210045Orig1s000 - Food and Drug Administration

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

210045Orig1s000

CLINICAL REVIEW(S)

DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS

Divisional Memo

NDA:

210045 Amlodipine + celecoxib (Consensi) for hypertension and osteoarthritis.

Sponsor: Kitov Pharma

Review date: 27 May 2018

Reviewer: N. Stockbridge, M.D., Ph.D., HFD-110

This memo conveys the Division's decision to approve this application.

This application has been the subject of reviews of CMC (Ladouceur, Sloan, Smith, Jiang, DeCiero, Dave, Li; 27 April 2018), pharmacology/toxicology (Hausner; 15 February 2018), clinical pharmacology (Pillai; 21 May 2018), clinical (McDowell; 23 April 2018), statistics (Kong; 10 April 2018), and pediatrics and maternal health (Mastroyannis; 4 May 2018).

This is a 505(b)(2) application relying upon safety and effectiveness of RLDs for amlodipine and celecoxib. The product will be available as tablets containing amlodipine 2.5, 5, or 10 mg and celecoxib 200 mg. There are no novel excipients. There are no remaining product quality issues, although two PMCs are set for evaluation of elemental impurities and for the dissolution method. The facility inspections were waived. A 24-month expiry is being granted.

There are no new nonclinical studies.

The combination at 10/200 mg was shown to be bioequivalent to the free tablets when administered either fed or fasted.

A multi-center, randomized, parallel, placebo controlled study was conducted to demonstrate that the combination preserved the blood pressure effect of amlodipine; no study was deemed necessary to demonstrate the preservation of pain relief. The study examined the effect on daytime mean systolic pressure, but the 24-hour mean effects were similar. From a baseline SBP of about 148 mmHg, the changes at 14 days were -2.1 on placebo (n=26), -0.5 on celecoxib 200 mg (n=30), -8.8 on amlodipine 10 mg (n=45), and -10.6 mmHg on the combination (n=49), ruling out loss of half of amlodipine's effect. The study was too small to develop meaningful information on subgroups. Adverse events were much as one would expect from the component drugs. There were no study conduct issues, and sites were not inspected. Kitov categorically responded to financial disclosure.

Labeling largely reflects nonclinical information, adverse event data, and special population considerations from the reference monotherapy labels.

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Reference ID: 4269387

-------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------

/s/ -----------------------------------------------------------NORMAN L STOCKBRIDGE 05/29/2018

Reference ID: 4269387

Clinical Review Tzu-Yun McDowell 505(b)(2) NDA210045 Celecoxib/Amlodipine Besylate (Consensi?)

Application Type Application Number(s)

Priority or Standard Submit Date(s)

Received Date(s) PDUFA Goal Date

Division/Office Reviewer Name(s) Review Completion Date Established/Proper Name (Proposed) Trade Name

Applicant Dosage Form(s)

Applicant Proposed Dosing Regimen(s)

Applicant Proposed Indication(s)/Population(s)

Recommendation on Regulatory Action Recommended

Indication(s)/Population(s) (if applicable)

CLINICAL REVIEW

NDA

210045

Standard

7/31/2017

7/31/2017

5/31/2018

Cardiovascular and Renal Products/ODE-I

Tzu-Yun McDowell

4/23/2018

Amlodipine and celecoxib

Consensi?

Kitov Pharmaceuticals, Ltd

Tablets (amlodipine/celecoxib): 2.5mg/200mg, 5mg/200mg and

10mg/200mg

Adult recommended starting dose (amlodipine/celecoxib):

5mg/200mg orally qd with maximum dose 10mg/200mg qd.

Small, fragile, or elderly patients, or patients with hepatic

insufficiency may be started on 2.5 mg/200mg

Patients who require

(b) (4) treatment

(b) (4) of osteoarthritis and

who also require the treatment of hypertension, to lower blood

pressure. Lowering blood pressure reduces the risk of fatal and

nonfatal CV events primarily strokes and myocardial infarctions.

Approve

Patients for whom treatment with both celecoxib for osteoarthritis and amlodipine for hypertension are appropriate

CDER Clinical Review Template

1

Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4252319

Clinical Review Tzu-Yun McDowell 505(b)(2) NDA210045 Celecoxib/Amlodipine Besylate (Consensi?)

