Merck Manual

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When Generic Substitution May Not Be Appropriate

When Generic Substitution May Not Be Appropriate

Drug Category



Antiasthmatic drugs taken by mouth


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



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


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

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


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


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

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.