Eliquis H-C-2148-X-004 EPAR - Assessment Report - Variation









TEXAS STATE BOARD OF PUBLIC ACCOUNTANCY

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Eliquis H-C-2148-X-004 EPAR - Assessment Report - Variation

20 sept. 2012 ACC. American College of Cardiology. ACS acute coronary syndrome. ADR adverse drug reaction. AE adverse event. AF atrial fibrillation.
eliquis h c x g epar assessment report extension en


266212Eliquis H-C-2148-X-004 EPAR - Assessment Report - Variation

7 Westferry Circus ł

Canary Wharf ł London E14 4HB ł United Kingdom An agency of the European Union Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E- mail info@ema.europa.eu Website www.ema.europa.eu

© European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.

20 September

2012

EMA/641505/2012

Committee for Medicinal Products for Human Use (CHMP) Assessment report

Eliquis

apixaban

Procedure No.:

EMEA/H/C/002148

/X/04/G Note Variation assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

Eliquis

CHMP assessment report

Page 2/84

Table of contents

1. Background information on the procedure .............................................. 5

1.1. Submission of the dossier ...................................................................................... 5

1.3. Steps taken for the assessment of the product ......................................................... 6

2. Scientific discussion ................................................................................ 6

2.1. Introduction......................................................................................................... 6

2.2. Quality aspects .................................................................................................... 8

2.2.1. Introduction ...................................................................................................... 8

2.2.2. Active Substance ............................................................................................... 8

2.2.3. Finished Medicinal Product .................................................................................. 9

2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 13

2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 13

2.2.6. Recommendation(s) for future quality development ............................................. 13

2.3. Non-clinical aspects ............................................................................................ 13

2.3.1. Pharmacology ................................................................................................. 13

2.3.2. Pharmacokinetics............................................................................................. 14

2.3.3. Toxicology ...................................................................................................... 14

2.3.4. Environmental risk assessment ........................................................................ 14

2.3.5. Discussion on non

-clinical aspects...................................................................... 15

2.3.6. Conclusion on the non-clinical aspects ................................................................ 16

2.4. Clinical aspects .................................................................................................. 16

2.4.1. Introduction .................................................................................................... 16

2.4.2. Pharmacokinetics............................................................................................. 21

2.4.3. Pharmacodynamics .......................................................................................... 23

2.4.4. Discussion on clinical pharmacology ................................................................... 24

2.4.5. Conclusions on clinical pharmacology ................................................................. 24

2.5. Clinical efficacy .................................................................................................. 24

2.5.1. Dose response study(ies) ................................................................................. 25

2.5.2. Main studies ................................................................................................... 26

2.5.3. Discussion on clinical efficacy ............................................................................ 50

2.5.4. Conclusions on the clinical efficacy ..................................................................... 51

2.6. Clinical safety .................................................................................................... 51

2.6.1. Discussion on clinical safety .............................................................................. 66

2.6.2. Conclusions on the clinical safety ....................................................................... 71

2.7. Pharmacovigilance .............................................................................................. 72

2.8. User consultation ............................................................................................... 76

3. Benefit-Risk Balance ........................................................................... 77

Benefits ................................................................................................................... 77

Risks

....................................................................................................................... 79

Benefit-risk balance .................................................................................................. 81

4. Recommendations ............................................................................... 83

Eliquis

CHMP assessment report

Page 3/84

List of abbreviations

ACC American College of Cardiology

ACS acute coronary syndrome

ADR adverse drug reaction

AE adverse event

AF atrial fibrillation

AHA American Heart Association

ALP alkaline phosphatase

ALS amyotrophic lateral sclerosis

ALT alanine aminotransferase

aPTT activated partial thromboplastin time

ASA acetylsalicylic acid (aspirin)

AUC area under the concentration curve

AUC(INF) area under the concentration-time curve to infinity

BID twice daily

CAD coronary artery disease

CDP clinical development plan

CI confidence interval

CLcr creatinine clearance

CLT total body clearance

CLT/F apparent clearance

Cmax maximum plasma concentration

CrCL creatinine clearance

CNS central nervous system

CRNM clinically relevant non-major

CSR Clinical Study Report

CT computed tomography

CV cardiovascular

CYP cytochrome P450

DMC Data Monitoring Committee

DAT Dual antiplatelet therapy

DVT deep vein thrombosis

EMA European Medicines Agency

E-R exposure-response

ESC European Society of Cardiology

EU European Union

FDA Food and Drug Administration

FXa factor Xa

GBS Guillain-Barre syndrome

GI gastrointestinal

GUSTO Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries Trial

HR hazard ratio

INR International Normalized Ratio

ICH International Conference on Harmonisation

7 Westferry Circus ł

Canary Wharf ł London E14 4HB ł United Kingdom An agency of the European Union Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E- mail info@ema.europa.eu Website www.ema.europa.eu

© European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.

