Pharmacy & Therapeutics - October 2008 - (Page 589)

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, reinitiating 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 about operating hazardous machinery, including automobiles, until they are reasonably certain that INVEGA® therapy does not affect them adversely [see Warnings and Precautions]. Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with INVEGA® [see Use in Specific Populations]. Nursing: 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. [See Use in Specific Populations]. Concomitant Medication: Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-thecounter drugs, as there is a potential for interactions [see Drug Interactions]. Alcohol: Patients should be advised to avoid alcohol while taking INVEGA® [see Drug Interactions]. Heat Exposure and Dehydration: Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions]. Administration: Patients should be informed that INVEGA® should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice something that looks like a tablet in their stool [see Dosage and Administration]. INVEGA® (paliperidone) Extended-Release Tablets Manufactured by: ALZA Corporation Mountain View, CA 94043 Distributed by: JANSSEN®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 OROS is a registered trademark of ALZA Corporation December 2007 ©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2008 10105902B 01JN651BS

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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