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Are Generic Drugs as Effective as Brand Name? - Not Always!

A number of patients with a history of good results on brand name antibiotics began experiencing difficulties when a generic was substituted. Therefore, if you have prescribed a brand name tetracycline for a patient using antibiotic therapy and have not specified d.a.w. or no substitutions, your patient is probably taking a generic version and may be having a less than significant response to the treatment. Some generic versions have been found to be ineffective for this treatment.

In order to market drugs, U.S. generic manufacturers must have a permit and approval from the Food and Drug Administration (FDA) indicating that the active ingredient is approximately the same as that of the brand name. The determination of drug approval is made according to whether it is pharmaceutically equivalent, bio-available, and bioequivalent.

Pharmaceutically Equivalent

Two drugs are considered pharmaceutical equivalents when they contain the same chemically active ingredient(s) and are identical in dosage form and strength. Tetracyclines such as minocycline are complex with many properties that may play an important part in treatment response in the arthritic patient. The fact that patients in remission (sometimes for years) while on antibiotic therapy saw a gradual return of symptoms when switched to a generic alerted us to a potential problem with some generics. In three test patients, these symptoms began to reverse immediately upon a return to the brand name version of the drug.

Pharmaceutical equivalence may be affected by many things.

1) variations in inert ingredients

2) plants in different parts of the world

may produce ingredients that vary in quality, and by batch and manufacturing methods. Until recently, 80% of drug ingredients came from plants in Western Europe. According to a NY Times article April 11, 1996, that is changing. Many ingredients are now being used from plants in China, Japan, South Korea, India and Eastern Europe where they are produced more cheaply. Bob Milanese, president of the National Association of Pharmaceutical Manufacturers, indicates that only a handful of these plants meet FDA standards. "Some others are questionable" due to the difficulty in finding people and budget to "get over and inspect these plants." Another factor which affects generic quality cited by the same article is the international buy outs and diversification allowing the combination of questionable ingredients into generic production.

3) In oral drugs, capsule content may be 7% over or 7% under the stated content, e.g. a 100 mg. capsule may be as low as 93 mg. or as high as 107 mg.

4) Manufacturers may shift their source of supply.

5) Once a drug has been approved by the FDA, manufacturers sometimes make changes to the formula which was originally submitted.

6) Many arthritic patients are elderly. The age of the patient may be a factor in pharmacokinetics. Digestive tract absorption of an oral drug may be altered by a variety of factors, including higher gastric pH, accelerated gastric emptying, and thinning and reduction of the absorptive surface. Bioavailability may be influenced by the increase (or decrease) in percent of body fat which is common in some with age. It may be even higher in sedentary persons (or persons in pain who are inactive in order to minimize discomfort.) This increased fat to lean ratio results in a reservoir for lipid-soluble drugs which is larger allowing those drugs to stay in the body longer, increasing the possibility of drug sensitivity by prolonging the half-life. Conversely, total water content declines with age. This decline allows a decreased volume of distribution for water-soluble drugs.

In addition to general approval, the FDA rates drugs with codes. All drugs with an "A" code are rated as being therapeutically equivalent; "B" coded drugs are those not rated equivalent Some pharmacies fill with B-rated drugs. At this time, it is recommended that no patient use a version of a drug with a B-rating. Clinical differences or serious bioequivalence problems with B-rated products have been reported for drugs such as prednisone, estrogen tablets, levodopa and phenytoin. In addition to The Orange Book, The Physician's Generix lists available generics as therapeutically equivalent or non-equivalent. Because the antibiotic protocol uses such low doses, leeway between versions which are effective and those which are not may be much more critical.

Bioavailability

In bioavailability, it can be assumed that the drug's effectiveness is related to the amount of product absorbed and the speed of absorption. However, in some cases, the pharmaceutically equivalent products can have different bioavailability. They may be absorbed either faster or slower than the brand name drug which may or may not be clinically significant.

The pH-dissolution profile of a product may have clinical relevance. Even if the coating is adequate to prevent release of the enzymes in the stomach where the ingredients are irreversibly inactivated, it may not dissolve at the pH of the duodenum after meals.

