Journal of Gerontological Nursing

geropharmacology 

Are Generic Drugs Dangerous for the Aged?

Peter P Lamy, PhD, RAGS

Abstract

Health care professionals must take an active role in indicating those areas where patients, especially the very old, may be at risk if certain cost-containment measures are initiated. Among those measures of concern is the mandatory substitution of brand name drugs with the cheapest generic drugs available.

On January 23, 1978, FDA responded to a request from the New York State Health Department to evaluate their list of drug products for therapeutic equivalence. On May 31, 1978, the Commissioner of the FDA informed all states that a list was being prepared of all prescription drug products approved by FDA for safety and effectiveness. Included was the agency's evaluation of their therapeutic equivalents, so multi-source products containing the same active ingrethent identical in strength and dosage form could be evaluated. The list was published in October, 1980 and has been revised since them.

Products considered to be therapeutically equivalent are coded "A." However, they are subdivided into those with no known or suspected bioequivalence problems, and those with actual or potential bioequivalence problems resolved with adequate in vivo anaVor in vitro evidence supporting bioequivalence.

Just recently, a list of drugs, to which FDA's Office of New Drug Evaluation has already granted paper NDA's, has been published.

It has been suggested that approval process of equivalents often depends on too few patients (as few as 12, in some documented instances). Furthermore, it is strongly suggested that so called equivalents may not be equivalent enough.

For instance, an antipsychotic generic is termed bioequivalent when 70% of the tests falls within ±30% of the innovator drug. When such a wide range of difference in medication is permitted, what are the clinical implications when a severely ill, elderly patient is switched from one product to another?

The very nature of the mental illnesses treated with phenothiazines mandates the use of bioavailable/bioequi valent drug products. These medically important drugs are used in the treatment of schizophrenia, organic psychosis, and the manic phase of manic-depressive illness. Such patients are often so disabled by the severity of their illness that they cannot give legal consent.

The nature of these disorders may cause toxic effects or lack of efficacy associated with the use of bioinequivaJent phenothiazine drug products to go unrecognized by physicians. The 1979 Final Task Force Report of the American College of Neuropsychopharmacology (ACNP) points out that "often any aberration in clinical symptoms is ascribed to the idiosyncracies of the patient and rarely ascribed to differences in drug products." It was the Task Force's opinion that bioavailability/bioequivalence and pharmacokinetics should be of major importance in the clinical use of psychotropics. This is due to the nature of the patient population, the need for chronic use of such drugs, and the extensive metabolism of psychotropic agents.

Clearly, one should give careful consideration to whether a patient, particularly an elderly patient, should be "switched" from one product to another and, even from one generic to another. Elderly females, in particular, are much more at risk to the side effects of phenothiazines, a danger that could be increased when a stronger but still equivalent product is used.

A similar potential problem exists with loop diuretics, particularly furosemide. In this instance, the generic may differ from the innovator drug by as much as ±20%. A 40 mg tablet, therefore, may have the clinical effect of a 32 mg tablet or a 48 mg tablet. By itself, that range in potency may be unacceptable in certain elderly. However, when an elderly patient is also maintained on digoxin (one of the top nine drugs used for those 85 years and older, as are…

Health care professionals must take an active role in indicating those areas where patients, especially the very old, may be at risk if certain cost-containment measures are initiated. Among those measures of concern is the mandatory substitution of brand name drugs with the cheapest generic drugs available.

On January 23, 1978, FDA responded to a request from the New York State Health Department to evaluate their list of drug products for therapeutic equivalence. On May 31, 1978, the Commissioner of the FDA informed all states that a list was being prepared of all prescription drug products approved by FDA for safety and effectiveness. Included was the agency's evaluation of their therapeutic equivalents, so multi-source products containing the same active ingrethent identical in strength and dosage form could be evaluated. The list was published in October, 1980 and has been revised since them.

Products considered to be therapeutically equivalent are coded "A." However, they are subdivided into those with no known or suspected bioequivalence problems, and those with actual or potential bioequivalence problems resolved with adequate in vivo anaVor in vitro evidence supporting bioequivalence.

Just recently, a list of drugs, to which FDA's Office of New Drug Evaluation has already granted paper NDA's, has been published.

It has been suggested that approval process of equivalents often depends on too few patients (as few as 12, in some documented instances). Furthermore, it is strongly suggested that so called equivalents may not be equivalent enough.

For instance, an antipsychotic generic is termed bioequivalent when 70% of the tests falls within ±30% of the innovator drug. When such a wide range of difference in medication is permitted, what are the clinical implications when a severely ill, elderly patient is switched from one product to another?

The very nature of the mental illnesses treated with phenothiazines mandates the use of bioavailable/bioequi valent drug products. These medically important drugs are used in the treatment of schizophrenia, organic psychosis, and the manic phase of manic-depressive illness. Such patients are often so disabled by the severity of their illness that they cannot give legal consent.

The nature of these disorders may cause toxic effects or lack of efficacy associated with the use of bioinequivaJent phenothiazine drug products to go unrecognized by physicians. The 1979 Final Task Force Report of the American College of Neuropsychopharmacology (ACNP) points out that "often any aberration in clinical symptoms is ascribed to the idiosyncracies of the patient and rarely ascribed to differences in drug products." It was the Task Force's opinion that bioavailability/bioequivalence and pharmacokinetics should be of major importance in the clinical use of psychotropics. This is due to the nature of the patient population, the need for chronic use of such drugs, and the extensive metabolism of psychotropic agents.

Clearly, one should give careful consideration to whether a patient, particularly an elderly patient, should be "switched" from one product to another and, even from one generic to another. Elderly females, in particular, are much more at risk to the side effects of phenothiazines, a danger that could be increased when a stronger but still equivalent product is used.

A similar potential problem exists with loop diuretics, particularly furosemide. In this instance, the generic may differ from the innovator drug by as much as ±20%. A 40 mg tablet, therefore, may have the clinical effect of a 32 mg tablet or a 48 mg tablet. By itself, that range in potency may be unacceptable in certain elderly. However, when an elderly patient is also maintained on digoxin (one of the top nine drugs used for those 85 years and older, as are many diuretics) and lithium (for which the blood level is critical in the very old), careful consideration must be taken before substitution is chosen.

A Proposal

It is most difficult to collect clinically valid data on these potential problems. First, scientific proof demands that a patient previously maintained satisfactorily on the innovator furosemide and then switched, exhibit worsening of control. This worsening is easily ascribed to a worsening of the disease. Secondly, control must be re-established by counter-switching and finally, there must be rechallenge. This is obviously not going to take place. Clinical proof, as already outlined, is often difficult to obtain since loss of medical control and worsening of the disease state most often present in a similar manner.

A different system should be applied. This system would revolve around the recognition that there are critical patients, critical diseases, and critical drugs for which generic substitution should never be mandated. In consideration, these categories are:

1 . Critical Patients:

Those 75 years and older;

Females, living alone with multiple pathology and on multiple drug regimens.

2. Critical Diseases:

Those diseases that are hard to stabilize, and for which it has been shown that concurrent drug therapy can be a destabilizing factor. They are depression, asthma, CHF, diabetes, other cardiac problems, and the psychoses.

3. Critical Drugs:

In view of the wide range allowed for "equivalency," the antipsychotics and the loop diuretics would be the first drugs so designated.

10.3928/0098-9134-19850401-12

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