CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210895Orig1s000 CLINICAL REVIEW(S) Clinical Review Ovidiu A. Galescu, MD NDA 210895 Welchol (colesevelam hydrochloride) CLINICAL REVIEW Application Type NDA 505(b)(1) Application Number(s) 210895 Priority or Standard Standard Submit Date(s) October 30, 2017 Received Date(s) October 30, 2017 PDUFA Goal Date August 30, 2018 Division/Office DMEP/OND Reviewer Name(s) Ovidiu A. Galescu Review Completion Date August 8, 2018 Established/Proper Name colesevelam hydrochloride (Proposed) Trade Name Welchol Chewable Bar Applicant Daiichi Sankyo, Inc. Dosage Form(s) Chewable Bar Applicant Proposed Dosing 1 chewable bar (3.75 grams colesevelam hydrochloride) / day Regimen(s) Applicant Proposed Primary Hyperlipidemia and Type 2 Diabetes Mellitus Indication(s)/Population(s) Recommendation on Complete Response due to facilities deficiency. No clinical Regulatory Action issues identified. Recommended Reduce elevated low-density lipoprotein cholesterol in adults Indication(s)/Population(s) and children ages 10-17 years Improve glycemic control in adults with type 2 diabetes mellitus CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4310681 Clinical Review Ovidiu A. Galescu, MD NDA 210895 Welchol (colesevelam hydrochloride) Table of Contents Glossary ..........................................................................................................................................9 1. Executive Summary...............................................................................................................11 1.1. Product Introduction......................................................................................................11 1.2. Conclusions on the Substantial Evidence of Effectiveness.............................................11 1.3. Benefit-Risk Assessment ................................................................................................12 ..................................................................................................................................................21 1.4. Patient Experience Data.................................................................................................22 2. Therapeutic Context..............................................................................................................22 2.1. Analysis of Condition......................................................................................................22 2.2. Analysis of Current Treatment Options .........................................................................26 3. Regulatory Background .........................................................................................................31 3.1. U.S. Regulatory Actions and Marketing History.............................................................31 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................32 3.3. Foreign Regulatory Actions and Marketing History .......................................................35 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................35 4.1. Office of Scientific Investigations (OSI) ..........................................................................35 4.2. Product Quality ..............................................................................................................35 4.3. Clinical Microbiology......................................................................................................40 4.4. Nonclinical Pharmacology/Toxicology ...........................................................................40 4.5. Clinical Pharmacology ....................................................................................................41 4.6. Devices and Companion Diagnostic Issues ....................................................................42 4.7. Consumer Study Reviews...............................................................................................42 5. Sources of Clinical Data and Review Strategy .......................................................................42 5.1. Review Strategy .............................................................................................................42 6. Labeling Recommendations ..................................................................................................44 6.1. Prescription Drug Labeling.............................................................................................44 7. Risk Evaluation and Mitigation Strategies (REMS) ................................................................46 CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4310681 Clinical Review Ovidiu A. Galescu, MD NDA 210895 Welchol (colesevelam hydrochloride) 8. Postmarketing Requirements and Commitments.................................................................46 9. Appendices............................................................................................................................46 9.1. Tables and Figures..........................................................................................................46 9.2. Label...............................................................................................................................47 1 Indications and Usage ...........................................................................................................49 1.1 Primary Hyperlipidemia .................................................................................................49 1.2 Type 2 Diabetes Mellitus................................................................................................49 1.3 Important Limitations of Use .........................................................................................49 2 Dosage and administration ...................................................................................................50 2.1 Primary Hyperlipidemia .................................................................................................50 2.2 Type 2 Diabetes Mellitus................................................................................................50 3 Dosage Forms and Strengths.................................................................................................51 4 Contraindications ..................................................................................................................51 5 Warnings and Precautions ....................................................................................................51 5.1 General...........................................................................................................................51 5.2 Serum Triglycerides........................................................................................................51 5.3 Vitamin K or Fat-Soluble Vitamin Deficiencies Precautions...........................................52 5.4 Gastrointestinal Disorders .............................................................................................52 5.5 Drug Interactions ...........................................................................................................52 5.6 Phenylketonurics............................................................................................................53 5.7 Macrovascular Outcomes ..............................................................................................53 6 Adverse Reactions.................................................................................................................53 6.1 Clinical Studies Experience.............................................................................................53 6.2 Post-marketing Experience ............................................................................................56 7 Drug Interactions...................................................................................................................58 8 Use in Specific Populations....................................................................................................59 8.1 Pregnancy.......................................................................................................................59 8.2 Lactation ........................................................................................................................59 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4310681 Clinical Review Ovidiu A. Galescu, MD NDA 210895 Welchol (colesevelam hydrochloride) 8.4 Pediatric Use ..................................................................................................................59 8.5 Geriatric Use ..................................................................................................................60 8.6 Hepatic Impairment .......................................................................................................60 8.7 Renal Impairment ..........................................................................................................60 10 Overdosage ...........................................................................................................................61 11 Description ............................................................................................................................61