Clinical Review(s)

[Pages:1198]CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

212595Orig1s000

CLINICAL REVIEW(S)

Clinical Review Andreea O Lungu NDA 212595 Metformin hydrochloride extended release (Riomet ER)

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 212595 Standard November 2, 2018 November 2, 2018 September 2, 2019 DMEP Andreea Lungu August 29, 2019 Metformin hydrochloride extended release (Riomet ER) Sun Pharma Oral solution 500 mg/5 mL Starting dose: 500 mg (5 mL) orally once daily, with the evening meal Increase the dose in increments of 500 mg (5 mL) weekly, up to a maximum dose of 2000 mg (20 mL) once daily, with the evening meal RIOMET ER is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and above with type 2 diabetes mellitus Approve the round bottle presentation

(b) (4)

RIOMET ER is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in patients 10 years of age and older with type 2 diabetes mellitus

CDER Clinical Review Template

1

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

Reference ID: 4484753

Clinical Review Andreea O Lungu NDA 212595 Metformin hydrochloride extended release (Riomet ER)

Table of Contents

Glossary........................................................................................................................................... 6

1. Executive Summary ................................................................................................................. 7

Product Introduction........................................................................................................ 7

Conclusions on the Substantial Evidence of Effectiveness .............................................. 7

Benefit-Risk Assessment ..................................................................................................... 8

.............................................................................................................................................. 8

Patient Experience Data................................................................................................. 12

2. Therapeutic Context .............................................................................................................. 12

Analysis of Condition...................................................................................................... 12

Analysis of Current Treatment Options ......................................................................... 12

3. Regulatory Background ......................................................................................................... 13

U.S. Regulatory Actions and Marketing History............................................................. 13

Summary of Presubmission/Submission Regulatory Activity ........................................ 13

Foreign Regulatory Actions and Marketing History....................................................... 14

4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on

Efficacy and Safety................................................................................................................. 14

Office of Scientific Investigations (OSI) .......................................................................... 14

Product Quality .............................................................................................................. 14

Clinical Microbiology ...................................................................................................... 17

Nonclinical Pharmacology/Toxicology ........................................................................... 17

Clinical Pharmacology .................................................................................................... 18

Devices and Companion Diagnostic Issues .................................................................... 21

Consumer Study Reviews ............................................................................................... 21

5. Sources of Clinical Data and Review Strategy ....................................................................... 22

Table of Clinical Studies.................................................................................................. 22

Review Strategy.............................................................................................................. 24

6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 24

CDER Clinical Review Template

2

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

Reference ID: 4484753

Clinical Review Andreea O Lungu NDA 212595 Metformin hydrochloride extended release (Riomet ER)

7. Integrated Review of Effectiveness ....................................................................................... 24

Assessment of Efficacy Across Trials .............................................................................. 24

Primary Endpoints................................................................................................... 24

Secondary and Other Endpoints ............................................................................. 24

Subpopulations ....................................................................................................... 24

Dose and Dose-Response........................................................................................ 24

Onset, Duration, and Durability of Efficacy Effects ................................................ 24

Additional Efficacy Considerations................................................................................. 25

Considerations on Benefit in the Postmarket Setting ............................................ 25

Other Relevant Benefits.......................................................................................... 25

Integrated Assessment of Effectiveness ........................................................................ 25

8. Review of Safety .................................................................................................................... 29

Safety Review Approach ................................................................................................ 29

Review of the Safety Database ...................................................................................... 29

Overall Exposure ..................................................................................................... 29

Relevant characteristics of the safety population: ................................................. 29

Adequacy of the safety database: .......................................................................... 29

! ! C !.................................................... 30

Issues Regarding Data Integrity and Submission Quality ....................................... 30

Categorization of Adverse Events ........................................................................... 30

Routine Clinical Tests .............................................................................................. 30

Safety Results ................................................................................................................. 30

Deaths ..................................................................................................................... 30

Serious Adverse Events........................................................................................... 30

Dropouts and/or Discontinuations Due to Adverse Effects ................................... 30

Significant Adverse Events ...................................................................................... 30

Treatment Emergent Adverse Events and Adverse Reactions ............................... 30

Laboratory Findings ................................................................................................ 30

Vital Signs ................................................................................................................ 30

Electrocardiograms (ECGs)...................................................................................... 31

CDER Clinical Review Template

3

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

Reference ID: 4484753

Clinical Review Andreea O Lungu NDA 212595 Metformin hydrochloride extended release (Riomet ER)

QT............................................................................................................................ 31

Immunogenicity............................................................................................... 31

Analysis of Submission-Specific Safety Issues................................................................ 31

Safety Analyses by Demographic Subgroups ................................................................. 31

Specific Safety Studies/Clinical Trials ............................................................................. 31

Additional Safety Explorations ....................................................................................... 31

Human Carcinogenicity or Tumor Development .................................................... 31

Human Reproduction and Pregnancy..................................................................... 31

