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Bioequivalence and Interchangeability of Generic Drugs

By

Daphne E. Smith Marsh

, PharmD, BC-ADM, CDE , College of Pharmacy, University of Illinois at Chicago

Last full review/revision Apr 2020| Content last modified Apr 2020
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NOTE: This is the Consumer Version. DOCTORS: Click here for the Professional Version
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Topic Resources

When one company develops a generic version of another company's brand-name drug, the new company’s experts in drug formulation must figure out how to make the drug. 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. (See also Overview of Generic Drugs and Drug Naming.)

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 (wheezing, shortness of breath, chest tightness) 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 U.S. Food and Drug Administration (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 U.S. Food and Drug Administration (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 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 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 antiseizure drug, are examples of such drugs. Finally, 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 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 (see table When Generic Substitution May Not Be Appropriate). 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, most pharmacies now include the reference brand name on the label when a generic product is substituted.

Caution should be exercised when considering switching brands of drugs that entered the market before the 1938 Federal Food, Drug, and Cosmetic Act took effect. The few drugs in this category that are still prescribed are exempt from generic drug requirements. Switching among different versions of these drugs is unwise because no standards are available by which to compare them.

Other drugs for which generic substitution may not be appropriate include drugs that are said to have a narrow margin of safety because the toxic dose is too close to the effective dose for the drug to be used safely.

Table
icon

When Generic Substitution May Not Be Appropriate

Drug Category

Examples

Comments

Antiasthmatic drugs taken by mouth

Theophylline

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

Anticoagulants

Warfarin

Toxic dose for the drug is too close to the effective dose for the drug to be used safely.

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.

Antiseizure drugs

Carbamazepine*, clonazepam, eslicarbazepine*, lamotrigine, oxcarbazepine, phenytoin*, topiramate, valproate, and zonisamide

Loss of seizure control has been reported after people switch brands. Continuity of the same brand, or the same generic preparation, is recommended.

Antihypertensive drugs

Modified-release preparations of diltiazem and nifedipine

Some generic versions are not bioequivalent to brand-name drugs. Modified-release preparations have different release characteristics and are not interchangeable.

Cardiovascular drugs

Digoxin (for heart failure and a very rapid heart rate)

Toxic dose is too close to the effective dose for the drug to be used safely.

Corticosteroid creams, lotions, and ointments

Alclometasone, amcinonide, betamethasone, clocortolone, desonide, desoximetasone, dexamethasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, fluticasone*, 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, prednisolone

Generic versions may not be bioequivalent to brand-name drugs and should not be freely interchanged for them.

Gout-control drugs

Colchicine

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

Hormones

Some brands of medroxyprogesterone, and methyltestosterone

Thyroid-replacement products

Hormones are usually taken in small doses, so differences in brands could produce major swings in response.

Some brands are not bioequivalent.

Psychiatric drugs

Lithium (for bipolar disorder)

Toxic dose for the drug is too close to the effective dose for the drug to be used safely.

Other drugs

Some brands of promethazine tablets and suppositories, and clozapine

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

* A generic drug is not available.

† Modified-release preparations of drugs are versions of the drug in which the preparation has been changed in some way, usually to slow the release of the active ingredient into the bloodstream. Modified-release drugs may be identified by the designations MR, LA (long-acting), XL (extra long), CR (controlled release), or SR (sustained release).

FDA = Food and Drug Administration.

More Information

Drugs Mentioned In This Article

Generic Name Select Brand Names
PROVERA
TESTRED
CORDRAN
APTIOM
TOPICORT
CORTEF, SOLU-CORTEF
TEGRETOL
CELESTONE SOLUSPAN, DIPROLENE, LUXIQ
KENALOG
No US brand name
OZURDEX
TRILEPTAL
CAPEX
VANOS
PROMETHEGAN
ELIXOPHYLLIN
ORAPRED, PRELONE
CUTIVATE, FLONASE
LAMICTAL
ELOCON, NASONEX
TOPAMAX
ZONEGRAN
KLONOPIN
COLCRYS
ADALAT CC, PROCARDIA
CLOZARIL
DILANTIN
CARDIZEM, CARTIA XT, DILACOR XR
COUMADIN
LITHOBID
LANOXIN
NOTE: This is the Consumer Version. DOCTORS: Click here for the Professional Version
Click here for the Professional Version
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