Regulatory History of the Interaction Between Aspirin and Other

Home , Celecoxib, Magnesium salicylate, Valdecoxib

Regulatory History of the Interaction Between Aspirin and Other Nonprescription NSAIDs April 24, 2016 Jenny Kelty, MD Medical Officer Division of Nonprescription Drug Products Office of Drug Evaluation IV CDER, FDA Agenda • Over-the-counter (OTC) regulatory pathways • OTC NSAIDS • OTC NSAID cardiovascular labeling history • OTC labeling of aspirin (ASA) and non-aspirin NSAID interaction

2 OTC Regulatory Pathways New Drug Application Monograph Similar to prescription drugs Notice and comment rulemaking Product-specific Ingredient- and category-specific regulation Application submitted for No FDA application or pre-marketing approval pre-approval

3 Currently Marketed OTC NSAIDs Drug Class Regulatory Pathway Aspirin (acetylated salicylate) Salicylates TFM IAAA Magnesium salicylate NDA Choline salicylate ANDA Sodium salicylate

Ibuprofen Propionic acid NDA derivative ANDA Naproxen Propionic acid NDA Naproxen sodium derivative ANDA

TFM IAAA = Tentative Final Monograph for Internal Analgesic, Antipyretic, and Antirheumatic Drug Products; FR = Federal Register; NDA = New Drug Application; ANDA = Abbreviated New Drug Application 4 Aspirin • Available in several dosage forms and strengths ranging from 81 mg to 500 mg • Indication – Temporary relief of minor aches and pains – Reduction of fever • OTC dosing available for adults and children 2 years of age and older

5 Aspirin Cardiovascular Professional Labeling (21 CFR 343.80) • Vascular Indications: ischemic stroke, transient ischemic attack, acute myocardial infarction (MI), prevention of recurrent MI, unstable angina pectoris, and chronic stable angina pectoris • Revascularization Procedures: coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), and carotid endarterectomy 6 OTC Ibuprofen • 1974 – Approved for prescription use under NDA for arthritic conditions • 1978 – Approved for prescription use under NDA in for moderate pain • 1984 – Approved for OTC use under NDA for minor pain relief and fever reduction • Available in a variety of strengths and formulations for children and adults as single-ingredient and combination drug products • OTC dosing available down to 6 months of age

7 OTC Naproxen Sodium • 1976 – Naproxen approved for prescription use under NDA • 1980 – Naproxen sodium approved for prescription use under NDA • 1994 – Naproxen sodium approved for OTC use under NDA for minor pain relief and fever reduction • Available OTC as tablet or capsule containing 220 mg naproxen sodium • OTC dosing in adults and children ≥12 years of age: – 220-440 mg every 8-12 hours – Max dose: 660 mg in 24 hours

8 OTC NSAID Cardiovascular Thromboembolic Risk Labeling History • 2005 Joint meeting of FDA’s Arthritis and Drug Safety & Risk Management Advisory Committees • 2014 Joint meeting of FDA’s Arthritis and Drug Safety & Risk Management Advisory

Committees 9 2005 Joint Meeting of FDA’s Arthritis and Drug Safety & Risk Management ACs • Do not use – right before or after heart surgery • When using this product the risk of heart attack or stroke may increase if you use more than directed or for longer than directed. 10 2014 Joint Meeting of Arthritis and Drug Safety & Risk Management ACs • Heart attack and stroke warning NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed. • Ask a doctor before use if – you have high blood pressure, heart disease, liver cirrhosis, kidney disease, or had a stroke.

11 Pharmacodynamic Interaction Between Ibuprofen and Aspirin • 2006 – FDA published Science Paper and Healthcare Practitioner Advisory detailing pharmacodynamic interaction between low dose 1 aspirin and OTC dose of ibuprofen • Timing of dosing of ibuprofen and low-dose aspirin is important for preserving the cardioprotective effect of aspirin • Clinical implication of this interaction may be important because the cardioprotective effect of aspirin, when used for secondary prevention of myocardial infarction, could be attenuated 1 https://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandprovider s/ucm161282.pdf 12 FDA Science Paper Recommendations • Health care providers should counsel patients about the appropriate timing of ibuprofen dosing if the patients are also taking aspirin for cardioprotective effects • Patients taking immediate release low-dose aspirin and ibuprofen 400 mg should take the ibuprofen at least 30 minutes after aspirin ingestion, or at least 8 hours before aspirin ingestion to avoid any potential interaction • Other nonselective OTC NSAIDs should be viewed as having potential to interfere with the antiplatelet effect of low-dose aspirin unless

proven otherwise 13

OTC Ibuprofen and Aspirin Interaction Labeling • Ask a doctor or pharmacist before use if you are – taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin.

14 Pharmacodynamic Interaction Between Naproxen and Aspirin • Capone et al (2005) – “Pharmacodynamic Interaction of Naproxen With Low-Dose Aspirin in Healthy Subjects” • Oldenhof et al (2010) – “Effect of Maximum OTC Doses of Naproxen Sodium or Acetaminophen on Low-Dose Aspirin Inhibition of Serum Thromboxane B2” • Anzellotti et al (2011) – “Low-Dose Naproxen Interferes With the Antiplatelet Effects of Aspirin in Healthy” Subjects • Gurbel et al (2017) – “Thromboxane Inhibition During Concurrent Therapy with Low-Dose Aspirin and Over-the-Counter Naproxen Sodium” 15

Aspirin-NSAID Interactions

Martin Rose, MD, JD Division of Cardiovascular and Renal Products April 24, 2018

Topics • Cyclooxygenase biology related to drug interactions • Aspirin-celecoxib interaction studies • Aspirin-ibuprofen interaction studies

2 Cyclooxygenase (COX) • A family of enzymes with two catalytic sites: arachidonic acid (AA) prostaglandin G2 (PGG2) PGH2 • Catalytic sites are substantially similar across the family, but non-catalytic sites differ – COX 1: Platelet precursors, GI endothelium – COX 2: WBC – Both 1 & 2: Vascular endothelium

Eicosanoid End-Products • A variety of clinically important eicosanoid end-products are formed from PGH2 by isomerases with variable expression across tissues. In platelets, the most

important end product is thromboxane A2 (TXA2)

