Bioequivalence and Interchangeability of Generic Medications

Manufacturers of generic medications must conduct studies to determine whether their version is bioequivalent to the original medication—that is, that the generic version releases its active ingredient (the medication) into the bloodstream at virtually the same speed and in virtually the same amounts as the original medication. Because the active ingredient in the generic medication has already been shown in testing of the brand-name medication to be safe and effective, bioequivalence studies only have to show that the generic version produces the same levels of medication in the blood over time and thus require only a relatively small number (24 to 36) of healthy volunteers.

Although people generally think of oral dosage forms, such as tablets, capsules, and liquids, when they think about generic prescription medications, generic versions of other medication dosage forms, such as injections, patches, inhalers, and others, must also meet a bioequivalence standard. In the United States, the U.S. Food & Drug Administration (FDA) sets bioequivalence standards for different medication dosage forms.

The manufacturer of the brand-name medication also must prove bioequivalence before a new form of an approved medication can be sold. New forms include new dosage forms or strengths of an existing brand-name drug product and any other modified form that is developed. 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.

In the United States, the U.S. Food & Drug Administration (FDA) evaluates every generic version of a medication. The FDA approves a generic medication if studies indicate that the original brand-name medication and the generic version are essentially bioequivalent. The FDA also makes sure that a new generic medication contains the appropriate amount of the active ingredient, that it is manufactured according to federal standards (Good Manufacturing Practices), and that the generic version differs from its brand-name counterpart in size, color, and shape—a legal requirement.

Ideally, any generic medication that is bioequivalent to its brand-name counterpart may be interchanged with it. For medications that are off patent, the generic medication may be the only form available. To limit costs, many doctors write prescriptions for generic medications whenever possible. Even if the doctor has prescribed a brand-name medication, the pharmacist may dispense a generic medication unless the doctor has written on the prescription that no substitution can be made. Also, insurance plans and managed care organizations may require that generic medications be prescribed and dispensed whenever possible to save money. Some insurance plans may allow a consumer to select a more expensive brand-name product prescribed by the doctor as long as the consumer pays the difference in cost. However, in some state-run programs, the consumer may not have a choice. If the doctor prescribes a generic medication, the pharmacist must dispense a generic medication. In most states, the consumer may insist on a brand-name medication even if the doctor and pharmacist recommend a generic medication.

Sometimes generic substitution may not be appropriate. For example, some available generic versions may not be precisely bioequivalent to the brand-name medication. Such generic medications may not be substituted by the pharmacist for the brand-name product. In cases in which small differences in the amount of medication in the bloodstream can make a very large difference in the medication’s effectiveness, generic medications are often not substituted for brand-name medications, even though bioequivalent generic products are available. Additionally, a generic product may not be appropriate if it contains an inactive ingredient to which the person is allergic. Thus, if a doctor specifies a brand-name medication on the prescription and the consumer wants an equivalent generic version, the consumer or pharmacist should discuss the matter with the doctor.

Medications that must be given in very precise amounts are less likely to be interchangeable, because the difference between an effective dose and a harmful dose (the margin of safety) or ineffective dose is small. Digoxin, used to treat people with heart failure, is an example. Switching from the brand-name version of digoxin to a generic product may cause problems, because the two versions may not be sufficiently bioequivalent. However, some generic versions of digoxin have been certified as bioequivalent by the FDA. Pharmacists and doctors can answer questions about which generic medications are interchangeable for their brand-name counterparts and which are not.Medications that must be given in very precise amounts are less likely to be interchangeable, because the difference between an effective dose and a harmful dose (the margin of safety) or ineffective dose is small. Digoxin, used to treat people with heart failure, is an example. Switching from the brand-name version of digoxin to a generic product may cause problems, because the two versions may not be sufficiently bioequivalent. However, some generic versions of digoxin have been certified as bioequivalent by the FDA. Pharmacists and doctors can answer questions about which generic medications are interchangeable for their brand-name counterparts and which are not.

A book published by the FDA each year and updated periodically also provides guidance about which medications are interchangeable. This book,Approved Drug Products With Therapeutic Equivalence Evaluations (also known as "the orange book" because the print version has a bright orange cover), is available both in print and online to anyone but is intended for use by doctors and pharmacists.

The substitution of a generic medication can sometimes cause other problems for the consumer. A doctor may write a prescription for a brand-name product and discuss the brand-name product with the consumer. If a pharmacist dispenses an equivalent generic product and the label does not also list the brand-name product, the consumer may mistakenly believe they have received the wrong medication from the pharmacist. To prevent this confusion, most pharmacies now include the brand name on the label when a generic product is substituted.