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Bioequivalence and Interchangeability of Generic Drugs
When a company develops a generic version of a brand-name drug, the company’s experts in drug formulation must figure out how to make it. It is not enough for them to simply reproduce the brand-name drug’s chemical structure or to buy the active ingredient from a chemical manufacturer.
Although 250 milligrams (mg) of a brand-name chemical is identical to 250 mg of the same generic chemical, a 250-mg generic pill containing that chemical may or may not have the same effect in the body as a 250-mg brand-name pill. That is because everything that is used in a particular product formulation affects how it is absorbed into the bloodstream. Inactive ingredients such as coatings, stabilizers, fillers, binders, flavorings, diluents, and others are necessary to turn a chemical into a usable drug product. These ingredients may be used to
Inactive ingredients are usually harmless substances that do not affect the body. However, because inactive ingredients can cause unusual and sometimes severe allergic reactions in a few people, one version, or brand, of a drug may be preferable to another. For example, chemicals called bisulfites (such as sodium metabisulfite), which are used as preservatives in many products, cause asthmatic allergic reactions in many people. Consequently, drug products containing bisulfites are prominently labeled as such.
Manufacturers must conduct studies to determine whether their version is bioequivalent to the original drug—that is, that the generic version releases its active ingredient (the drug) into the bloodstream at virtually the same speed and in virtually the same amounts as the original drug. Because the active ingredient in the generic drug has already been shown in testing of the brand-name drug to be safe and effective, bioequivalence studies only have to show that the generic version produces virtually the same levels of drug 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 drugs, generic versions of other drug dosage forms, such as injections, patches, inhalers, and others, must also meet a bioequivalence standard. The FDA sets bioequivalence standards for different drug dosage forms.
The manufacturer of the brand-name drug also must prove bioequivalence before a new form of an approved drug 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, 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.
The FDA evaluates every generic version of a drug. The FDA approves a generic drug if studies indicate that the original brand-name drug and the generic version are essentially bioequivalent. The FDA also makes sure that a new generic drug contains the appropriate amount of the active (drug) 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.
Theoretically, any generic drug that is bioequivalent to its brand-name counterpart may be interchanged with it. For drugs that are off-patent, the generic drug may be the only form available. To limit costs, many doctors write prescriptions for generic drugs whenever possible. Even if the doctor has prescribed a brand-name drug, the pharmacist may dispense a generic drug unless the doctor wrote on the prescription that no substitution can be made. Also, insurance plans and managed care organizations may require that generic drugs be prescribed and dispensed whenever possible to save money. Some 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 has no say. If the doctor prescribes a generic drug, the pharmacist must dispense a generic drug. In most states, the consumer may insist on a brand-name drug even if the doctor and pharmacist recommend a generic drug.
Sometimes generic substitution may not be appropriate. For example, some available generic versions may not be bioequivalent to the brand-name drug. Such generic drugs may still be used, but they may not be substituted for the brand-name product. In cases in which small differences in the amount of drug in the bloodstream can make a very large difference in the drug’s effectiveness, generic drugs are often not substituted for brand-name drugs, although bioequivalent generic products are available. Warfarin, an anticoagulant, and phenytoin, an anticonvulsant, are examples of such drugs. Finally, a generic product may not be appropriate if it contains an inactive ingredient that the person is allergic to. Thus, if a doctor specifies a brand-name drug on the prescription and the consumer wants an equivalent generic version, the consumer or pharmacist should discuss the matter with the doctor.
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 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 drugs 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 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 both in print and online to anyone but is intended for use by doctors and pharmacists. See Approved Drug Products With Therapeutic Equivalence Evaluations.
The substitution of a generic drug 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 reference (brand-name product), the consumer may not know how the generic product relates to the drug the doctor prescribed. To prevent this confusion, pharmacists should include the reference brand name on the label when a generic product is substituted.
When Generic Substitution May Not Be Appropriate
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