Platelet Activation/Aggregation • Activation triggers: – Tissue collagen – Thrombin – Adenosine diphosphate (ADP) • Upon activation, platelets release their contents, including: – ADP promotes further platelet activation – TXA2 promotes platelet activation and vasoconstriction – Activated platelets are sticky, aggregate and form a platelet plug

COX Inhibition by Aspirin & NSAIDS • Aspirin irreversibly acetylates and inhibits COX-1; it also acetylates COX-2, but modifies its activity • Platelets cannot replace the inactivated COX-1 and are affected by lower doses of aspirin than other tissues • IC 50 of aspirin for COX-2 is ~ 10 X that for COX-1 • NSAIDS have differing specificity for COX-1 vs. COX-2 – NSAID binding to COX is concentration- dependent 6

NSAIDS – COX Specificity

Source: Antman et. al. Circulation 2005; 112:759-770 7 Aspirin-NSAID Interaction • Timing is key: if an NSAID already occupies the internal COX-1 binding site, aspirin cannot access its acetylation site • Timing in interaction studies is affected by: – Timing of the last NSAID dose prior to aspirin and timing of the next NSAID dose – Aspirin formulation (immediate release vs. enteric coated) – Dose of the NSAID and aspirin

8 Dosing, Tmax and Half-life of NSAIDs

Dose Tmax / Plasma Half-Life Immediate release (IR) 75-325 mg OD (for coronary 0.5-1 h / aspirin indications) ~ 20 min Enteric coated (EC) aspirin same 3.5 to 6 h / Ibuprofen 200-400 mg q 4 to 6 hr (OTC) 1-2 h / Up to 800 mg QID (Rx) 1.8-2 h Naproxen 200 mg BID (OTC) 1-4 h / Up to 1500 mg day (Rx) 12-17 h Celecoxib Up to 200 mg BID (Rx) 3 h / 11 h 9 US Sales Data – Aspirin 81 mg Tablets

Source: IMS National Sales Perspectives database 10 Assessing Aspirin’s Effects on Platelet Activation/Aggregation

• In vitro thromboxane B2 (TXB2) generation – After activation and degranulation, platelet-derived TXA2 in blood is rapidly converted to TXB2, which can be reliably assessed in serum – 1 mL whole blood is placed in glass tube and left at 37° C for one hour to clot

– Serum is spun off and assayed for TXB2 concentration before and after an intervention

– TXB2 inhibition is calculated as (1- (Cpost/Cpre)) x 100% 11

Aspirin-Celecoxib Interaction Studies

12 GD Searle Study N49-00-02-150 Effect of Celecoxib on the Anti-Platelet Activity of “Low-Dose” Aspirin in Healthy Subjects • Single center, P1, randomized, double-blind, parallel-arm, placebo- controlled study in confined healthy volunteers age 18-55 (8/arm) • Days 1-4: celecoxib 200 mg q 12 h or matching placebo • Day 5: all subjects receive a single dose of randomized study drug and one 325 mg IR aspirin tablet at 8 AM • PD Assessments: Day 1, hour 0 (predose) and Day 5, hours 0, 2 and 8 – Thromboxane B2 in whole blood – Platelet aggregation (light transmission) using the following agonists: collagen type 1 (100 µg/mL), ADP (20 µM) and arachidonic acid (AA, 500 µg/mL)

Percent Inhibition of Platelet Function Parameters Parameter / Time Placebo Celecoxib

TxB2 Concentration Day 5, Hour 0 19.20 35.41 Day 5, Hour 2 99.70 99.64 Day 5, Hour 8 99.36 99.01 Aggregation (AA) Day 5, Hour 0 3.83 5.14 Day 5, Hour 2 94.76 96.07 Day 5, Hour 8 93.98 95.26

Source: Study Report, Table 8.C 14 Aspirin-Celecoxib Interaction - Conclusion Studies in volunteers demonstrate that celecoxib 200 mg bid does not interfere with the antiplatelet activity of aspirin used at the doses recommended for cardioprotection in the US.

15 Aspirin-Ibuprofen Interaction Studies

16 Wyeth Studies of Aspirin-Ibuprofen Interaction AA-02-21: 2-way crossover trial in 31 volunteers • IR chewable aspirin 81 mg given in the AM before ibuprofen 400 mg x 6 days • Doses separated by 0, 15, 30 or 120 minutes • Endpoints: – Baseline-controlled inhibition of serum TXB2 and arachidonic acid stimulated platelet aggregation, both performed using blood drawn 24 h after the Day 6 aspirin dose 17 Wyeth Studies of Aspirin-Ibuprofen Interaction AA-02-21: TXB2 inhibition on Day 6

Error bars: interquartile range Source: Study Report, Figure 1 18 Wyeth Studies of Aspirin-Ibuprofen Interaction AA-02-22: 2-way crossover trial in 39 volunteers • Ibuprofen 400 mg given in the morning before IR chewable aspirin 81 mg x 6 days • Doses separated by 2, 4, 6 or 8 hours • Control: IR chewable aspirin 81 mg only x 6 days • All subjects had at least 90% TXB2 inhibition after daily 81 mg IR aspirin x 3 days • Endpoints: – Baseline-controlled inhibition of serum TXB2 and arachidonic acid stimulated platelet aggregation, both performed using blood drawn 24 h after the Day 6 aspirin dose

19 Wyeth Studies of Aspirin-Ibuprofen Interaction AA-02-22: TXB2 and platelet aggregation inhibition

Error bars: interquartile range Source: Study Report, Figure 1 20 Aspirin-Ibuprofen Interaction: Conclusions • The available data indicate that ibuprofen administration can attenuate the antiplatelet effects of aspirin. • Timing of dosing of ibuprofen relative to aspirin and the aspirin formulation have major effects on the extent of the interaction. • A three or four times daily ibuprofen regimen that does not attenuate the antiplatelet effects of enteric coated aspirin has not yet been identified.

