Pharmacy & Therapeutics - March 2008 - (Page 156) Table 2. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication: EPS Group Percentage of Patients 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, Parkinsonism a 9, 11, 3, 15, 14; Akathisia b 6, 6, 4, 7, 9; Use of anticholinergic medications c 10, 10, 9, 22, 22. a: 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) b: For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2 c: Percent of patients who received anticholinergic medications to treat emergent EPS Table 3. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term: EPS Group Percentage of Patients 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, 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; 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 Laboratory Test Abnormalities: In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, a between-group comparison 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]. Weight Gain: In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, the proportions of subjects meeting a weight gain criterion of ≥ 7% of body weight were compared, revealing a similar incidence of weight gain for INVEGA® 3 mg and 6 mg (7% and 6%, respectively) compared with placebo (5%), and a higher incidence of weight gain for INVEGA® 9 mg and 12 mg (9% and 9%, respectively). Other Findings Observed During Clinical Trials: 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]. 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. 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. DRUG INTERACTIONS Potential for INVEGA® to Affect Other Drugs: Given the primary CNS effects of paliperidone [see Adverse Reactions], 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]. 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. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. 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. Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology]. 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. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate and well controlled studies of INVEGA® in pregnant women. INVEGA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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). Labor and Delivery: The effect of INVEGA® on labor and delivery in humans is unknown. Nursing Mothers: Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. In animal studies, risperidone and 9-hydroxyrisperidone were excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Caution should be exercised when INVEGA® is administered to a nursing woman. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone. Pediatric Use: Safety and effectiveness of INVEGA® in patients < 18 years of age have not been established. 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]. Overall, of the total number of subjects in 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], 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]. Renal Impairment: Dosing must be individualized according to the patient’s renal function status [see Dosage and Administration]. 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. PATIENT COUNSELING INFORMATION Physicians are advised to discuss the following issues with patients for whom they prescribe INVEGA®. Orthostatic Hypotension: Patients should be advised that there is risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions]. Interference with Cognitive and Motor Performance: As INVEGA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned
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