Overview of Aspirin and NSAIDs Label Warnings

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Overview of Aspirin and NSAIDs Label Warnings

• William E. Gilbertson, PharmD.
• Division OTC Drug Products

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Advisory Panel Conclusions (1977)

• Safety well-established for the majority of the
  population and risk benefit ratio is low.
• Risks can be identified and labeling provided for
  safe OTC use.
• Adult Dose
• 325 to 650 every 4 hours not to exceed
  4,000 mg in 24 hours for lt 10 days.
• Childrens Dose
• Age-based dosing for children gt 2 years based
  on a standard 81-mg dosage unit

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Advisory Panel Conclusions (1977)

• Aspirin has several adverse effects on the GI
  tract ranging from relatively mild to severe.
• Mild gastric distress (minor stomach pain,
  heartburn, or nausea).
• Superficial mucosal irritation and minor occult
  bleeding.
• Serious mucosal erosion, ulceration, or
  life-threatening massive GI bleeding.
• Massive bleeding is relatively rare and
  unpredictable.

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Advisory Panel Conclusions (1977)

• Irritation or exacerbation of stomach ulcers,
  stomach irritation, and intestinal inflammation
  occurs in a significant number of individuals
  that take aspirin.
• Particularly at risk are individuals with a
  history or symptoms of GI problems.

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Advisory Panel Conclusions (1977)

• Acute ingestion of aspirin has a significant
  effect on duodenal bleeding and a synergistic
  effect with alcohol in bleeding from duodenal
  ulcers.
• Aspirin may potentiate bleeding from GI lesions
  even though aspirin alone may not initiate the
  lesion.
• Insufficient evidence to include an alcohol
  warning.

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Advisory Panel Conclusions (1977)

• Recommended warning
• Caution Do not take this product if you have
  stomach distress, ulcers or bleeding problems
  except under the advice and supervision of a
  physician.
• Carbaspirin and other nonaspirin salicylates
  (choline, magnesium, sodium) have similar safety
  profiles and should also bear warning.

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Advisory Panel Conclusions (1977)

• Use of aspirin in the general population
• Although prolonged use of high doses of aspirin
  may produce kidney disease in some individuals,
  the risk is insignificant in the recommended
  target population.
• A warning regarding aspirin causing kidney
  disease is unwarranted for OTC use.

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Advisory Panel Conclusions (1977)

• Use of aspirin in subjects with renal disease
• Evidence suggests aspirin may contribute to or
  exacerbate chronic or acute renal disease (other
  than analgesic kidney disease).
• Not clear whether aspirin contributes to renal
  deterioration in individuals with analgesic
  kidney disease.
• Warning is premature as definitive studies are
  lacking.

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Tentative Final Monograph (TFM) (1988)

• Adult Dose
• 325 to 650 mg every 4 hours
• 325 to 500 mg every 3 hours
• 650 to 1,000 mg every 6 hours not to exceed 4,000
  mg in 24 hours for lt 10 days.
• Childrens Dose
• Age-based dosing for children gt 2 years based
  on an 80- or 81-mg or a 325-mg dosage unit

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FDA Conclusions in TFM (1988)

• Recommended warning
• Do not take this product if you have stomach
  problems (heartburn, upset stomach, stomach pain)
  that persist or recur, or if you have ulcers or
  bleeding problems except under the advice and
  supervision of a physician.

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Timeline

• 1977 OTC Advisory Panel Report
• 1984 Ibuprofen approved for OTC use
• 1988 Tentative Final Monograph
• 1993 Naproxen sodium approved for OTC use 1993
  NDAC (June) considers alcohol warning for
  acetaminophen
• 1993 NDAC (September) considers alcohol
  warning for aspirin and NSAIDS
• 1995 Ketoprofen approved for OTC use

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NDAC Meeting (September 1993)

• Data Reviewed
• Risk of upper GI bleeding associated with alcohol
  and aspirin, ibuprofen, and naproxen sodium.
• Additive effects of these ingredients with
  alcohol.
• Alcohol's ability to potentiate aspirin-prolonged
  bleeding times.
• Effects of aspirin on ethanol pharmacokinetics.
• Panel's conclusions on monograph ingredients.

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Questions to NDAC (1993)

• Are data sufficient to support an alcohol warning
  for aspirin, ibuprofen, and naproxen sodium?
• Are data sufficient to support an alcohol warning
  for the other monograph salicylates?
• Type of information an alcohol warning should
  include, i.e., organ specific information or
  statement of risk?
• What information should appear in labeling of
  combination products containing aspirin and
  acetaminophen?

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NDAC Conclusions (1993)

• Aspirin, ibuprofen, and naproxen sodium increases
  the risk of upper GI bleeding in heavy alcohol
  users or abusers and a warning is warranted.
• No consensus on an organ-specific warning.
• No data to support a warning for nonaspirin
  salicylates.
• No specified level of alcohol consumption need be
  mentioned.

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FDA Conclusions (1997)

• History of heavy alcohol use or abuse may
  increase the risk of adverse GI effects,
  including serious GI bleeding and a warning is
  needed.
• Specific warnings are more effective and should
  include organ-specific information.
• Products with no warning may lead consumers to
  conclude that they are safer to use with alcohol.
  
• Nonaspirin salicylates should also bear an
  alcohol warning.

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Alcohol Warning

• Final Rule (1998)
• Alcohol warning If you consume 3 or more
  alcoholic drinks every day, ask your doctor
  whether you should take aspirin or other pain
  relievers/fever reducers. Aspirin may cause
  stomach bleeding.
• Combinations of acetaminophen and aspirin should
  be labeled May cause liver damage and stomach
  bleeding.

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Aspirin Professional Labeling FR(1998)

• WARNINGS
• GI Side Effects
• stomach pain,
• heartburn,
• nausea,
• vomiting, and
• gross GI bleeding.

• PRECAUTIONS
• Renal Failure
• Avoid aspirin in patients with severe renal
  failure (glomerular filtration rate less than 10
  mL/minute).

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Aspirin Professional Labeling
FR(1998)ADVERSE REACTIONS

• Urogenital
• interstitial nephritis,
• pappilary necrosis,
• proteinuria,
• renal insufficiency, and
• failure

• GI Side Effects
• dyspepsia,
• GI bleeding, ulceration,
• perforation,
• nausea,
• vomiting.

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Ibuprofen Proposed Rule (2002)

• Ask a doctor before use if you have
• Stomach problems that last or come back, such as
  heartburn, upset stomach, or pain
• Ulcers
• Bleeding problems
• High blood pressure
• Heart or kidney disease
• Are taking a diuretic
• Over 65 years of age

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