Aspirin-Naproxen Drug Interaction

Joint Meeting of the Arthritis Advisory Committee and Drug Safety and Risk Communication Advisory Committee

Sudharshan Hariharan, PhD Team Leader, Division of Clinical Pharmacology-1 Office of Clinical Pharmacology, CDER, FDA April 24, 2018 Outline • Background • Early publications • Low dose aspirin-Naproxen OTC dose interaction study (Gurbel et al, 2018) – Design – Results – Conclusions • Summary www.fda.gov 2 Background • FDA Science Paper (2006) – Potential for attenuation of aspirin’s antiplatelet effect when used with ibuprofen

• Mechanism of Interaction – Competitive binding of non-steroidal anti-inflammatory drug (NSAID) to cyclooxygenase-1 (COX-1)

• Naproxen – Reversible, non-selective NSAID – Prescription and over the counter (OTC) use

• Pharmacokinetics – Half-life [aspirin: 15-20 minutes, naproxen: 12-17 hours] – Tmax [immediate-release (IR) aspirin: 0.5-1 hours, enteric-coated (EC) aspirin: 3-4 hours, naproxen: 1-4 hours] www.fda.gov 3 Inhibition of COX-1 Activity Naproxen v Low Dose Aspirin Capone et al 2007

Values reported as mean ± SD *P < 0.05, #P < 0.05 v aspirin at 24 h (nonparametric test) **P < 0.01 v aspirin at 24 h, P < 0.05 (parametric test) www.fda.gov Capone et al J Pharmacol Exp Ther. 2007 322(2): 453-60 4 In vitro, Naproxen Interacts with Aspirin’s COX-1 Activity Capone et al 2005 A

2 C Platelet TxB Platelet

B TxB2 Platelet TxB2 Platelet www.fda.gov Capone et al J Am Coll Cardiol. 2005 45(8): 1295-301 5 Early Clinical Studies Evaluating Naproxen-Aspirin Interaction • Capone et al 2005 – Naproxen 500 mg BID 2 hours before and after IR aspirin 100 mg (6 days) v Control – Limitation: • Higher prescription dose of naproxen • No evaluation during naproxen washout

• Oldenhof et al 2010 – Naproxen 220 mg TID + EC aspirin 81 mg (5 days) v Control – Limitation: • Higher OTC dose of naproxen • Evaluation of during naproxen washout, but confounded with outliers www.fda.gov Capone et al J Am Coll Cardiol. 2005 45(8): 1295-301; Oldenhof et al Curr Med Res Opin. 2010 26(6): 1497-504 6 Low Dose Naproxen Interferes with Aspirin’s COX-1 Activity Anzellotti et al 2011

2 hours separation

7 www.fda.gov Anzellotti et al Arthritis Rheum. 2011 63(3): 850-9 Basis for Gurbel et al 2018 Study

• Characterize drug interaction liability following lower (once-daily) naproxen OTC doses

• Explore different timing of administration

• Follow patients longer during naproxen washout

• Remove confounding effects of aspirin non-compliance to increase the sensitivity to identify an interaction www.fda.gov 8

Gurbel et al 2018 Low Dose IR Aspirin-Naproxen OTC Dose Interaction Study

www.fda.gov Gurbel et al J Thromb Thrombolysis. 2018 45(1): 18-26 9 Treatment Arms • Group 1: 10 days of IR ASA 81 mg and NAP 220 mg QD given concomitantly

• Group 2: 10 days of NAP 220 mg QD 30 min before ASA

• Group 3: 10 days of NAP 220 mg QD administered 8 hours before ASA

• Group 4: 10 days of IR ASA 81 mg alone

• Group 5: 10 days of IR ASA 81 mg administered 30 min before NAP 220 mg QD

• Group 6: 10 days of NAP 220 mg BID where first dose is administered 30 min before IR ASA 81 mg www.fda.gov 10 Pharmacodynamic Assessments • Pharmacodynamic variables – Serum thromboxane B2 (TxB2) – Arachidonic acid (AA) induced platelet aggregation – TxB2 from PRP

• Timing of assessment – On Days 7, 16, 17 and 19 at 1, 3, 6, 12, 18, and 24 hours post aspirin dose

• Primary endpoint – The mean and lower bound of the corresponding one-sided 95% CI for serum TxB2 at hour 24 on Day 16 – A positive interaction was defined as the one-sided 95% CI for serum TxB2 at hour 24 on Day 16 to be < 95% www.fda.gov 11

Results Naproxen interacts with aspirin

Inhibition of serum TXB2 (%) at Day 16, 24 hours

www.fda.gov Source: Clinical Study Report #15525 12 IR ASA 81 mg Group 4 (Control)

First day of Last day of Day 1 Day 3 treatment treatment wash-out Day 7 Day 16 wash-out www.fda.gov Source: Adapted from Clinical Study Report #15525 13 IR ASA 81 mg + NAP 220 mg Group 1

First day of Last day of Day 1 Day 3 treatment treatment wash-out Day 7 Day 16 wash-out www.fda.gov Source: Adapted from Clinical Study Report #15525 14 NAP 220 mg 30 min IR ASA 81 mg Group 2

First day of Last day of Day 1 Day 3 treatment treatment wash-out Day 7 Day 16 wash-out www.fda.gov Source: Adapted from Clinical Study Report #15525 15 NAP 220 mg 8 hours IR ASA 81 mg Group 3

First day of Last day of Day 1 Day 3 treatment treatment wash-out Day 7 Day 16 wash-out www.fda.gov Source: Adapted from Clinical Study Report #15525 16 IR ASA 81 mg 30 min NAP 220 mg Group 5

First day of Last day of Day 1 Day 3 treatment treatment wash-out Day 7 Day 16 wash-out www.fda.gov Source: Adapted from Clinical Study Report #15525 17 NAP 220 mg BID 30 min IR ASA 81 mg Group 6

First day of Last day of Day 1 Day 3 treatment treatment wash-out Day 7 Day 16 wash-out www.fda.gov Source: Adapted from Clinical Study Report #15525 18 Study Conclusions

• Interaction between aspirin and naproxen is evident

• Interaction is greater when naproxen is dosed 30 min prior to aspirin

• Interaction is also evident (at trough) even when naproxen is dosed 8 hours prior to aspirin

www.fda.gov 19 Study Conclusions

• Interaction is minimized when aspirin is taken 30 min prior to naproxen – Only applicable to IR aspirin

