremor group includes: Tremor Parkinsonism group includes: Cogwheel rigidity, extrapyramidal disorder, muscle rigidity Dyskinesia group includes: Dyskinesia, muscle contractions involuntary Overall percentage of patients with EPS-related AE 0 6 25 22 40 Hyperkinesia 0 4 6 11 17 Dystonia 0 2 0 11 14 Tremor 0 2 6 7 11 Parkinsonism 0 0 6 2 14 Dyskinesia 0 2 6 2 6 Dystonia Class Effect: 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. 6.8 Laboratory Test Abnormalities In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between INVEGA® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA® was associated with increases in serum prolactin [see Warnings and Precautions (5.7)]. 6.9 Other Adverse Reactions Observed During Premarketing Evaluation of INVEGA® The following additional adverse reactions occurred in < 2% of INVEGA®-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by INVEGA®-treated subjects who participated in other clinical studies. Cardiac disorders: bradycardia, palpitations Eye disorders: eye movement disorder Gastrointestinal disorders: flatulence General disorders: edema Immune system disorders: anaphylactic reaction Infections and infestations: urinary tract infection Investigations: alanine aminotransferase increased, aspartate aminotransferase increased Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity Nervous system disorders: opisthotonus Psychiatric disorders: agitation, insomnia, nightmare Reproductive system and breast disorders: breast discomfort, menstruation irregular, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion Skin and subcutaneous tissue disorders: pruritus, rash Vascular disorders: hypertension The safety of INVEGA® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA® in adults with schizophrenia [see Clinical Studies (14)]. In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase. 6.10 Postmarketing Experience The following adverse reactions have been identified during postapproval use of INVEGA®; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, ileus, priapism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention. 6.11 Adverse Reactions Reported With Risperidone Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.
7 DRUG INTERACTIONS Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. (7.1) Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with INVEGA®. (7.1) Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of INVEGA® when a strong inducer of both CYP3A4 and P-gp (e.g., carbamazepine) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of INVEGA®. (7.2) Co-administration of divalproex sodium increased Cmax and AUC of paliperidone by approximately 50%. Adjust dose of INVEGA® if necessary based on clinical assessment. (7.2) 7.1 Potential for INVEGA® to Affect Other Drugs Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], INVEGA® should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA® is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.9)]. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown. Pharmacokinetic interaction between lithium and INVEGA® is unlikely. In a drug interaction study, co-administration of INVEGA® (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when INVEGA® 3–15 mg/day was added to their existing valproate treatment. 7.2 Potential for Other Drugs to Affect INVEGA® Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate. Co-administration of INVEGA® 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of INVEGA® should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA® should be re-evaluated and decreased if necessary. Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an interaction study in healthy subjects in which a single 3 mg dose of INVEGA® was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown. Co-administration of a single dose of INVEGA® 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for INVEGA® should be considered when INVEGA® is co-administered with valproate after clinical assessment. Pharmacokinetic interaction between lithium and INVEGA® is unlikely.
8 USE IN SPECIFIC POPULATIONS Renal impairment: Dosing must be individualized according to renal function status. (2.5) Elderly: Same as for younger adults (adjust dose according to renal function status). (2.4) Nursing Mothers: The benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone. (8.3) Pediatric Use: Safety and effectiveness in the treatment of schizophrenia not established in patients less than 12 years of age. Safety and effectiveness in the treatment of schizoaffective disorder not established in patients less than 18 years of age. (8.4) 8.1 Pregnancy Pregnancy Category C. There are no adequate and well controlled studies of INVEGA® in pregnant women. Use of first generation antipsychotic drugs during the last trimester of pregnancy has been associated with extrapyramidal symptoms in the neonate. These symptoms are usually self-limited. It is not known whether paliperidone, when taken near the end of pregnancy, will lead to similar neonatal signs and symptoms. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated during the period of organogenesis with up to 8 times the maximum recommended human dose of paliperidone (on a mg/m2 basis). In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, there were increases in pup deaths seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m2 basis (see risperidone package insert). Non-teratogenic Effects Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. INVEGA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Paliperidone is excreted in human breast milk. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone. 8.4 Pediatric Use Safety and effectiveness of INVEGA® in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received INVEGA® in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. Safety and effectiveness of INVEGA® for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of INVEGA® for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied. 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. 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 maximum recommended human dose 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® on growth and sexual maturation have not been fully evaluated in children and adolescents. 8.5 Geriatric Use The safety, tolerability, and efficacy of INVEGA® were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of INVEGA® (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of INVEGA® (3 mg to 15 mg once daily) [see Clinical Studies (14)]. There were no subjects ≥ 65 years of age in the schizoaffective disorder studies. Overall, of the total number of subjects in schizophrenia clinical studies of INVEGA® (n = 1796), including those who received INVEGA® or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.5)]. 8.6 Renal Impairment Dosing must be individualized according to the patient's renal function status [see Dosage and Administration (2.5)]. 8.7 Hepatic Impairment No dosage adjustment is required in patients with mild to moderate hepatic impairment. INVEGA® has not been studied in patients with severe hepatic impairment.

