Is there positive evidence from a "dechallenge - rechallenge" study?

Two patients showed evidence for positive dechallenge followed by positive rechallenge.

Ventricula tachycardia: 1 case with positive dechallenge and rechallenge.

Dechallenge and rechallenge play an important role in determining whether a causal relationship between an event and a drug exists.

Dechallenge and rechallenge refer to a drug being stopped and restarted in a patient, respectively.

• Dechallenge and rechallenge information, if relevant.

A positive dechallenge has occurred, for example, when an adverse event abates or resolves completely following the drug's discontinuation.

Sleep apnea abated when ketotifen was discontinued (positive dechallenge).

Positive dechallenge

The resp onse to withdrawal of the drug (dechallenge) sho uld be clinically plausible.

Detection of Dechallenge in spontaneous Reporting System

Positive dechallenge ALT returned to normal

In addition, dechallenge and rechallenge information from adverse reaction reports is important in establishing the causal association between the product and the adverse reaction.

Additional information valuable in the assessment of the report includes: relevant medical history; response to dechallenge (stopping the drug); and response to rechallenge (restarting the drug).

• the rationale for suspecting a causal relationship (e.g., pharmacodynamic mechanism, temporal relationship, positive rechallenge or dechallenge, etc.);

6 NA/M Granulocytopenia 4 mo Not yet recovered Positive dechallenge NA

The most recent Periodic Safety Update Report (PSUR) dated March 24, 2006, includes one case of ventricular tachycardia confirmed by positive dechallenge and rechallenge.

Probable/Likely A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge).

The significance of the changes and likely relation to the treatment should be assessed, e.g., by analysis of such features as relationship to dose, relationship to drug concentration, disappearance on continued therapy, positive dechallenge, positive rechallenge, and the nature of concomitant therapy.

If information is available after the cessation of drug (e.g. dechallenge), drug-induced hepatocellular injury is suggested if the decrease of ALT is more than 50% of the excess over the upper limit of normal within 8 days and no additional elevation of ALT within a month.

The most compelling evidence of a causal association derives from the results of liver biopsies, and cases in which there has been a positive dechallenge or a positive rechallenge.