• Interaction with a BID regimen of naproxen is more evident during the naproxen wash-out period than the concomitant treatment period

www.fda.gov 20 Summary

• Unequivocal evidence for a drug interaction between aspirin and naproxen • The clinical significance of this interaction remains unknown • Relative timing of administration may minimize interaction • Interaction with aspirin for higher prescription doses of naproxen will exist, however, following treatment discontinuation with naproxen

www.fda.gov 21

Regulatory History: NSAID-associated Cardiovascular Thrombotic Events

Joint Meeting of the Arthritis Advisory Committee and Drug Safety and Risk Communication Advisory Committee April 24-25, 2018

Judith A. Racoosin, MD, MPH Deputy Director for Safety Division of Anesthesia, Analgesia, and Addiction Products Agenda • Drug Utilization • Regulatory History – 2005 AC Meeting/ Subsequent Regulatory Actions – 2014 AC Meeting/ Subsequent Regulatory Actions

2 Outpatient: Prescription Data Nationally estimated number of prescriptions dispensed for celecoxib, ibuprofen, or naproxen single-ingredient products from U.S. outpatient retail pharmacies, 2006 through 2017

50.0 Ibuprofen single ingredient Naproxen single ingedient Celecoxib 44.8 45.0

40.0

35.0

30.0 28.0

25.0

18.0 20.0 16.4

15.0 11.0 10.0 7.3 Number of prescriptions (millions)

5.0

0.0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Ye ar Source: IQVIA™ Static History Data (2006-2011) and National Prescription Audit (2012-2017). Years 2006-2017. Extracted February 2017. 3 Outpatient: Patient Data Nationally estimated number of patients who received a dispensed prescription for celecoxib, ibuprofen, or naproxen single ingredient products from U.S. outpatient retail pharmacies, stratified by patient age groups, 2013 through 2017

10.0 2013 9.0 2014 2015 8.0 2016 2017 7.0

6.0

5.0

4.0

3.0 Number of patients (millions) 2.0

1.0

0.0 Ibuprofen Naproxen Celecoxib Ibuprofen Naproxen Celecoxib Ibuprofen Naproxen Celecoxib Ibuprofen Naproxen Celecoxib 0-24 years 25-44 years 45-64 years 65 years or older

Molecule and age groups

Source: IQVIA™ Total Patient Tracker (TPT Enhanced 2017). Years 2013-2017. Extracted March 2017

Unique patient counts may not be added across time periods or products due to the possibility of double counting those patients who may have received multiple treatements during the study period. 4 Over-the-Counter: Sales Data Nationally estimated number of OTC packages sold for ibuprofen and naproxen single ingredient products to consumers from U.S. retail store outlets*, 2012 through 2016

Ibuprofen single ingredient Naproxen single ingredient 200.0 173.9 172.6 180.0 Ibuprofen 160.0

140.0

120.0

100.0

80.0 61.7 64.0 Naproxen 60.0 Number of unit sold (millions) 40.0

20.0

0.0 2012 2013 2014 2015 2016 Ye ar Source: OTC Ingredient Level Report. Years 2012-2016. Extracted January 2018.

*Retail store outlets includes consumer purchases from pharmacies in drug stores, grocery supermarkets, mass merchandiser stores, and select club stores. Specialty stores, convenience stores, internet sales, phone sales, and kiosks are not included. 5 Agenda • Drug Utilization • Regulatory History – 2005 AC Meeting/ Subsequent Regulatory Actions – 2014 AC Meeting/ Subsequent Regulatory Actions

6 Feb 2005 Joint Meeting of the Arthritis AC and Drug Safety and Risk Management AC

• Convened to discuss the risk of cardiovascular thrombotic events with COX-2 selective NSAIDs (e.g., rofecoxib, celecoxib, valdecoxib) and non-selective NSAIDs (e.g., ibuprofen, naproxen, diclofenac, and others) that occurred in large Randomized Clinical Trials (RCTs) of COX-2 selective NSAIDs.

7 Results of Large RCTs Involving Celecoxib • Provided as a reminder of the data that was discussed at the February 2005 AC meeting • Anti-platelet Trialist’s Collaboration (APTC) composite endpoint: – Deaths: cardiovascular and unknown cause – Non-fatal myocardial infarction (MI) – Non-fatal stroke (ischemic & hemorrhagic) • The APTC composite endpoint was not the primary endpoint in all the studies

Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients.

BMJ.1994;308:81–106. 8 Celecoxib- large RCTs

9 CLASS trial: Time to Event for Composite Cardiovascular Endpoint

Source: White et al; Am J Cardiology 2002 10 APC/ PreSAP Time to event for CV outcome*

*Composite outcome of death from cardiovascular causes, myocardial infarction, stroke, or heart failure

Solomon SD, Pfeffer MA, McMurray JJ, et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 2006;114(10):1028-35. 11 Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) Time to Cardiovascular Death, MI, Stroke, CHF, or TIA

200 mg BID

220 mg BID

ADAPT Research Group (2006) Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer’s 12 Disease Anti-inflammatory Prevention Trial (ADAPT). PLoS Clin Trials 1(7): e33. doi:10.1371/ journal.pctr.0010033 April 2005 FDA Conclusions Based on assessments of cardiovascular (CV) risk in RCTs evaluating the efficacy of COX-2 selective and non-selective NSAIDs in OA/RA/chemoprevention indications, and the discussion of such studies at the Feb 2005 AC meeting, FDA made the following conclusions:

– The COX-2 selective NSAIDs celecoxib, rofecoxib, and valdecoxib, are associated with an increased risk of serious adverse CV events compared to placebo. The available data do not permit a rank ordering of these drugs with regard to CV risk. – Data from large long-term controlled clinical trials that have included a comparison of COX-2 selective and non-selective NSAIDs do not clearly demonstrate that the COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs. – Long-term placebo-controlled clinical trial data are not available to adequately assess the potential for the non-selective NSAIDs to increase the risk of serious adverse CV events. 13

