Pharmacy & Therapeutics - March 2008 - (Page 155) 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. 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, 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. Potential for Cognitive and Motor Impairment: Somnolence and sedation were reported in subjects treated with INVEGA® [see Adverse Reactions]. 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. Seizures: During premarketing clinical trials (the three placebo-controlled, 6-week, fixeddose 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. 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. 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. Priapism: Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with INVEGA ®, paliperidone shares this pharmacologic activity and, therefore, may be associated with this risk. Severe priapism may require surgical intervention. 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. 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. 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. Use in Patients with Concomitant Illness: Clinical experience with INVEGA® in patients with certain concomitant illnesses is limited [see Clinical Pharmacology]. 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]. Monitoring: Laboratory Tests: No specific laboratory tests are recommended. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning] • Cerebrovascular adverse events, including stroke, in elderly patients with dementiarelated psychosis [see Warnings and Precautions] • Neuroleptic malignant syndrome [see Warnings and Precautions] • QT prolongation [see Warnings and Precautions] • Tardive dyskinesia [see Warnings and Precautions] • Hyperglycemia and diabetes mellitus [see Warnings and Precautions] • Hyperprolactinemia [see Warnings and Precautions] • Potential for Gastrointestinal Obstruction [see Warnings and Precautions] • Orthostatic hypotension and syncope [see Warnings and Precautions] • Potential for cognitive and motor impairment [see Warnings and Precautions] • Seizures [see Warnings and Precautions] • Dysphagia [see Warnings and Precautions] • Suicide [see Warnings and Precautions] • Priapism [see Warnings and Precautions] • Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions] • Disruption of body temperature regulation [see Warnings and Precautions] • Antiemetic effect [see Warnings and Precautions] • Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see Warnings and Precautions] Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions] The most common adverse reactions in clinical trials (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate in any of the dose groups) were akathisia and extrapyramidal disorder. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in 2% of INVEGA®-treated subjects) were nervous system disorders [see Adverse Reactions]. 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. 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. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Table 1 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies, 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 1. Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials in Adult Subjects with Schizophrenia*: Body System or Organ Class (Dictionary-derived Term) Percent of Patients Reporting Event Placebo (N=355) first, INVEGA® 3 mg once daily (N=127) second, 6 mg once daily (N=235) third, 9 mg once daily (N=246) fourth, 12 mg once daily (N=242) fifth, Total percentage of subjects with adverse reactions 37, 48, 47, 54, 60; 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; 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,
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