Pediatrics and Assessment of Effects on Growth ................................................... 31

Overdose, Drug Abuse Potential, Withdrawal, and Rebound ................................ 31

Safety in the Postmarket Setting.................................................................................... 31

Safety Concerns Identified Through Postmarket Experience ................................. 32

Expectations on Safety in the Postmarket Setting ................................................. 32

Additional Safety Issues From Other Disciplines .................................................... 32

Integrated Assessment of Safety................................................................................ 32

9. Advisory Committee Meeting and Other External Consultations......................................... 33

10. Labeling Recommendations .................................................................................................. 33

Prescription Drug Labeling ......................................................................................... 33

Nonprescription Drug Labeling................................................................................... 34

11. Risk Evaluation and Mitigation Strategies (REMS) ................................................................ 34

12. Postmarketing Requirements and Commitments................................................................. 34

13. Appendices ............................................................................................................................ 34

References .................................................................................................................. 34

Financial Disclosure .................................................................................................... 34

CDER Clinical Review Template

4

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

Reference ID: 4484753

Clinical Review

Andreea O Lungu

NDA 212595

Metformin hydrochloride extended release (Riomet ER)

Table of Tables

Table 1 PK parameters of test product (A or B) and reference product (R)................................. 19

Table 3 Comparison of Pharmacokinetic Parameters of Metformin IR in Pediatric Patients with

T2DM and Healthy Adults vs Metformin XR in Healthy Adults .................................................... 20

Table 2 Effects of Metformin Immediate Release and Extended-Release Metformin on Glycemic

Parameters in Patients with Type 2 Diabetes Mellitus................................................................. 28

CDER Clinical Review Template

5

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

Reference ID: 4484753

Clinical Review Andreea O Lungu NDA 212595 Metformin hydrochloride extended release (Riomet ER)

Glossary

AC AE AR BRF CDER CMC CV DPP-4 ER FDA GCP GLP-1 GLP-1 RA IND iPSP IR NDA OCS OPQ OSI PD PI PK PMC PMR PREA REMS SAE TEAE TZD T2DM

advisory committee adverse event adverse reaction Benefit Risk Framework Center for Drug Evaluation and Research chemistry, manufacturing, and controls cardiovascular Dipeptidyl peptidase-4 extended release Food and Drug Administration good clinical practice glucagon-like peptide 1 GLP-1 receptor agonist Investigational New Drug Application initial pediatric study plan Immediate release new drug application Office of Computational Science Office of Pharmaceutical Quality Office of Scientific Investigation pharmacodynamics prescribing information or package insert pharmacokinetics postmarketing commitment postmarketing requirement Pediatric Research Equity Act risk evaluation and mitigation strategy serious adverse event treatment emergent adverse event thiazolidinedione type 2 diabetes mellitus

CDER Clinical Review Template

6

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

Reference ID: 4484753

Clinical Review Andreea O Lungu NDA 212595 Metformin hydrochloride extended release (Riomet ER)

1. Executive Summary

Product Introduction

Metformin is a biguanide used as a first-line treatment for type 2 diabetes mellitus (T2DM). It was approved in 1994 in the US, and its efficacy and safety are well known. It is currently available in tablet form [immediate release (IR) and extended release (ER) formulations], and liquid form (IR formulation).

The applicant has developed a formulation of Metformin Hydrochloride Extended Release Oral Suspension 100 mg/ml, as an alternative for patients who have difficulty in swallowing such as elderly and pediatric patients. The proposed trade name for the product is Riomet ER. The applicant filed a 505(b)(2) application using Glucophage, and Glucophage XR as reference listed drugs. Glucophage was approved by the US FDA on October 22, 1998, and Glucophage XR on October 13, 2000.

The applicant is proposing the following indication for Riomet ER:

Metformin hydrochloride for extended-release oral suspension is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.

Conclusions on the Substantial Evidence of Effectiveness

No efficacy studies were performed with the drug product under review. The metformin extended release oral suspension (Riomet ER) product was bridged to the Glucophage XR product via a bioequivalence (BE) study, and therefore the findings of effectiveness with Glucophage XR can be extended to Riomet ER.

Glucophage XR is only approved for use in adults, but shares approved labeling with Glucophage IR which is metformin immediate-release and is indicated to improve glycemic control in adult and pediatric patients 10 years of age and older with T2DM. The reason behind Glucophage XR not being specifically approved for pediatric use is not clear but it is unrelated to safety and efficacy, possibly pertaining to potential swallowability issues or to business reasons by the innovator. In adults with T2DM, Glucophage XR and Glucophage IR are switched for one another, and this is reflected by the following statement in the approved product labeling, under the Dosage and Administration section, Adult Dosage section: P receiving [Glucophage IR] may be switched to [Glucophage XR] once daily at the same total P ! !C) from [Glucophage XR] at a

CDER Clinical Review Template

7

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

Reference ID: 4484753

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