April 2005 FDA Conclusions (2) – Pending the availability of additional long-term controlled clinical trial data, the available data are best interpreted as being consistent with a class effect of an increased risk of serious adverse CV events for COX-2 selective and non-selective NSAIDs. – Short-term use of NSAIDs to relieve acute pain, particularly at low doses, does not appear to confer an increased risk of serious adverse CV events (with the exception of valdecoxib in hospitalized patients immediately post-operative from coronary artery bypass graft [CABG] surgery). – In the absence of any demonstrated advantage over nonselective NSAIDs, the overall benefit versus risk profile for valdecoxib is unfavorable for marketing because it is associated with an increased rate of serious and potentially life-threatening skin reactions compared to other COX-2 selective agents 14 April 2005 FDA Actions Based on these conclusions, the following actions were taken: – Recommended withdrawal of valdecoxib – Revision of the labeling of all NSAIDs to include the following • A boxed warning highlighting the potential for increased risk of CV events with these drugs and the well-described, serious, and potentially life-threatening gastrointestinal (GI) bleeding associated with their use. • Addition of a contraindication for use in patients immediately post- operative from CABG surgery. • Dispensing of a Medication Guide with every prescription NSAID at the time it is dispensed to better inform patients about the CV and GI risks. – Revision of non-prescription (OTC) NSAID labeling to include more specific information about the potential GI and CV risks, and information to assist consumers in the safe use of those drugs. – Agency request for sponsors of non-selective NSAIDs to conduct and submit a comprehensive review and analysis of available controlled clinical trial databases to further evaluate the potential for increased CV risk. 15 Evaluations Subsequent to 2005 Action

• Review of submissions from development programs of non-selective NSAIDs did not provide additional actionable data • FDA recognized the need for comparative data on CV thrombotic risk with COX-2 selective and non-selective NSAIDs • Postmarketing commitment requested of Pfizer for comparative trial of celecoxib vs. naproxen and ibuprofen

16 Agenda • Drug Utilization • Regulatory History – 2005 AC Meeting/ Subsequent Regulatory Actions – 2014 AC Meeting/ Subsequent Regulatory Actions

17 Continued Monitoring of the Issue

• Are there data to better refine the understanding of time to event for cardiovascular risk with NSAIDs? Early hazard versus increased risk with cumulative use (or both, depending on the population)?

• Are there data to support differential CV risk across the specific NSAIDs?

• Are there data that suggest specific vulnerable populations (e.g., history of MI, CV risk factors, post- operative coronary artery bypass graft [CABG] surgery or others) for NSAID-associated CV risk? 18 Regulatory Action Following 2014 AC Meeting

• Based on FDA’s review and the advisory committees’ recommendations, the prescription NSAID labels were revised to reflect the following information regarding CV risk: – Time to event: The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID. – Dose-response: The risk appears greater at higher doses. – Product-specific risk: The accrued evidence suggests that CV risk is not the same for all NSAIDs; however, there is not adequate information to determine whether the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.

19 Regulatory Action Following 2014 AC Meeting (2) • Labeling revisions (continued): – At-risk population: • NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied. – Vulnerable populations: • In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline. • Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack. – There is an increased risk of heart failure with NSAID use. 20

CLINICAL ASSESSMENT OF THE PRECISION TRIAL

Anjelina Pokrovnichka, MD Medical Officer Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II

2 Presentation Outline

• PRECISION trial – Important trial design features – Trial results • Ambulatory Blood Pressure Monitoring (ABPM) substudy

3 Important Trial Design Features

4 Key Inclusion Criteria

• Osteoarthritis (OA) or rheumatoid arthritis (RA) for at least 6 months • Established cardiovascular disease (CVD) or at risk for CVD • Receiving chronic analgesia for at least 6 months and taking analgesics ≥50% of the time – In the Investigator’s opinion, subject required and was eligible for chronic, daily therapy with nonsteroidal anti- inflammatory drug (NSAID) – RA subjects: if taking disease modifying anti-rheumatic drug (DMARD) or oral corticosteroids, duration >= 3 months and stable dosing for 1 month

5 Key Exclusion Criteria • Unstable angina, uncontrolled hypertension (HTN), myocardial infarction (MI), stroke, coronary artery bypass graft (CABG), cardiac or non-cardiac major surgery within 3 months • Congestive heart failure (CHF) Class III or IV New York Heart Association (NYHA) or left ventricular dysfunction with ejection fraction (EF) ≤35% • Esophageal, gastric, pyloric, or duodenal ulceration within 60 days • History of gastrointestinal (GI) perforation, obstruction, or bleed within 6 months • Creatinine exceeding 1.7 mg/dL in men or 1.5 mg/dL in women 6 Dosing

• Randomization: The lowest dose strength of the assigned treatment • Subsequent visits: Dose adjustments allowed (increase or decrease) within the mandated dosing range • Following labeling, max dose of celecoxib for OA (90% of study population) limited to 100 mg bid • Interpret safety data presented in the context of doses administered for drugs under comparison

7 Concomitant Medications

• Other NSAIDs and high dose aspirin prohibited • Allowed: – Aspirin cardioprophylaxis – Preventive pharmacotherapy for CVD – Gastroprotective agent • Protocol-defined non-NSAID analgesic rescue medications for patients on treatment or for those who discontinued treatment but stayed in the study 8

Medications After Study Drug Discontinuation • Within 30 days: – Prohibited use of open-label celecoxib, ibuprofen, or naproxen • Beyond 30 days: – Strongly recommended to avoid use of any NSAID or cyclooxygenase (COX)-2 inhibitor – Manage pain with designated analgesic rescue medications

9 Discontinuation of Subjects • Patients who discontinued treatment were encouraged to remain in the trial for continued follow-up • Reasons for both discontinuing treatment and trial were captured • Patients who experienced any one of the following events were to be discontinued from treatment and followed: – Antiplatelet Trialists’ Collaboration (APTC) endpoint – Clinically significant CV, renal, GI, or anemia endpoints – Additional criteria for HTN and liver and renal laboratory abnormalities 10 Trial Results • Characterization of the study population – Baseline characteristics – Duration of exposure and follow-up – Dose administered – Subject disposition • Primary endpoint • Analysis of potential aspirin interaction • Secondary and tertiary endpoints • General Safety 11

