Bioequivalence and Interchangeability
Legally, bioequivalence of different versions of a drug can vary by up to 20%, because for most drugs, such variation does not noticeably alter effectiveness or safety. However, actual differences between FDA-approved generic and trade-name drugs are generally much smaller than the allowable 20%. Actual differences are typically only about 3.5% on average and rarely exceed 10% in any single study of bioequivalence.
Bioequivalence must be proved for any new form of a drug. New forms include new dosage forms or strengths of an existing trade-name drug product and any other modified form that is developed, as well as new generic drugs. Sometimes the form that was originally tested is modified for commercial reasons. For example, tablets may need to be made sturdier, flavoring or coloring may be added or changed, or inactive ingredients may be changed to increase consumer acceptance.
Sometimes generic substitution is not appropriate. For example, some generic versions cannot be determined to be bioequivalent to the original drug because no standards for comparison have been established. These versions may not be interchanged freely for the original drug.
Drugs that must be given in very precise amounts are less likely to be interchangeable, because the difference between an effective dose and a harmful or an ineffective dose (the margin of safety) is small. Digoxin, used to treat people with heart failure, is an example. Switching from a trade-name version of digoxin to a generic version may cause problems, because the two versions may not be sufficiently bioequivalent. Pharmacists and doctors can answer questions about which generic drugs are interchangeable for their trade-name counterparts and which are not.
A book published by the FDA each year and updated periodically also provides guidance about which drugs are interchangeable. This book, Approved Drug Products With Therapeutic Equivalence Evaluations (also known as "the orange book" because it has a bright orange cover), is available to anyone but is intended for use by doctors and pharmacists (see Appendix III).
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