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22037 Guanfacine Clinpharm PREA

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22037 Guanfacine Clinpharm PREA CLINICAL REVIEW Application Type: NDA Submission Number: 22,037 Submission Code: Letter Date: August 24, 2006 Stamp Date: August 27, 2006 PDUFA Goal Date: June 24, 2007 Reviewer Name: Robert L. Levin, M.D. Review Completion Date: June 12, 2007 Established Name: Guanfacine hydrochloride Proposed Trade Name: Intuniv Therapeutic Class: Central ά-2adrenergic-receptor agonist Applicant: Shire Priority Designation: S Formulation: Oral, extended-release tablet Dosing Regimen: Once daily Indication: Attention-Deficit/Hyperactivity D/O Intended Population: Pediatrics (ages 6-17) 1 Table of Contents 1 EXECUTIVE SUMMARY……………………………………………………………5 1.1 RECOMMENDATION ON REGULATORY ACTION………………………………5 1.2 RECOMMENDATIONS ON POSTMARKETING ACTIONS…………………..……5 1.2.1 Risk Management Activity……………………………………………………….6 1.2.2 Required Phase 4 Commitments…………………………………………………6 1.2.3 Other Phase 4 Requests……………………………………………………………6 1.3 SUMMARY OF CLINICAL FINDINGS………………………………………………6 1.3.1 Brief Overview of the Clinical Program………………………………………….6 1.3.2 Efficacy………………………………………………………………………….…..7 1.3.3 Safety……………………………………………………………………………..7 1.3.4 Dosing Regimen and Administration………………………………………………9 1.3.5 Drug-Drug Interactions……………………………………………………………10 1.3.6 Special Populations………………………………………………………………..11 2 INTRODUCTION AND BACKGROUND……………………………….......................13. 2.1 PRODUCT INFORMATION………………………………………………………..…13 2.2 CURRENTLY AVAILABLE TREATMENTS FOR INDICATION………………….14 2.3 AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE U.S…………….14 2.4 IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS.15 2.5 PRESUBMISSION REGULATORY ACTIVITY……………………………………16 3 SIGNIFICANT FINDINGS FROM OTHER DISCIPLINES…………………………18 3.1 STATISTICS FINDINGS…………………………………………………….……….18 3.2 PHARMACOMETRICS FINDINGS…………………………………………..…….19 3.3 CARDIORENAL QT INTERDISCIPLINARY REVIEW TEAM (QTIRT) …………20 3.4 BIOPHARMACEUTICS FINDINGS………………………………20 3.5 OFFICE OF SURVEILLANCE AND EPIDEMIOLOGY CONSULTS……………...21 3.6 CHEMISTRY FINDINGS……………………………………………………………..21 3.7 DDMAC, DMETS, DSI………………………………………………………………..22 3.8 PHARMACOLOGY/TOXICOLOGY…………………………………………………22 4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY……………22 4.1 SOURCES OF CLINICAL DATA……………………………………………………23 4.2 TABLES OF CLINICAL STUDIES…………………………………………….……23 4.3 REVIEW STRATEGY……………………………………………………………….…23 4.4 DATA QUALITY AND INTEGRITY…………………………………………………..23 4.5 COMPLIANCE WITH GOOD CLINICAL PRACTICES………………………….…23 5 CLINICAL PHARMACOLOGY…………………………………………………..……24 5.1 PHARMACOKINETICS……………………………………………………………..24 5.2 PHARMACODYNAMICS…………………………..……………………………….28 6 INTEGRATED REVIEW OF EFFICACY………………………………………………..29 6.1 INDICATION…………………………………………………………………………29 6.2 DISCUSSION OF ENDPOINTS………………………………………………..……30. 6.3 STUDY DESIGN……………………………………………………………….……30 2 6.4 EFFICACY FINDINGS………………………………………………………….……34 7 EXPOSURE TO STUDY DRUG……………………………………………….……..47 7.1 TOTAL EXPOSURE TO STUDY DRUG IN CLINICAL PROGRAM………….…47 7.2 EXPOSURE TO STUDY DRUG IN CONTROLLED, SHORT-TERM TRIALS…47 7.3 EXPOSURE TO STUDY DRUG IN PHASE 1 AND PHASE 2 STUDIES…………47 7.4 EXPOSURE TO STUDY DRUG IN LONG-TERM, OPEN-LABEL STUDIES.…47 8 INTEGRATED REVIEW OF SAFETY……………………………………………….……51 . 8.1 SAFETY FINDINGS IN CONTROLLED STUDIES…………………………………51 8.1.1 Deaths………………………………………………………………………………51 8.1.2 Serious Adverse Events…………………………………………………………51 8.1.3 Discontinuations Due to Adverse Events……………………………………...…52 8.1.4 Other Significant Adverse Events……………………………………………53 8.1.5 Common Adverse Events…………………………………………………………56 8.1.6 Less Common Adverse Events………………………………………………….57 8.1.7 Vital Signs Findings………………………………………………………………57 8.1.8 Electrocardiogram (ECG) Findings……………………………………………58 8.1.9 Clinical Laboratory Findings…………………………………………………….65 8.1.10 Special Safety Study 205- Co-Administration of Stimulants and Guanfacine…66 8.1.11 Special Safety Study 206- Cognitive Function Tests……………………………67 8.1.12 Drug Discontinuation Phenomena (Special Safety Study 102)…………………70 8.1.13 Abuse Potential……………………………………………………………………70 8.1.14 Human Reproduction and Pregnancy Data………………………………………71 8.1.15 Assessment of Effect on Growth (weight and height)…………………………..71 8.1.16 Overdose Experience…………………………………………………………72 8.2 SAFETY FINDINGS IN SAFETY UPDATE AND LONG-TERM STUDIES……74 8.3 POSTMARKETING SAFETY DATA (Sponsor)……………………………………82 9 ADDITIONAL CLINICAL ISSUES…………………………………………………………85 9.1 DOSING REGIMEN AND ADMINISTRATION……………………………………..85 9.2 DRUG-DRUG INTERACTIONS……………………………………………………86 9.3 SPECIAL POPULATIONS……………………………………………………………87 9.4 PEDIATRICS………………………………………………………………………88 9.5 LITERATURE REVIEW (FDA AND SPONSOR) ……………………………….