Analysis Populations

• Intent-to-treat (ITT): all randomized subjects • Modified intent-to-treat (mITT): all randomized subjects who received at least one dose of study drug and had at least one post-baseline visit • Safety population: all randomized subjects who received at least one dose of study drug 12

Subjects’ Baseline Characteristics

• Trial population consisted of: – Predominantly white females (64% females vs 36% males) – 90% OA – Mean age of 63 years • The following characteristics were balanced across treatment groups: age, weight, blood pressure (BP), labs, CV risk factors, aspirin use, DMARD use, medical history, smoking history, and pain severity • 77% had no evidence of active CVD but trial population was enriched for those at risk for CVD • 46% used aspirin at baseline 13

Subject Follow-up and Treatment Exposure F/u to study Celecoxib Ibuprofen Naproxen discontinuation (ITT) (N=8072) (N=8040) (N=7969) Follow-up (months) Mean (SD) 34.4 (13.4) 34.0 (13.7) 34.4 (13.4) Median 42.2 42.1 42.2 Max 79.9 89.6 86.1

Treatment exposure Celecoxib Ibuprofen Naproxen (Safety population) (N=8030) (N=7992) (N=7933) Treatment exposure (months) Mean (SD) 20.9 (16.1) 19.7 (16.1) 20.6 (16.0) Median 18.5 16.2 18.2 Max 51.2 58.5 82.0 F/U=Follow-up; SD=standard deviation; max=maximum 14 Source: FDA statistical reviewer Use of Study Drug After APTC Event • 1/3 of patients (N=113) stayed on study drug after APTC event despite requirement to discontinue treatment • 20% stayed on study drug for > 1 month after APTC event

307 subjects with APTC event while on treatment

Subjects, n(%) Time treatment discontinued relative to APTC event 194 (63%) Same day 33 (11%) 1 to 10 days

20 (6%) 11 to 30 days

19 (6%) 31-100 days 41 (13%) Scattered from 101-1135 days

Source: FDA statistical reviewer 15

Mean Individual Dose Celecoxib 100- Ibuprofen 600-800 Naproxen 375-500 200 mg bid mg tid mg bid (N=8072) (N=8040) (N=7969) Subjects with 8069 (99.9%) 8036 (99.9%) 7969 (99.9%) dispensing data, (N %) Mean dose in mg, (SD) 104 (18) 682 (82) 426 (51)

OA subjects with 7256 (90%) 7204 (90%) 7176 (90%) dispensing data, (N %)

Mean dose in mg, (SD) 100 (3.2) 682 (82) 426 (51)

RA subjects with 813 (10%) 832 (10%) 790 (10%) dispensing data, (N %) Mean dose in mg, (SD) 142 (41) 682 (82) 425 (51)

Source: Adapted from Applicant’s Table 14.4.1.4.1a from CSR 16 Dose Escalation

Treatment Group Celecoxib Ibuprofen Naproxen 200 mg bid 800 mg tid 500 mg bid (N%) (N%) (N%) mITT

Overall - N 8030 7990 7933

Dose escalated -% 6% 55% 55%

OA - N 7220 7162 7146 Dose escalated -% 0.2% 55% 55% RA - N 810 828 787 Dose escalated -% 56% 57% 55%

Source: Adapted from Applicant’s Table 1.2 submitted January 12, 2018 17 Medications Used During Trial • 17% of all subjects were reported to have used non-study celecoxib, ibuprofen, or naproxen for ≥ 7 consecutive days (termed “cross-in” by the Applicant) – Finding similar across treatment groups (ITT) • 28% of all subjects were reported to have used any non-study NSAIDs: – Finding similar across treatment groups (ITT) • Rescue: 26% of all subjects and similar b/w groups for type and frequency 18

Subject Disposition Celecoxib Ibuprofen Naproxen Total N (%) N (%) N (%) N (%) All Randomized (ITT) 8072 8040 7969 24081

Treated 8030 7992 7933 23955

Completed treatment 33% 29% 32% 31% Discontinued 66% 70% 67% 68% treatment Missing EOT status 0.6% 0.6% 0.6% 0.6%

Completed study 70% 70% 71% 70% Discontinued study 29% 30% 29% 29% Missing EOS status 0.7% 0.7% 0.7% 0.7% EOT=end of treatment; EOS=end of study Source: Adapted from Applicant’s Table 1 submitted November 8, 2017 19

Reasons for Treatment Discontinuation Celecoxib Ibuprofen Naproxen Total N (%) N (%) N (%) N (%) Discontinued treatment 5363 5584 5361 16308 Subject died 0.8% 1% 1% 1% Does not meet 0.5% 0.6% 0.4% 0.5% entrance criteria Insufficient clinical 10% 9% 9% 9% response Lost to follow-up 6% 5% 5% 5% Medication error 1 1 0 2 without AE No longer willing to 17% 15% 16% 16% participate Other 9% 9% 9% 9% Protocol violation 1% 0.9% 0.8% 0.9% Study terminated by 3 0 2 5 Sponsor Adverse event (AE) 23% 28% 26% 25% Investigator declined 0.3% 0.2% 0.2% 0.3% further participation Withdrew consent 0.1% 0.2% 0.2% 0.2%

Source: Adapted from several Applicant’s tables from study report 20

Reasons for Trial Discontinuation

Celecoxib Ibuprofen Naproxen Total N (%) N (%) N (%) N (%) Discontinued study 2316 2365 2262 6943 Subject died 2% 2% 3% 3% Does not meet 0.2% 0.2% 0.1% 0.2% entrance criteria Investigator declined 1% 0.9% 0.8% 1% further participation Lost to follow up 8% 8% 7% 8% Other 2% 2% 2% 2% Study terminated by 0.1% 4 subjects 0.1% 0.1% Sponsor No longer willing to 7% 7% 7% 7% participate Withdrew consent 8% 9% 8% 8% Adverse event 0.3% 0.5% 0.5% 0.4% Insufficient clinical 2 subjects (0%) 4 subjects (0%) 3 subjects (0%) 9 subjects (0%) response

