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NDA/BLA Multidisciplinary Review and Evaluation NDA Multidisciplinary Review and Evaluation {NDA 211415} {Quzyttir (cetirizine hydrochloride injection) for intravenous use} NDA/BLA Multidisciplinary Review and Evaluation Application type NDA Application number(s) 211415 Priority or standard Standard Submit date(s) December 7, 2018 Received date(s) December 7, 2018 PDUFA goal date October 7, 2019 Division/office Division of Pulmonary, Allergy, and Rheumatology Products Review completion date October 3, 2019 Established/proper name Cetirizine (Proposed) Trade name Quzyttir Pharmacologic class Histamine-1 (H1) receptor antagonist Applicant JDP Therapeutics Dosage form Intravenous solution: 10 mg/mL Applicant-proposed dosing Adults and adolescents шϭ2 years: 10 mg regimen Children 6 to 11 years: 5 or 10 mg Children 6 months to 5 years: 2.5 mg Recommended dosage regimen is once every 24 hours as needed. Applicant proposed Treatment of acute urticaria in adults and children 6 months of age indication(s)/population(s) and older Recommendation on Approval regulatory action Recommended Same as proposed indication(s)/population(s) (if applicable) Recommended dosing Same as proposed and clarified as needed for acute urticaria. regimen Reference ID: 4501367 NDA Multidisciplinary Review and Evaluation {NDA 211415} {Quzyttir (cetirizine hydrochloride injection) for intravenous use} Table of Contents Table of Tables .................................................................................................................... 1 Table of Figures ................................................................................................................... 2 Reviewers of Multidisciplinary Review and Evaluation ...................................................... 3 Glossary ............................................................................................................................... 7 1. Executive Summary ......................................................................................................... 8 1.1. Product Introduction ................................................................................................ 8 1.2. Conclusions on the Substantial Evidence of Effectiveness ...................................... 8 1.3. Benefit-Risk Assessment ........................................................................................ 10 1.4. Patient Experience Data ......................................................................................... 13 2. Therapeutic Context ..................................................................................................... 14 2.1. Analysis of Condition .............................................................................................. 14 2.2. Analysis of Current Treatment Options ................................................................. 14 3. Regulatory Background ................................................................................................. 18 3.1. U.S. Regulatory Actions and Marketing History ..................................................... 18 3.2. Summary of Presubmission/Submission Regulatory Activity ................................ 18 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 20 4.1. Office of Scientific Investigations ........................................................................... 20 4.2. Product Quality....................................................................................................... 20 4.3. Clinical Microbiology .............................................................................................. 20 4.4. Devices and Companion Diagnostic Issues ............................................................ 20 5. Nonclinical Pharmacology/Toxicology .......................................................................... 21 5.1. Executive Summary ................................................................................................ 21 5.2. Referenced NDAs, BLAs, DMFs ............................................................................... 22 5.3. Drug ........................................................................................................................ 22 5.4. Drug Formulation ................................................................................................... 23 5.5. Pharmacology ......................................................................................................... 24 5.6. ADME/PK ................................................................................................................ 24 5.7. Toxicology ............................................................................................................... 24 5.7.1. General Toxicology .......................................................................................... 24 5.7.2. Genetic Toxicology ........................................................................................... 27 5.7.3. Carcinogenicity ................................................................................................ 27 5.7.4. Reproductive and Developmental Toxicology ................................................. 28 5.7.5. Other Toxicology Studies ................................................................................. 28 5.8. Exposure Margins ................................................................................................... 30 ii Version date: October 12, 2018 Reference ID: 4501367 NDA Multidisciplinary Review and Evaluation {NDA 211415} {Quzyttir (cetirizine hydrochloride injection) for intravenous use} 6. Clinical Pharmacology ................................................................................................... 31 6.1. Executive Summary ................................................................................................ 31 6.2. Summary of Clinical Pharmacology Assessment .................................................... 31 6.2.1. Pharmacology and Clinical Pharmacokinetics ................................................. 31 6.2.2. General Dosing and Therapeutic Individualization ......................................... 32 6.3. Comprehensive Clinical Pharmacology Review ..................................................... 32 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ......................... 32 6.3.2. Clinical Pharmacology Questions .................................................................... 34 7. Sources of Clinical Data and Review Strategy ............................................................... 41 7.1. Table of Clinical Studies .......................................................................................... 41 7.2. Review Strategy ...................................................................................................... 42 8. Statistical and Clinical Evaluation ................................................................................. 43 8.1. Review of Relevant Individual Trials Used to Support Efficacy: ETTAU-03 ............ 43 8.1.1. Trial Design ...................................................................................................... 43 8.1.2. Study Population.............................................................................................. 44 8.1.3. Analysis Populations ........................................................................................ 45 8.1.4. Primary Endpoint ............................................................................................. 46 8.1.5. Secondary Efficacy Endpoints .......................................................................... 47 8.1.6. Statistical Analysis Plan .................................................................................... 47 8.1.7. Study Results .................................................................................................... 50 8.1.8. Integrated Assessment of Effectiveness .......................................................... 60 8.2. Review of Safety ..................................................................................................... 60 8.2.1. Safety Review Approach .................................................................................. 60 8.2.2. Review of the Safety Database ........................................................................ 60 8.2.3. Overall Exposure .............................................................................................. 60 8.2.4. Population Characteristics ............................................................................... 60 8.2.5. Adequacy of the Safety Database .................................................................... 61 8.2.6. Adequacy of Applicant’s Clinical Safety Assessments ..................................... 61 8.2.7. Safety Results ................................................................................................... 61 8.2.8. Analysis of Submission-Specific Safety Issues ................................................. 63 8.2.9. Safety Analyses by Demographic Subgroups................................................... 64 8.2.10. Specific Safety Studies/Clinical Trials ............................................................ 64 8.2.11. Safety in the Postmarket Setting ................................................................... 67 8.2.12. Integrated Assessment of Safety ..................................................................
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