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NDA/BLA Multi-disciplinary Review and Evaluation NDA 214154 Nextstellis (drospirenone and estetrol tablets) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) NDA 214154 (IND 110682) Priority or Standard Standard Submit Date(s) April 15, 2020 Received Date(s) April 15, 2020 PDUFA Goal Date April 15, 2021 Division/Office Division of Urology, Obstetrics, and Gynecology (DUOG) / Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (ORPURM) Review Completion Date April 15, 2021 Established/Proper Name drospirenone and estetrol tablets (Proposed) Trade Name Nextstellis Pharmacologic Class Combination hormonal contraceptive Applicant Mayne Pharma LLC Dosage form Tablet Applicant proposed Dosing x Take one tablet by mouth at the same time every day. Regimen x Take tablets in the order directed on the blister pack. Applicant Proposed For use by females of reproductive potential to prevent Indication(s)/Population(s) pregnancy Recommendation on Approval Regulatory Action Recommended For use by females of reproductive potential to prevent Indication(s)/Population(s) pregnancy (if applicable) Recommended Dosing x Take one pink tablet (drospirenone 3 mg, estetrol Regimen anhydrous 14.2 mg) by mouth at the same time every day for 24 days x Take one white inert tablet (placebo) by mouth at the same time every day for 4 days following the pink tablets x Take tablets in the order directed on the blister pack 1 Reference ID: 4778993 NDA/BLA Multi-disciplinary Review and Evaluation NDA 214154 Nextstellis (drospirenone and estetrol tablets) Table of Contents Table of Tables .................................................................................................................... 5 Table of Figures ................................................................................................................... 7 Reviewers of Multi-Disciplinary Review and Evaluation .................................................... 8 Glossary ............................................................................................................................. 12 1. Executive Summary ....................................................................................................... 15 Product Introduction .............................................................................................. 15 Conclusions on the Substantial Evidence of Effectiveness .................................... 16 Benefit-Risk Assessment ........................................................................................ 20 Patient Experience Data ......................................................................................... 24 2. Therapeutic Context ..................................................................................................... 26 Analysis of Condition .............................................................................................. 26 Analysis of Current Treatment Options ................................................................. 26 3. Regulatory Background ................................................................................................. 28 U.S. Regulatory Actions and Marketing History ..................................................... 28 Summary of Presubmission/Submission Regulatory Activity ................................ 28 4. Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 30 Office of Scientific Investigations (OSI) .................................................................. 30 Product Quality....................................................................................................... 31 Clinical Microbiology .............................................................................................. 32 Devices and Companion Diagnostic Issues ............................................................ 33 5. Nonclinical Pharmacology/Toxicology .......................................................................... 33 Executive Summary ................................................................................................ 33 Referenced NDAs, BLAs, DMFs............................................................................... 42 Pharmacology ......................................................................................................... 42 Primary Pharmacology of Estetrol Monohydrate ............................................ 42 Secondary Pharmacology of Estetrol Monohydrate ....................................... 44 Safety Pharmacology of Estetrol Monohydrate .............................................. 45 Pharmacology of Drospirenone ....................................................................... 46 ADME/PK ................................................................................................................ 47 Pharmacokinetics of Estetrol Monohydrate.................................................... 47 Pharmacokinetics of Drospirenone ................................................................. 60 Toxicology ............................................................................................................... 61 General Toxicology of Estetrol Monohydrate ................................................. 61 2 Reference ID: 4778993 NDA/BLA Multi-disciplinary Review and Evaluation NDA 214154 Nextstellis (drospirenone and estetrol tablets) General Toxicology of Combined Estetrol Monohydrate and Drospirenone ................................................................................................. 66 Genetic Toxicology of Estetrol Monohydrate .................................................. 69 Carcinogenicity of Estetrol Monohydrate ....................................................... 73 Reproductive and Developmental Toxicology of Estetrol Monohydrate ........ 74 Other Toxicology Studies of Estetrol Monohydrate ........................................ 83 Summary of Toxicity of Drospirenone ............................................................. 83 6. Clinical Pharmacology ................................................................................................... 84 Executive Summary ................................................................................................ 84 Summary of Clinical Pharmacology Assessment .................................................... 85 Pharmacology and Clinical Pharmacokinetics ................................................. 85 General Dosing and Therapeutic Individualization ......................................... 88 Comprehensive Clinical Pharmacology Review ..................................................... 90 General Pharmacology and Pharmacokinetic Characteristics ......................... 90 Clinical Pharmacology Questions .................................................................... 91 7. Sources of Clinical Data and Review Strategy ............................................................... 98 Table of Clinical Studies .......................................................................................... 98 Review Strategy.................................................................................................... 107 8. Statistical and Clinical and Evaluation ........................................................................ 107 Review of Relevant Individual Trials Used to Support Efficacy ............................ 107 Study MIT-Es0001-C302 (Study C302) ........................................................... 107 Study Results .................................................................................................. 112 Supportive Effectiveness Information From Study C301 .............................. 121 Integrated Assessment of Effectiveness ........................................................ 124 Review of Safety ................................................................................................... 124 Safety Review Approach ................................................................................ 124 Review of the Safety Database ...................................................................... 125 Adequacy of Applicant’s Clinical Safety Assessments ................................... 129 Safety Results ................................................................................................. 131 Analysis of Submission-Specific Safety Issues ............................................... 142 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ....................................................................................... 145 Safety Analyses by Demographic Subgroups................................................. 145 Specific Safety Studies/Clinical Trials............................................................. 146 Additional Safety Explorations ...................................................................... 146 Safety in the Postmarket Setting ................................................................. 147 3 Reference ID: 4778993 NDA/BLA Multi-disciplinary Review and Evaluation NDA 214154 Nextstellis (drospirenone and estetrol tablets) Integrated Assessment of Safety................................................................. 147 Statistical Issues .................................................................................................... 148 Conclusions and Recommendations
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