Source: Adapted from several Applicant’s tables from study report 21

Primary Endpoint

• Statistical methods • Changes in planned analyses • Division’s analyses

22 APTC Events by Aspirin Use Subjects not on aspirin Celecoxib Ibuprofen Naproxen mITT (N=4347) (N=4295) (N=4293) Subjects with APTC, N (%) 57 (1.3%) 74 (1.7%) 67 (1.6%) Median f/u, Years 1.6 1.4 1.6 IR of APTC (100 PY) 0.7 1 0.9 Subjects on aspirin Celecoxib Ibuprofen Naproxen mITT (N=3683) (N=3695) (N=3640) Subjects with APTC, N (%) 77 (2.1%) 81 (2.2%) 77 (2.1%) Median f/u, Years 1.6 1.3 1.6 IR of APTC (100 PY) 1.2 1.3 1.2

IR=incidence rate; PY=patient years Source: Adapted from several Applicant’s tables from study report 23

Secondary and Tertiary Endpoints

• Additional CV, GI, renal, and all-cause mortality • Lack of a prespecified hierarchical statistical testing plan – Results considered hypothesis-generating only • Data and analyses for secondary and tertiary endpoints should only be interpreted descriptively 24 Secondary and Tertiary Results

mITT Celecoxib Ibuprofen Naproxen N=8030 N=7990 N=7933 GI events CSGIE 27 (0.3%) 59 (0.7%) 52 (0.7%) IDA of GI origin 27 (0.3%) 58 (0.7%) 66 (0.8%) CSRE or hospitalization for CHF or HTN CS Renal Events 42 (0.5%) 73 (0.9%) 62 (0.8%) Hospitalization for CHF 28 (0.3%) 38 (0.5%) 35 (0.4%) Hospitalization for HTN 25 (0.3%) 37 (0.5%) 32 (0.4%) Any of the above 89 (1.1%) 139 (1.7%) 120 (1.5%) All-cause mortality Death of any cause 53 (0.7%) 73 (0.9%) 79 (1%) GI=gastrointestinal; CS=clinically significant; CSGIE=clinically significant gastrointestinal events; IDA=iron deficiency anemia; CHF=congestive heart failure Source: Adapted from several Applicant’s tables from study report 25

General Safety

26 Deaths (all causes)

ITT Celecoxib Ibuprofen Naproxen Total

N=8072 N=8040 N=7969 N=24081 Deaths – CRF dataset 189 (2.3%) 193 (2.4%) 228 (2.9%) 610 (2.5%)

Deaths – adjudicated 191 (2.4%) 198 (2.5%) 232 (2.9%) 621 (2.6%) dataset

CRF=Case report form Source: Adapted from Applicant’s tables from study report 27 Deaths by Trial Period Death during 30 days following drug d/c was higher for all groups

CRF Celecoxib Ibuprofen Naproxen database N= 8030 N= 7992 N= 7933 DB 30 days F/U DB 30 days F/U DB 30 days F/U after after after drug d/c drug d/c drug d/c Deaths, N (IR 27 (0.2) 27 (4.6) 135 (1.6) 40 (0.3) 32 (5.5) 119 (1.3) 47 (0.4) 32 (5.5) 148 (1.7) 100 PY) Reason drug d/c N(IR 100 PY) AE 4 (0.7) 69 (0.8) 1 (0.2) 65 (0.7) 3 (0.5) 79 (0.9) Death 22 (3.9) 66 (0.8) 30 (5.3) 54 (0.6) 27 (5.0) 69 (0.8) Other 1 1 2 Source: Adapted from Applicant’s Table 1b submitted March 23, 2018 28 Deaths by Arthritis Type Adjudicated Celecoxib Ibuprofen Naproxen Total All randomized N=8072 N=8040 N=7969 N=24081 Deaths, % 191 (2.4%) 198 (2.5%) 232 (2.9%) 621 (2.6%) CV, % 101 (1.3%) 108 (1.3%) 125 (1.6%) 334 (1.4%) Non-CV, % 90 (1.1%) 90 (1.1%) 107 (1.3%) 287 (1.2%) RA subjects 813 832 791 2436 Deaths, % 21 (2.6%) 26 (3.1%) 43 (5.4%) 90 (3.7%) CV, % 13 (1.6%) 14 (1.7%) 18 (2.3%) 45 (1.9%) Non-CV, % 8 (1%) 12 (1.4%) 25 (3.2%) 45 (1.9%) OA subjects 7259 7208 7178 21645 Deaths, % 170 (2.3%) 172 (2.4%) 189 (2.6%) 531 (2.5%) CV, % 88 (1.2%) 94 (1.3%) 107 (1.5%) 289 (1.3%) Non-CV, % 82 (1.1%) 78 (1.1%) 82 (1.1%) 242 (1.1%)

Deaths collected during the entire duration of the trial, no matter on or off treatment 29 Source: Adapted from Applicant’s table from study report

Select Serious Adverse Events

TESAE by PT Celecoxib Ibuprofen Naproxen N=8030 N=7992 N=7933 N (%) of subjects With SAE 1481 (18%) 1637 (21%) 1622 (20%) D/C due to SAE 501 (6%) 582 (7%) 562 (7%) MI 45 (0.6%) 70 (0.9%) 48 (0.6%) UA 45 (0.6%) 41 (0.5%) 61 (0.8%) CAD 42 (0.5%) 40 (0.5%) 45 (0.6%) CHF 31 (0.4%) 41 (0.5%) 41 (0.5%) Chest pain 52 (0.6%) 84 (1.1%) 73 (0.9%) HTN 18 (0.2%) 35 (0.4%) 21 (0.3%) Anemia 15 (0.2%) 34 (0.4%) 25 (0.3%) Gastric ulcer 1 12 (0.2%) 5 (0.1%) Acute kidney injury 36 (0.4%) 40 (0.5%) 31 (0.4%)

SAE=serious adverse event; TESAE=treatment emergent serious adverse event; MI=myocardial infarction; UA=unstable angina CAD=coronary artery disease; PT=preferred term 30 Source: Adapted from Applicant’s table from study report Adverse Events Leading to Drug Discontinuation