Save on the cost of Invega

With Our Invega Discount Card

Be sure to ask your pharmacist not to substitute another card for ours as we are confident we offer the highest savings possible.

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Frequently Asked Questions

There are no catches to this. Simply print the card, take it to your pharmacy, and save. If you still have questions just read below...

How Do I Know My Pharmacy Will Accept It?
That's simple. The card is accepted at ALL CHAIN PHARMACIES such as CVS, Rite Aid, and Walgreens. If you don't know if your pharmacy accepts the card simply call them and give them the BIN and PCN numbers on the card. The card is accepted at most pharmacies. If you call a few one is sure to accept it.
Can I Use This In Conjunction With My Insurance?
No, unfortunately insurance companies don't allow "double-savings". However, if your insurance does not cover certain drugs (ex - cosmetic drugs, brand names, prenatal vitamins, etc) then this card may save you money. Also if your insurance requires you to pay a deductible on your brand name drugs before covering them, then this card may also provider greater savings!
How Much Will This Card Save Me?
You can expect to save between 10% - 75% off standard retail pricing. The discount varies depending on what type and brand of drug (generic or brand-name) you are purchasing.
This Sounds Too Good To Be True. Is This A Scam?
Absolutely not. As you can see there are no fees, ever. We will never ask for credit card information at any time. The reason this card works is simply because pharmacies are willing to provide a discount in order to earn your business.
My Pharmacy Isn't Included. Can They Participate?
Yes! There are pharmacies who accept the pharmacy savings card that are not on our list. If you find one please email us and we'll update the list. If they are not a current partner and are interested, email us and we'll contact them to try and convince them to participate. You may also choose to call around and see if someone else in your area accepts it.
Is this the same as an Invega copay card?
No this is not a copay card, It is good for the cash paying customer and cannot be used to reduce your copay.
Savings of 70%!
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Savings of over $200!
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Savings of over 50%!
I had printed out 3 different discount cards on the internet and asked the pharmacist to check prices. The lowest price was $289. I searched the internet some more, I found this site, gave the pharmacy your card and the cost was $130. What a big savings, I can't thank this site enough. - Linda S.

Accepted at over 59,000 pharmacies nationwide including

Accepted At Over 59,000 Pharmacies Nationwide!

Including...
  • Including...
  • Cub Pharmacy
  • Kmart
  • HEB
  • Target
  • Winn Dixie
  • Costco
  • Safeway
  • Kroger
  • Tom Thumb
  • CVS
  • Brookshire`s
  • Rite Aid
  • Fred`s Pharmacy
  • Walmart
  • Long Drugs
  • Walgreens
  • Giant
  • Save Mart Pharmacy
  • Fred Meyer
  • We Care Pharmacy
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And thousands of independent pharmacies nationwide!

Paliperidone (trade name Invega), also known as 9-hydroxyrisperidone, is a dopamine antagonist of the atypical antipsychotic class of medications. It is developed by Janssen Pharmaceutica. Invega is an extended release formulation of paliperidone that uses the OROS extended release system to allow for once-daily dosing. Paliperidone palmitate (trade name Invega Sustenna, named Xeplion in Europe) is a long-acting injectable formulation of paliperidone palmitoyl ester indicated for once-monthly injection after an initial titration period. This drug is used to get out of a manic episode and also at lower doses as maintenance for bipolar disorder. It is also used for schizophrenia and schizoaffective disorder.

Wikipedia contributors. "Invega" Wikipedia, The Free Encyclopedia. Wikipedia, The Free Encyclopedia, Jul 3, 2012. Web. Jul 6, 2012.

Invega Coupon

Currently we do not have any available, however you can receive an instant discount at your pharmacy with our Invega discount card. Create one instantly

Important Note

The information on this website is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist or other healthcare professional. It should not be construed to indicate that use of the drug is safe, appropriate, or effective for you. Consult your healthcare professional before using this drug.

This prescription discount card cannot be used in conjunction with insurance. However, some members find they save more when using the card rather than there prescription coverage.

This Invega discount should not be confused with an Invega coupon while they are essentially the same this discount card only needs to be handed to your pharmacist once and will provide continuous savings every time your prescription is filled. The only time you will need to use it again is if you change pharma

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Save up to 75% on your medication
Save up to 75% on your medication