1. OTC NSAIDs AND NEPHROTOXICITY Juan Carlos Pelayo, M. D
OTC NSAIDs AND NEPHROTOXICITY Juan Carlos Pelayo, M.D. On Behalf Of The Division Of Cardio-Renal Drug Products FDA OTC Advisory Committee - September 20, 2002

2. QUESTIONS TO ADDRESS:
ARE NON-PRESCRIPTION DOSES OF OTC NSAIDs NEPHROTOXIC?
IF SO,
WHAT IS THE OUTCOME OF A RISK-BENEFIT ANALYSIS?

3. NSAID-INDUCED NEPHROTOXICITY (PRESCRIPTION DOSES)
EDEMA
HYPERKALEMIA
 BLOOD PRESSURE
 SERUM CREATININE / ARF
PROTEINURIA / NS / INTERSTITIAL NEPHRITIS
ACUTE PAPILLARY NECROSIS
CRF

4. AT RISK POPULATIONS VOLUME DEPLETION UNDERLYING KIDNEY DISEASE
HEART FAILURE
LIVER DYSFUNCTION WITH ASCITES
ELDERLY
PREGNANCY

5. NSAID-INDUCED NEPHROTOXICITY (PRESCRIPTION DOSES)
WHAT ARE THE RATES OF OCCURRENCE OF NSAID-RELATED KIDNEY ADVERSE EVENTS FOR PRESCRIPTION DOSES?

6. NSAID-INDUCED NEPHROTOXICITY (PRESCRIPTION DOSES)
STUDY DESIGN
PROSPECTIVE, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP DESIGN
TREATMENT DURATION 18 WEEKS
361 HEALTHY SUBJECTS WITH OSTEOARTHRITIS WERE EVALUATED PER GROUP
RENAL ADVERSE EVENTS AS REPORTED BY THE INVESTIGATORS
IBUPROFEN 2400 mg/DAILY vs.. PLACEBO

7. EDEMA 18 Weeks

8. HYPERKALEMIA 18 Weeks

9. HYPERTENSION 18 Weeks

10.  SERUM CREATININE 18 Weeks

11. PROTEINURIA 18 Weeks

12. NSAID-INDUCED NEPHROTOXICITY (PRESCRIPTION DOSES)
ACUTE RENAL FAILURE 0%
INTERSTITIAL NEPHRITIS 0%
ACUTE PAPILLARY NECROSIS 0%

13. OTC NSAIDs IBUPROFEN (1984) NAPROXEN (1994) KETOPROFEN (1995)
Max. Dose 1200 mg/Daily (40% Prescription Dose)
NAPROXEN (1994)
Max. Dose 600 mg/Daily (40% Prescription Dose)
KETOPROFEN (1995)
Max. Dose 75 mg/Daily (25% Prescription Dose)

14. NSAID-INDUCED NEPHROTOXICITY
DOSE LEVEL vs. NEPHROTOXICITY?

15. ASSESSMENT OF THE NEPHROTOXIC RISK ASSOCIATED WITH OTC NSAIDs
PROSPECTIVE, RANDOMIZED, PLACEBO-CONTROLLED AND ADEQUATELY POWERED STUDIES COMPARING NON- vs. PRESCRIPTION DOSES OF NSAIDs
HEALTHY POPULATION
AT RISK POPULATIONS

16. ASSESSMENT OF NEPHROTOXIC RISK ASSOCIATED WITH OTC NSAIDs
RETROSPECTIVE, UNCONTROLLED AND UNDERPOWERED STUDIES
META-ANALYSES
CASE REPORTS

17. ASSESSMENT OF NEPHROTOXIC RISK ASSOCIATED WITH OTC NSAIDs
NATIONAL KIDNEY FOUNDATION
DATABASE OF 556 ARTICLES ON ASPIRIN, ACETOMINOPHEN, ASPIRIN-ACETOMINOPHEN COMBINATIONS, AND NSAID-RELATED NEPHROTOXICITY.

18. NATIONAL KIDNEY FOUNDATION POSITION PAPER (1996)
RECOMMENDATION
“THERE SHOULD BE AN EXPLICIT LABEL WARNING PATIENTS TAKING OVER-THE-COUNTER NSAIDs OF THE POTENTIAL RENAL RISKS OF CONSUMING THE DRUGS.”
[American Journal of Kidney Disease, Vol 27, No 1, 1996:pp ]

19. ASSESSMENT OF NEPHROTOXIC RISK ASSOCIATED WITH OTC NSAIDs
ADVERSE EVENT REPORTING SYSTEM

20. AERS FOR RENAL FAILURE REPORTED FOR OTC NSAIDs

21. RISK-BENEFIT ANALYSIS
THE BENEFIT OBTAINED FROM THE USE OF OTC NSAIDs ONLY RELATES TO THE RELIEF OF SYMPTOMS

22. RISK-BENEFIT ANALYSIS
USE OF OTC NSAIDs CARRIES A NOMINAL RISK OF NEPHROTOXICITY.
HOWEVER, THERE ARE NO DATA AVAILABLE TO QUANTITATIVELY DEFINE THE RISK. THIS LACK OF INFORMATION PREVENTS US FROM REACHING A CONCLUSION ABOUT WHETHER THE RISK CHANGES WITH DOSE.