20 September

2012

EMA/641505/2012

Committee for Medicinal Products for Human Use (CHMP) Assessment report

Eliquis

apixaban

Procedure No.:

EMEA/H/C/002148

/X/04/G Note Variation assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

Eliquis

CHMP assessment report

Page 2/84

Table of contents

1. Background information on the procedure .............................................. 5

1.1. Submission of the dossier ...................................................................................... 5

1.3. Steps taken for the assessment of the product ......................................................... 6

2. Scientific discussion ................................................................................ 6

2.1. Introduction......................................................................................................... 6

2.2. Quality aspects .................................................................................................... 8

2.2.1. Introduction ...................................................................................................... 8

2.2.2. Active Substance ............................................................................................... 8

2.2.3. Finished Medicinal Product .................................................................................. 9

2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 13

2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 13

2.2.6. Recommendation(s) for future quality development ............................................. 13

2.3. Non-clinical aspects ............................................................................................ 13

2.3.1. Pharmacology ................................................................................................. 13

2.3.2. Pharmacokinetics............................................................................................. 14

2.3.3. Toxicology ...................................................................................................... 14

2.3.4. Environmental risk assessment ........................................................................ 14

2.3.5. Discussion on non

-clinical aspects...................................................................... 15

2.3.6. Conclusion on the non-clinical aspects ................................................................ 16

2.4. Clinical aspects .................................................................................................. 16

2.4.1. Introduction .................................................................................................... 16

2.4.2. Pharmacokinetics............................................................................................. 21

2.4.3. Pharmacodynamics .......................................................................................... 23

2.4.4. Discussion on clinical pharmacology ................................................................... 24

2.4.5. Conclusions on clinical pharmacology ................................................................. 24

2.5. Clinical efficacy .................................................................................................. 24

2.5.1. Dose response study(ies) ................................................................................. 25

2.5.2. Main studies ................................................................................................... 26

2.5.3. Discussion on clinical efficacy ............................................................................ 50

2.5.4. Conclusions on the clinical efficacy ..................................................................... 51

2.6. Clinical safety .................................................................................................... 51

2.6.1. Discussion on clinical safety .............................................................................. 66

2.6.2. Conclusions on the clinical safety ....................................................................... 71

2.7. Pharmacovigilance .............................................................................................. 72

2.8. User consultation ............................................................................................... 76

3. Benefit-Risk Balance ........................................................................... 77

Benefits ................................................................................................................... 77

Risks

....................................................................................................................... 79

Benefit-risk balance .................................................................................................. 81

4. Recommendations ............................................................................... 83

Eliquis

CHMP assessment report

Page 3/84

List of abbreviations

ACC American College of Cardiology

ACS acute coronary syndrome

ADR adverse drug reaction

AE adverse event

AF atrial fibrillation

AHA American Heart Association

ALP alkaline phosphatase

ALS amyotrophic lateral sclerosis

ALT alanine aminotransferase

aPTT activated partial thromboplastin time

ASA acetylsalicylic acid (aspirin)

AUC area under the concentration curve

AUC(INF) area under the concentration-time curve to infinity

BID twice daily

CAD coronary artery disease

CDP clinical development plan

CI confidence interval

CLcr creatinine clearance

CLT total body clearance

CLT/F apparent clearance

Cmax maximum plasma concentration

CrCL creatinine clearance

CNS central nervous system

CRNM clinically relevant non-major

CSR Clinical Study Report

CT computed tomography

CV cardiovascular

CYP cytochrome P450

DMC Data Monitoring Committee

DAT Dual antiplatelet therapy

DVT deep vein thrombosis

EMA European Medicines Agency

E-R exposure-response

ESC European Society of Cardiology

EU European Union

FDA Food and Drug Administration

FXa factor Xa

GBS Guillain-Barre syndrome

GI gastrointestinal

GUSTO Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries Trial

HR hazard ratio

INR International Normalized Ratio

ICH International Conference on Harmonisation


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