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MULTI-DISCIPLINE REVIEW Summary Review Office Director Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 208901Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multi-disciplinary Review and Evaluation – NDA 208901 NDA 208901: Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 208901 Priority or Standard Standard Submit Date(s) February 16, 2018 Received Date(s) February 16, 2018 PDUFA Goal Date December 16, 2018 Division Division of Anti-Infective Products Review Completion Date November 28, 2018 Established Name Itraconazole (Proposed) Trade Name TOLSURA Pharmacologic Class Azole antifungal Code name SUBA-itraconazole Applicant Mayne Pharma International Pty Ltd. Formulation(s) Oral capsule-65 mg Dosing Regimen 130 mg to 260 mg daily Applicant Proposed Treatment of the following fungal infections in Indication(s)/Population(s) immunocompromised and non-immunocompromised patients: 1) Blastomycosis, pulmonary and extrapulmonary 2) Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and 3) Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to Amphotericin B therapy. (b) (4) Regulatory Action Approval Approved Treatment of the following fungal infections in Indication(s)/Population(s) immunocompromised and non-immunocompromised adult patients: x Blastomycosis, pulmonary and extrapulmonary x Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and x Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. (b) (4) 1 Reference ID: 4360457 NDA Multi-disciplinary Review and Evaluation – NDA 208901 Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 6 Additional Reviewers of Application ............................................................................................. 10 Glossary ......................................................................................................................................... 11 1 Executive Summary ............................................................................................................... 13 1.1. Product Introduction ...................................................................................................... 13 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 13 1.3. Benefit-Risk Assessment ................................................................................................ 14 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 ......................................................................................................... 23 3.1 U.S. Regulatory Actions and Marketing History ............................................................. 23 3.2 Summary of Presubmission/Submission Regulatory Activity ........................................ 23 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 26 4.1 Office of Scientific Investigations (OSI) .......................................................................... 26 4.2 Product Quality .............................................................................................................. 26 4.3 Devices and Companion Diagnostic Issues ......................................................................... 27 5 Nonclinical Pharmacology/Toxicology................................................................................... 27 5.1 Executive Summary ........................................................................................................ 27 5.2 Referenced NDAs, BLAs, DMFs ........................................................................................... 30 6 Clinical Pharmacology ............................................................................................................ 31 6.1 Executive Summary ........................................................................................................ 31 6.2 Summary of Clinical Pharmacology Assessment ............................................................ 34 6.2.1 Pharmacology and Clinical Pharmacokinetics ........................................................ 34 6.2.2 General Dosing and Therapeutic Individualization ................................................. 34 6.3 Comprehensive Clinical Pharmacology Review ............................................................. 34 2 Reference ID: 4360457 NDA Multi-disciplinary Review and Evaluation – NDA 208901 6.3.1 General Pharmacology and Pharmacokinetic Characteristics ................................ 34 6.3.2 Clinical Pharmacology Questions ............................................................................ 34 7 Statistical and Clinical Evaluation .......................................................................................... 44 8 Clinical Microbiology Review ................................................................................................. 44 9 Review of Safety .................................................................................................................... 45 9.1 Safety Review Approach .................................................................................................... 46 9.1.1 Review of the Safety Database ................................................................................ 46 9.1.2 Safety Results .......................................................................................................... 47 9.1.3 Analysis of Submission-Specific Safety Issues ......................................................... 55 9.2 Integrated Assessment of Safety ................................................................................... 55 10 Advisory Committee Meeting and Other External Consultations ......................................... 64 11 Pediatrics ............................................................................................................................... 64 12 Labeling Recommendations .................................................................................................. 64 12.1. Prescribing Information .............................................................................................. 64 12.2. Patient Labeling .......................................................................................................... 65 13 Risk Evaluation and Mitigation Strategies (REMS) ................................................................ 66 14 Postmarketing Requirements and Commitments ................................................................. 66 15 Appendices ............................................................................................................................ 66 15.1. References .................................................................................................................. 66 15.2. Financial Disclosure .................................................................................................... 66 15.3. Nonclinical Pharmacology/Toxicology........................................................................ 68 15.4. OCP Appendices (Technical documents supporting OCP recommendations) ........... 68 16 Division Director (Clinical) .................................................................................................... 111 3 Reference ID: 4360457 NDA Multi-disciplinary Review and Evaluation – NDA 208901 Table of Tables Table Title Page Number 1 Benefit Risk Assessment for TOLSURA 16 2 Summary of Treatment Armamentarium Relevant to Proposed 19 Indications 3 Drug Product Composition 27 4 Clinical Studies Conducted 31 5 MPG012: TOLSURA Capsules 130 mg [2 X 65] vs. SPORANOX Capsules 36 100 mg [2 X 100 mg] dosed QD for 15 days in 20 healthy volunteers under fed conditions 6 MPG013: TOLSURA Capsules 130 mg [2 X 65mg] vs. SPORANOX 36 capsules 100 mg [2 X 100mg] dosed TID from Days 1-3 and QD on Day 4 in 15 healthy volunteers under fed conditions 7 MPG015: TOLSURA Capsules 130 mg [2 X 65mg] vs. SPORANOX 37 capsules 200 mg [2 X 100mg] dosed BID in for 14 days followed by once on Day 15 in 16 healthy volunteers under fed conditions 8 Predicted Median Itraconazole Exposure after Single and Repeat Doses 38 of TOLSURA and SPORANOX Capsules 9 MPG009: Single dose TOLSURA capsules 65mg [1 X 65mg] vs. 41 SPORANOX capsules 100 mg [1 X 100mg] in healthy volunteers under fasted and fed conditions 10 MPG017: TOLSURA capsules 130 mg [2 X 65mg] administered under 42 fed and fasted conditions in 24 healthy volunteers 11 MPG016: Single Dose TOLSURA capsules 130 mg [2 X 65mg] 42 administered alone or with omeprazole 40 mg QD for 7 days under fasted
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