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Bioequivalence and Interchangeability of Generic Drugs

by Harold M. Silverman, PharmD

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

  • Provide bulk so that a tablet is large enough to handle

  • Keep a tablet from crumbling between the time it is manufactured and the time it is used

  • Help a tablet dissolve in the stomach or intestine

  • Provide a pleasant taste and color

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.

Bioequivalence

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.

Evaluation and Approval Procedures

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.

Interchangeability and Substitution

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 or an ineffective dose (the margin of safety) 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

Drug Category

Examples

Comments

Drugs on the market before the 1938 Federal Food, Drug, and Cosmetic Act

Despite efforts by the FDA, some brands of thyroid hormone replacement products, which are still not bioequivalent

Pre-1938 drugs are exempt from generic drug requirements, but only a few of these are still prescribed. Switching among different versions is unwise because no standards are available by which to compare them. Caution is needed when switching brands.

Drugs with little difference between a toxic dose and an effective dose (a narrow margin of safety)

Anticonvulsants such as phenytoin, carbamazepine, and valproate; digoxin (for heart failure and a very rapid heart rate); and the anticoagulant warfarin

The margin of safety is relatively small. Too little drug may not work, and too much drug may have side effects.

Antihypertensive drugs

Reserpine and reserpine plus polythiazide

Generic versions are not bioequivalent to brand-name drugs.

Antiasthmatic drugs taken by mouth

Theophylline, dyphylline, and some brands of aminophylline

Different versions are generally not bioequivalent. If one version is working, it should not be interchanged for another unless absolutely necessary.

Corticosteroid creams, lotions, and ointments

Alclometasone, amcinonide, betamethasone, clocortolone, desonide, desoximetasone, dexamethasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, mometasone, and triamcinolone

These products are standardized by tests of skin response, and many have been rated as bioequivalent by the FDA. But response varies, and different drug vehicles (creams, ointments, gels) can affect product potency. Response may be unpredictable. So, if one version is effective, it should not be interchanged for another.

Corticosteroid tablets

Dexamethasone, triamcinolone, and others

Many generic versions are not bioequivalent to brand-name drugs and should not be freely interchanged for them.

Hormones

Esterified estrogen (estrogen replacement therapy in postmenopausal women), some brands of medroxyprogesterone, and most generic brands of methyltestosterone

The two brands of esterified estrogen are not bioequivalent. Hormones are usually taken in small doses, so differences in brands could produce major swings in response.

Antihyperglycemic drugs

Glyburide (for type 2 diabetes)

One version of glyburide, Diabeta, may not be interchanged for any other. All other versions are considered interchangeable.

Drugs to control gout

Colchicine

Generic versions of individual drugs are not bioequivalent to one another.

Antipsychotic drugs

Chlorpromazine tablets

Generic versions are not bioequivalent to the brand-name version.

Antidepressants

A few brands of amitriptyline and one brand of amitriptyline plus perphenazine

Not all versions are interchangeable. A pharmacist can advise whether the FDA considers a particular generic drug bioequivalent to the brand-name drug

Potassium

Most long-acting potassium replacement products in tablet form

Long-acting potassium products in capsule (not tablet) form are considered bioequivalent and may be interchanged

Other drugs

Fluoxymesterone, some brands of promethazine tablets and suppositories, chloramphenicol capsules, and clozapine

Generic versions may not bioequivalent. Although any version can be effective, versions should not be interchanged.

FDA = Food and Drug Administration.

Resources In This Article

Drugs Mentioned In This Article

  • Generic Name
    Select Brand Names
  • LANOXIN
  • PROVERA
  • No US brand name
  • ELIXOPHYLLIN
  • CORDRAN
  • DIABETA, GLYNASE
  • OZURDEX
  • VANOS
  • KENALOG
  • CUTIVATE, FLONASE
  • TEGRETOL
  • TESTRED
  • TOPICORT
  • CLOZARIL
  • COUMADIN
  • DILANTIN
  • CORTEF, SOLU-CORTEF
  • PROMETHEGAN
  • COLCRYS
  • ELOCON, NASONEX
  • CELESTONE SOLUSPAN, DIPROLENE, LUXIQ