NDA 211367 Multi-disciplinary Review and Evaluation NDA 211367 Slynd (drospirenone) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 211367 Priority or Standard Standard Submit Date(s) July 27, 2018 Received Date(s) July 27, 2018 PDUFA Goal Date May 27, 2019 Division/Office Division of Bone Reproductive and Urologic Products (DBRUP)/Office of Drug Evaluation III (ODE III) Review Completion Date May 24, 2019 Established Name Drospirenone (DRSP) Research Name LF111 (Proposed) Trade Name Slynd Pharmacologic Class Progestin Applicant Exeltis USA Inc. Formulation(s) Oral tablets Dosing Regimen One 4-mg oral DRSP tablet daily for 24 consecutive days followed by one inert tablet daily for 4 consecutive days Indication/Population Prevention of pregnancy in females of reproductive potential Recommendation on Approval Regulatory Action 1 Version date: September 8, 2017 for initial rollout (NME/original BLA reviews) Reference ID: 4437951 NDA 211367 Multi-disciplinary Review and Evaluation NDA 211367 Slynd (drospirenone) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .................................................... 7 Additional Reviewers of Application ................................................................................... 7 Reviewers Team and Signature Approvals ......................................................................... 8 Glossary ............................................................................................................................. 10 1. Executive Summary ....................................................................................................... 11 1.1. Product Introduction .............................................................................................. 11 1.2. Conclusions on the Substantial Evidence of Effectiveness .................................... 13 1.3. Benefit-Risk Assessment ........................................................................................ 15 1.4. Patient Experience Data ......................................................................................... 18 2. Therapeutic Context ..................................................................................................... 19 2.1. Analysis of Condition .............................................................................................. 19 2.2. Analysis of Current Treatment Options ................................................................. 19 3. Regulatory Background ................................................................................................. 21 3.1. U.S. Regulatory Actions and Marketing History ..................................................... 21 3.2. Summary of Presubmission/Submission Regulatory Activity ................................ 21 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 25 4.1. Office of Scientific Investigations ........................................................................... 25 4.2. Product Quality....................................................................................................... 25 4.3. Clinical Microbiology .............................................................................................. 26 4.4. Devices and Companion Diagnostic Issues ............................................................ 26 5. Nonclinical Pharmacology/Toxicology .......................................................................... 27 5.1. Executive Summary ................................................................................................ 27 5.2. Referenced NDAs, BLAs, DMFs ............................................................................... 27 5.3. Pharmacology ......................................................................................................... 27 5.4. ADME/PK ................................................................................................................ 28 5.5. Toxicology ............................................................................................................... 28 5.5.1. General Toxicology .......................................................................................... 28 5.5.2. Genetic Toxicology ........................................................................................... 28 5.5.3. Carcinogenicity ................................................................................................ 28 5.5.4. Reproductive and Developmental Toxicology ................................................. 28 5.5.5. Other Toxicology Studies ................................................................................. 28 6. Clinical Pharmacology ................................................................................................... 29 6.1. Executive Summary ................................................................................................ 29 6.1.1. Recommendations ........................................................................................... 29 6.2. Summary of Clinical Pharmacology Assessment .................................................... 29 2 Version date: September 8, 2017 for initial rollout (NME/original BLA reviews) Reference ID: 4437951 NDA 211367 Multi-disciplinary Review and Evaluation NDA 211367 Slynd (drospirenone) 6.2.1. Pharmacology and Clinical Pharmacokinetics ................................................. 29 6.2.2. General Dosing and Therapeutic Individualization ......................................... 30 6.3. Comprehensive Clinical Pharmacology Review ..................................................... 31 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ......................... 31 6.3.2. Clinical Pharmacology Questions .................................................................... 32 7. Sources of Clinical Data and Review Strategy ............................................................... 36 7.1. Table of Clinical Studies .......................................................................................... 36 7.2. Review Strategy ...................................................................................................... 38 8. Statistical and Clinical and Evaluation .......................................................................... 39 8.1. Review of Relevant Individual Trials Used to Support Efficacy .............................. 39 8.1.1. A Pivotal, Multicenter, Non-Comparative Trial on the Contraceptive Efficacy, Safety, Tolerability and Pharmacokinetics of LF111 (Drospirenone 4.0 mg) During 13 Cycles (Study CF111/303) ......................... 39 8.1.2. Study Results .................................................................................................... 45 8.1.3. Assessment of Efficacy Across Trials ............................................................... 55 8.1.4. Integrated Assessment of Effectiveness .......................................................... 55 8.2. Review of Safety ..................................................................................................... 55 8.2.1. Safety Review Approach .................................................................................. 55 8.2.2. Review of the Safety Database ........................................................................ 56 8.2.3. Adequacy of Applicant’s Clinical Safety Assessments ..................................... 63 8.2.4. Safety Results ................................................................................................... 63 8.2.5. Analysis of Submission-Specific Safety Issues ................................................. 75 8.2.6. Clinical Outcome Assessment Analyses Informing Safety/Tolerability ........... 79 8.2.7. Safety Analyses by Demographic Subgroups................................................... 79 8.2.8. Specific Safety Studies/Clinical Trials............................................................... 81 8.2.9. Additional Safety Explorations ........................................................................ 81 8.2.10. Safety in the Postmarket Setting ................................................................... 82 8.2.11. Integrated Assessment of Safety ................................................................... 82 SUMMARY AND CONCLUSIONS ........................................................................................ 82 8.3. Statistical Issues ...................................................................................................... 82 8.4. Conclusions and Recommendations ...................................................................... 82 9. Advisory Committee Meeting and Other External Consultations ................................ 83 10. Pediatrics ..................................................................................................................... 84 11. Labeling Recommendations ........................................................................................ 85 11.1. Prescription Drug Labeling ................................................................................... 85 12. Risk Evaluation and Mitigation Strategies .................................................................. 86 13. Postmarketing Requirements and Commitment ........................................................ 87 3 Version date: September 8,