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

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