Celecoxib Ibuprofen Naproxen N=8030 N=7992 N=7933 Number (%) of subjects AEs by PT leading to drug d/c in ≥1% HTN 78 (1%) 140 (1.8%) 106 (1.3%) Blood Cr increased 54 (0.7%) 105 (1.3%) 49 (0.6%)

PT=preferred term Cr=creatinine Source: Adapted from Applicant’s table from study report

31 Most Common Adverse Events

Celecoxib Ibuprofen Naproxen (N=8030) (7992) (N=7933) N (%) of subjects AEs by PT

HTN 776 (10%) 1039 (13%) 871 (11%) Anemia 221 (3%) 437 (6%) 331 (4%) IDA 57 (0.7%) 18 (0.2%) 133 (1.7%) Hgb decreased 73 (0.9%) 147 (1.8%) 127 (1.6%) Renal failure 51 (0.6%) 109 (1.4%) 83 (1%) Blood Cr increased 148 (1.8%) 270 (3.4%) 154 (1.9%)

Hgb=hemoglobin PT=preferred term Source: Adapted from Applicant’s table from study report 32 ABPM Substudy • Primary endpoint: Change in 24-hour mean ambulatory systolic blood pressure (SBP) at Month 4 compared with baseline • Analysis of Covariance (ANCOVA), mITT • 80% power at 0.0167 level of significance to detect 3 mmHg difference between any two treatment groups • N=444 included in the analysis – Mean age of 62 years, 80% Caucasian, 54% females

33 Mean 24-hour SBP – Change From Baseline

LS=least square; vs=versus 34 Source: Applicant’s table from study report Division of Epidemiology Literature Review Update • Time frame: December 04, 2012 to January 24, 2018 • Focused on studies that advance our understanding of NSAIDs-associated thrombotic CV risk, with respect to: – a differential CV risk between NSAIDs – vulnerable populations – risk factors – time to CV adverse event • Division of Epidemiology did not identify any new information to support additional labeling changes based on their review 35

Conclusion • Celecoxib carries CV risk that is no worse than CV risk with ibuprofen or naproxen • Additional CV, GI, renal, and all-cause mortality outcomes must be interpreted descriptively • No new safety alerts • Celecoxib did not adversely affect mean 24-hour SBP • All outcomes must be interpreted in the context of the doses given in the trial 36

Statistical Assessment of the PRECISION Trial

Joint Meeting of Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee April 24, 2018

Bo Li, PhD Office of Biostatistics Office of Translational Sciences Outline • PRECISION Overview

• Trial Results

• Conclusions www.fda.gov 2 Outline • PRECISION Overview

• Trial Results

• Conclusions www.fda.gov 3 Trial Design

• Overall: Multi-center, randomized, double blind, triple-dummy, active-controlled, 3-arm parallel group, event-driven CV outcome trial

• Population: OA or RA patients with established CVD or risk factors for CVD

• Treatment groups 1:1:1 – Celecoxib 100-200 mg bid – Ibuprofen 600-800 mg tid – Naproxen 375-500 mg bid

www.fda.gov 4 Trial Design • Primary outcome: The Antiplatelet Trialists Collaboration (APTC) composite endpoint – CV death – Non-fatal MI – Non-fatal stroke • APTC events were adjudicated by a clinical events committee

• Non-inferiority design: To rule out pre-specified excess risk of APTC for celecoxib vs. naproxen/ibuprofen

www.fda.gov 5 Trial Design • Analysis population – ITT: all randomized subjects – Modified ITT (mITT): all randomized subjects who received at least 1 dose of study medication and had at least 1 post-baseline visit

• Event censoring – ITT Analysis: on-study censoring (both on- and off- treatment) – mITT Analysis: on-treatment + 30 days censoring

www.fda.gov 6 Trial Design (Original) • Criteria for demonstrating non-excessive CV risk of celecoxib vs. naproxen/ibuprofen – HR ≤ 1.12 for both ITT and mITT analyses; and – The upper limit (UL) of the two-sided 95% CI of the HR < 1.33 for ITT analysis; and – The upper limit of the two-sided 95% CI of the HR < 1.33 for mITT analysis.

• 90% power to rule out 1.33 margin – 762 total APTC events needed in ITT analysis – 762 total APTC events needed in mITT analysis

• The study would continue until 762 APTC events were accrued and all subjects had the opportunity for 18 months of follow-up; No maximum length of follow-up specified

www.fda.gov 7 Trial Design (Amended) Protocol Amendment 4 (May 6, 2010) • 90% 80% power to rule out 1.33 margin . ITT analysis: 762 580 total APTC events needed . mITT analysis: 762 580 total APTC events needed • Maximum study participation = 42 months

Protocol Amendment 6 (July 7, 2011) • Risk margin criteria . The upper limit of the 95% CI of the HR < 1.33 1.4 for mITT analysis • 80% Power . To rule out 1.33 margin in ITT analysis: 580 total APTC events needed . To rule out 1.4 margin in mITT analysis: 580 420 total APTC events needed • ITT analysis: data truncated at Month 30 • MITT analysis: data truncated at Month 42 (+ 30 days) www.fda.gov 8 Methods • Primary analysis: Time to first adjudicated APTC – ITT analysis: on-study by Month 30 – mITT analysis: on-treatment + 30 days

• Primary analysis model: Cox model – Include treatment as explanatory variable – Include covariates for OA/RA, baseline aspirin use and region

www.fda.gov 9 Methods • Adjudicated secondary/tertiary endpoints (CV-related) – MACE*: APTC + revascularization + hospitalization for unstable angina (UA) + hospitalization for TIA – Death from any cause • Analyzed using the time-to-event method similar to that used for APTC

Endpoints other than APTC: • Not part of a pre-specified hierarchical testing plan; • Considered exploratory www.fda.gov *MACE: Major Adverse Cardiovascular Events 10 Outline • PRECISION Overview

• Trial Results

• Conclusions www.fda.gov 11 Trial Subjects • First randomization: October 21, 2006 • Last randomization: June 30, 2014 • Last subject last visit: April 12, 2016

• 24081 subjects randomized at 923 centers globally – Celecoxib arm: 8072 subjects – Ibuprofen arm: 8040 subjects – Naproxen arm: 7969 subjects

www.fda.gov 12

Subject Disposition