Altered metabolite concentrations with amiodarone generic substitution cannot be observed without monitoring

The use of amiodarone has grown rapidly, resulting in the marketing of several generic formulations. The adequacy of the testing used to approve these formulations as bioequivalent has been questioned, and mounting clinical evidence suggests that in some patients, substitution with generic amiodarone can cause serious problems. The effects of switching amiodarone formulations may take weeks to develop, leaving the relationship between the events unrecognized. In animal models, the toxicity of desethylamiodarone, an active metabolite partly formed during amiodarone absorption, is greater than that of its parent compound. High metabolite to amiodarone ratios have been associated with clinical toxicity. Because measuring serum amiodarone and metabolite is not standard clinical practice, aberrations after switching formulations will be missed. Major changes in metabolite concentrations were documented in four patients switched to a generic formulation, suggesting that the tests used for regulatory approval failed to identify the cumulative effects of differing excipients on amiodarone metabolism during absorption. Physicians should monitor patients for several months after a switch in amiodarone formulation is made. Regulatory criteria for bioequivalence of amiodarone need to be reconsidered.