Info

Total Score

ADR probability classification based on total score

9 Highly probable

5-8 Probable

1-4 Possible

0 Doubtful

ADR probability classification based on total score

9 Highly probable

5-8 Probable

1-4 Possible

0 Doubtful a Reproduced with permission from Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA etal. Clin Pharmacol Ther 1981;30:239-45.

TABLE 25.5 Clinical Evidence Suggestive of Causality

• Temporal relationship

• Positive dechallenge

• Positive rechallenge

• Dose-response relationship

• Biological plausibility

• Absence of alternative etiologies

• Objective confirmation

• Prior reports of reaction

• Past history of reaction to same or related medication probability that an ADR was caused by a specific medication. The presence of some or all of the elements listed in Table 25.5 increases the probability of drug culpability in association with an ADR.

A chronological or temporal relationship between the administration of a drug and the development of an adverse reaction is essential for establishing causality. The time to onset of reaction must be plausibly related to the administration of the drug. However, because some reactions may not appear for weeks or months after the start of therapy with a medication, they may be erroneously implicated as the cause of the reaction. The presence or absence of alternative etiologies and confounding variables also must be investigated (49, 56). A history of the reaction in a patient receiving the same drug or a similar compound increases the possibility that the association may be causal, and prior reports of similar reactions lend credibility to a cause-and-effect relationship. The absence of prior reports decreases the likelihood but does not eliminate the possibility that the reaction is due to the medication in question. If a precedent cannot be found, the plausibility of the reaction should be based on a consideration of the known clinical pharmacology of the drug (56). Further evidence to support an assertion of drug culpability requires objective data, such as abnormally high serum drug concentrations, specific physical examination findings, or other laboratory or diagnostic data characteristic of a drug reaction.

A positive dechallenge (i.e., when a reaction resolves after a drug is discontinued or a specific antagonist is administered) suggests that the medication may be culpable. A positive rechallenge (i.e., when signs or symptoms of the reaction recur after the drug is readministered) provides even more convincing evidence linking the drug to the reaction, but may not be ethically permissible and clinically justifiable. In any case, rechallenge should be done only after dechal-lenge is complete and signs and symptoms of the reaction have completely abated (57). The probability of a cause-and-effect relationship is further strengthened if the reaction worsens when a higher dose of the medication is administered. To further evaluate the probability of a drug-induced effect, Naranjo (58) suggests that a placebo challenge be considered.

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