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OTC NSAIDs AND NEPHROTOXICITY Juan Carlos Pelayo, M.D. On Behalf Of The Division Of Cardio-Renal Drug Products FDA OTC A

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

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OTC NSAIDs AND NEPHROTOXICITY Juan Carlos Pelayo, M.D. On Behalf Of The Division Of Cardio-Renal Drug Products FDA OTC A

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  1. OTC NSAIDsANDNEPHROTOXICITYJuan Carlos Pelayo, M.D.On Behalf OfThe Division Of Cardio-Renal Drug ProductsFDA 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. EDEMA18 Weeks

  8. HYPERKALEMIA18 Weeks

  9. HYPERTENSION18 Weeks

  10.  SERUM CREATININE18 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) • 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 162-165.]

  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 • BENEFIT • THE BENEFIT OBTAINED FROM THE USE OF OTC NSAIDs ONLY RELATES TO THE RELIEF OF SYMPTOMS

  22. RISK-BENEFIT ANALYSIS • RISK • 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.

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