Table of Contents

Glossary........................................................................................................................................... 7

1. Executive Summary ................................................................................................................. 9 Product Introduction........................................................................................................ 9 Conclusions on the Substantial Evidence of Effectiveness .............................................. 9 Benefit-Risk Assessment .................................................................................................. 9 Patient Experience Data................................................................................................. 16

2. Therapeutic Context .............................................................................................................. 16 Analysis of Condition...................................................................................................... 16 Analysis of Current Treatment Options ......................................................................... 17

3. Regulatory Background ......................................................................................................... 20 U.S. Regulatory Actions and Marketing History............................................................. 20 Summary of Presubmission/Submission Regulatory Activity ........................................ 23 Foreign Regulatory Actions and Marketing History ....................................................... 25

4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 25 Office of Scientific Investigations (OSI) .......................................................................... 25 Product Quality .............................................................................................................. 25 Clinical Microbiology ...................................................................................................... 25 Nonclinical Pharmacology/Toxicology ........................................................................... 25 Clinical Pharmacology .................................................................................................... 25 Devices and Companion Diagnostic Issues .................................................................... 26 Consumer Study Reviews ............................................................................................... 26

5. Sources of Clinical Data and Review Strategy ....................................................................... 26 Table of Clinical Studies.................................................................................................. 26 Review Strategy.............................................................................................................. 29

6. Review of Relevant Individual Trials Used to Support Efficac ............................................... 29 KIT-302-03-01-Study Design ................................................................................... 29 KIT-302-03-01-Study Results................................................................................... 34

CDER Clinical Review Template

2

Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4252319

Clinical Review Tzu-Yun McDowell 505(b)(2) NDA210045 Celecoxib/Amlodipine Besylate (Consensi?)

7. Integrated Review of Effectiveness ....................................................................................... 41

8. Review of Safety .................................................................................................................... 41 Safety Review Approach ................................................................................................ 41 Review of the Safety Database ...................................................................................... 41 Overall Exposure ..................................................................................................... 41 Relevant characteristics of the safety population: ................................................. 41 Adequacy of the safety database: .......................................................................... 41 Adequacy of Applicant's Clinical Safety Assessments.................................................... 42 Issues Regarding Data Integrity and Submission Quality ....................................... 42 Categorization of Adverse Events ........................................................................... 42 Routine Clinical Tests .............................................................................................. 42 Safety Results ................................................................................................................. 42 Deaths ..................................................................................................................... 42 Serious Adverse Events ........................................................................................... 42 Dropouts and/or Discontinuations Due to Adverse Effects ................................... 42 Significant Adverse Events ...................................................................................... 43 Treatment Emergent Adverse Events and Adverse Reactions ............................... 43 Laboratory Findings ................................................................................................ 44 Vital Signs ................................................................................................................ 48 Electrocardiograms (ECGs)...................................................................................... 48 QT............................................................................................................................ 48 Immunogenicity .................................................................................................... 48 Analysis of Submission-Specific Safety Issues ................................................................ 48 Safety Analyses by Demographic Subgroups ................................................................. 48 Additional Safety Explorations ....................................................................................... 48 Safety in the Postmarket Setting.................................................................................... 48 Safety Concerns Identified Through Postmarket Experience................................. 48 Expectations on Safety in the Postmarket Setting ................................................. 48 Additional Safety Issues From Other Disciplines .................................................... 49 Integrated Assessment of Safety ................................................................................... 49

CDER Clinical Review Template

3

Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4252319

Clinical Review Tzu-Yun McDowell 505(b)(2) NDA210045 Celecoxib/Amlodipine Besylate (Consensi?)

9. Advisory Committee Meeting and Other External Consultations......................................... 49

10. Labeling Recommendations .................................................................................................. 49 Specific Safety Studies/Clinical Trials ......................................................................... 49 Prescription Drug Labeling ......................................................................................... 49

11. Risk Evaluation and Mitigation Strategies (REMS) ................................................................ 50

12. Postmarketing Requirements and Commitments................................................................. 50

13. Appendices ............................................................................................................................ 50 References .................................................................................................................. 50

CDER Clinical Review Template

4

Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4252319

Clinical Review Tzu-Yun McDowell 505(b)(2) NDA210045 Celecoxib/Amlodipine Besylate (Consensi?)

Table of Tables

Table 1 Summary of Most Common Chronic Pain Treatment for OA .......................................... 18 Table 2 Approved Oral Antihypertensive Drugs ........................................................................... 19 Table 3 Boxed warning for CELEBREX ........................................................................................... 22 Table 4 Summary of important regulatory activities.................................................................... 23 Table 5 List of Clinical Studies relevant to this NDA ..................................................................... 27 Table 6 Schedule of efficacy, safety and PK measurements ........................................................ 31 Table 7 Demographic and baseline characteristics of the ITT population ................................... 37 Table 8 Mean SBPday at Baseline, End of Study and Change from Baseline (ITT population) ...... 38 Table 9 Mean BP for at Baseline, End of Study and Change from Baseline (ITT population) ...... 40 Table 10 Summary of Treatment Emergent Orthostatic Hypotension AEs in KIT-301-02 ........... 43 Table 11 Summary of Common Treatment Emergent Adverse Events and Adverse Drug Reactions in KIT-302-03-01: .......................................................................................................... 44

CDER Clinical Review Template

5

Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4252319

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