Pharmacy & Therapeutics - December 2008 - (Page 709)

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. 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 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 in full PI]. 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 in full PI]. 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 in full PI], 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 in full PI]. Renal Impairment: Dosing must be individualized according to the patient’s renal function status [see Dosage and Administration in full PI]. 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 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 in full PI]. Manufactured by: ALZA Corporation Mountain View, CA 94043 OR Janssen Cilag Manufacturing, LLC Gurabo, Puerto Rico 00778 Manufactured for: Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 OROS is a registered trademark of ALZA Corporation ©Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007 10105903B Revised: September 2008 01JN821BS

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Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

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