OTC NSAIDs AND NEPHROTOXICITY Juan Carlos Pelayo, M.D. On Behalf Of The Division Of CardioRenal Drug

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OTC NSAIDsANDNEPHROTOXICITYJuan Carlos
Pelayo, M.D.On Behalf OfThe Division Of
Cardio-Renal Drug Products FDA OTC Advisory
Committee - September 20, 2002
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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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NSAID-INDUCED NEPHROTOXICITY(PRESCRIPTION DOSES)

• EDEMA
• HYPERKALEMIA
• ? BLOOD PRESSURE
• ? SERUM CREATININE / ARF
• PROTEINURIA / NS / INTERSTITIAL NEPHRITIS
• ACUTE PAPILLARY NECROSIS
• CRF

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AT RISK POPULATIONS

• VOLUME DEPLETION
• UNDERLYING KIDNEY DISEASE
• HEART FAILURE
• LIVER DYSFUNCTION WITH ASCITES
• ELDERLY
• PREGNANCY

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NSAID-INDUCED NEPHROTOXICITY(PRESCRIPTION DOSES)

• WHAT ARE THE RATES OF OCCURRENCE OF NSAID-RELATED
  KIDNEY ADVERSE EVENTS FOR PRESCRIPTION DOSES?

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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

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EDEMA18 Weeks
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HYPERKALEMIA 18 Weeks
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HYPERTENSION18 Weeks
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? SERUM CREATININE18 Weeks
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PROTEINURIA 18 Weeks
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NSAID-INDUCED NEPHROTOXICITY(PRESCRIPTION DOSES)

• ACUTE RENAL FAILURE 0
• INTERSTITIAL NEPHRITIS 0
• ACUTE PAPILLARY NECROSIS 0

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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)

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NSAID-INDUCED NEPHROTOXICITY

• DOSE LEVEL vs. NEPHROTOXICITY?

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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

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ASSESSMENT OF NEPHROTOXIC RISK ASSOCIATED WITH
OTC NSAIDs

• RETROSPECTIVE, UNCONTROLLED AND UNDERPOWERED
  STUDIES
• META-ANALYSES
• CASE REPORTS

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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.

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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, 1996pp 162-165.

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ASSESSMENT OF NEPHROTOXIC RISK ASSOCIATED WITH
OTC NSAIDs

• ADVERSE EVENT REPORTING SYSTEM

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AERS FOR RENAL FAILURE REPORTED FOR OTC NSAIDs
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RISK-BENEFIT ANALYSIS

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

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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.