…88 9.6 POSTMARKETING RISK MANAGEMENT PLAN………………………………88 10 OVERALL ASSESSMENT………………………………………………………………89 10.1 CONCLUSIONS……………………………………………………………………89 10.2 RECOMMENDATION ON REGULATORY ACTION…………………………91 10.3 RECOMMENDATION ON POSTMARKETING ACTION………………………91 10.4 LABELING REVIEW………………………………………………….…………93 . 11 APPENDIX……………………………………………………………………………124 3 1 EXECUTIVE SUMMARY 1.1 Recommendations on Regulatory Action I recommend that the Division of Psychiatry Products take an Approvable action for NDA 22-037. In my opinion, the sponsor has demonstrated the efficacy and safety of Intuniv (guanfacine extended-release) in the treatment of Attention Deficit-Hyperactivity Disorder (ADHD) in children and adolescents (ages 6-17 years-old). Studies 301 and 304 were adequate and well-controlled trials that demonstrated the efficacy of Intuniv, as measured by the change in mean Attention Deficit-Hyperactivity Disorder Rating Scale- IV (ADHD-RS-IV) scores. There was a statistically and clinically significant difference in the treatment effect of Intuniv compared to placebo in both placebo-controlled trials. Furthermore, the treatment effect was dose-related and exposure-related. In my opinion, treatment with Intuniv was reasonably safe and well tolerated in the trials. While there were clinically significant adverse events in the trials, many of the potential safety concerns can be managed largely through rational dosing on an mg/kg basis. For, a considerable portion of the common and significant adverse events appear to be dose- related and exposure-related. Guanfacine exposures were highly correlated (inversely) with subjects’ body weights. Furthermore, the sponsor used fixed doses, instead of dosing per body weight in the trials. 1.2 Recommendations on Postmarketing Actions 1.2.1 Required Postmarketing Commitments • The sponsor should conduct a dedicated, thorough QT study of guanfacine in healthy adult subjects. (Preliminary details will be discussed below in the Cardiorenal QT Interdisciplinary Review Team consult). • The sponsor should conduct a controlled trial in adolescent subjects with ADHD, in order to confirm that treatment with Intuniv is safe and effective in this population. • The sponsor should conduct a controlled trial of adjunctive treatment with guanfacine stimulant medications in children and adolescents with ADHD. • The sponsor should continue to collect ECG data in ongoing pediatric trials. • The sponsor should conduct a placebo-controlled maintenance trial to assess the long-term efficacy and safety of guanfacine in children and adolescents with ADHD. This should probably be a placebo-controlled randomized withdrawal study. • The sponsor should conduct a separate long-term safety study, focusing on the following safety concerns: growth, weight gain, metabolic effects, QT interval prolongation, syncope and other cardiovascular safety parameters, seizures, sedative adverse events, cognitive performance, and effects on growth hormone and bilirubin concentrations. 4 1.2.2 Risk Management Activity The sponsor should submit a detailed Risk Management Plan that focuses on managing the potential cardiovascular risks of QT prolongation, syncope, hypotension, and bradycardia. Risk management should also focus on the common sedative adverse events. The plan should include a detailed discussion of the exposure-related and dose-related risks and a dosing and titration plan based on body weight. In addition, it would be useful for the sponsor to develop a Med Guide or similar form of communication for educating patients, parents, and caregivers about the potential safety concerns listed above. In developing a Risk Management Plan, the sponsor should probably consult with pediatric cardiologists. Finally, the sponsor should incorporate should incorporate the data from the American Association of Poison Control Centers publication on pediatric guanfacine overdosages in the labeling for Intuniv™. 1.2.1 Other Phase 4 Requests We will consider recommending that the sponsor conduct specific drug interaction studies, including guanfacine interactions with: valproic acid and moderate inhibitors of the CYP3A4/5 system. 1.3 Summary of Clinical Findings 1.3.1 Brief Overview of the Clinical Program The clinical development program for Intuniv included ten (10) studies in children and adolescents with a diagnosis of ADHD and eight (8) studies in healthy adult volunteers. The studies in ADHD subjects were: 107, 201, 202, 203, 205, 206, 301, 303, 304, and 305. Studies 301 and 304 were the two (2) pivotal controlled efficacy and safety trials. Studies 303 and 305 were long-term, open-label extension studies of 301 and 205/304, respectively. The eight healthy volunteer studies included studies 101, 102, 103, 104, 106, 108, 109, and 110. Intuniv was used in all of the clinical studies with the exception of studies 101, 201, 202, and 203, which used formulations that are no longer being
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