Bioequivalence

In bioequivalence studies, the goal of testing is to determine if the drugs are functionally equivalent. The FDA requires that any approved drug be effective within a 20% range of the original patented or brand name drug. This means that the effectiveness may be 20% greater or 20% less effective than the brand name so that two generic drugs could contain as much as a 40% difference from each other. Therefore, a drug may be legally chemically equivalent but not at the same time clinically equivalent. A study run on a generic of the anti-seizure, Tegretol, found the generic allowed breakthrough seizures.

An example of how the above factors may affect the bioavailability and clinical effectiveness is seen by applying these factors to tetracycline. At one extreme, a 500 mg. dose of tetracycline taken in 2-250 mg. capsules which is 20% lower in effectiveness, 7% low in the mg. amount in each capsule (14% dose total) and which is taken with food, decreasing the absorption rate (<50%), could provide as low as 136 mg of tetracycline that is available to the body. Correspondingly, the same 2-250 mg. capsules making a total dose of 500 mg. which is 20% more effective, 7% over on mg. in capsule and taken without food (increasing the absorption rate to 77%), provides 555 mg that is functionally available to the system. It should be noted the food-drug interaction is less a factor with minocycline and doxycycline as they are absorbed differently.

In addition to the ±20% difference allowed in bioavailability by the FDA and the ±7% of the stated capsule content allowed by the U.S. Pharmacopoeia, there are other considerations which should be considered when using a generic drug.

1) Some drugs lose potency while on the shelf, so drug companies increase the strength so as the drug ages, it will still provide a therapeutic level. This means patients who use the drug soon after production when the dose may be stronger may be getting an overdose.

2) There is a risk that a generic substitution could result in a change in serum concentration

3) Such a change may lead to signifi-cant adverse effects or loss of benefit

4) The risk that patients may receive different generics each time they fill their prescription, changing the response to the drug.

5) Cost of brand names is usually, but not always, higher than for a generic.

6) Blood tests can become necessary to determine adequate concentrations, excessive, possibly toxic concentrations or low, possibly ineffective concentra-tions

7) The cost of the time and effort spent in adjusting the dose (if needed)

Bioequivalence may be effected by the type of study; e.g. two brand name pharmaceutical equivalents were each compared with a placebo in separate trials but were not compared with each other for bioequivalence. Thus while each was effective, it cannot be assumed that they produce the same clinical effect. Bioequivalence studies are performed on healthy volunteers and thus may not account for the full pharmacologic and therapeutic impact of generic substitution on patients with disease.

Conclusion

A pharmacist may legally fill a prescription in the United States with either the brand name or a generic without consulting either the patient or the physician. A prescription may not even be filled consistently with the same generic. To assure continuity for the patient, the physician should indicate on the prescription no substitutions or dispense as written (daw).

The purpose of this article is not to condemn generic drugs for many are as effective as the brand name and even come from the same manufacturing company, but are repackaged and sold by another company as their own generic brand. Our purpose is, however, to provide a warning not to assume that all drugs with the same generic title are equal and will have the same clinical effect, even though many drug reps say they are equal. This is particularly true of the tetracycline family because it is one of the oldest families of antibiotics being first patented in 1953. Since a patent is good for 17 years, the original tetracycline has been available for generic reproduction for some 25 years.

References:

Brooke PA, Resistant Prices, A study of competitive strains in the antibiotic markets, 1976, Ballinger Pub.

Hendeles L, Hochhaus G, Kazerounian S, Generic and alternative brand-name pharmaceutical equivalents: Select with caution, Am J Hosp Pharm, 1993; 50:2, 323-329.

Medical Information Department, Lederle Labs, telephone conversations.

Mandell GL, Douglas RG, Jr., Bennett JE, Principals and Practice of Infectious Diseases, Wiley Medical Pub, 1985.

Mikati M, Bassett N, Schachter S, Double-blind randomized study comparing brand-name and generic phenytoin monotherapy, Epilepsia, 1992; 33:2, 359-364.

Oles KS, Penry JK, Smith LD, Anderson RL, Dean, JC, Riela AR, Therapeutic bioequivalency study of brand name versus generic carbamazepine, Neurology, 1992, 42:6, 1147-52.

Physician's Generix?, Data Pharmaceutica, 1996.

Reinstein PH, Regulatory status of pancreatic enzyme preparations, JAMA, 1990; 263:18, 2491-2492.

Stoughton RB, Are generic formulations equivalent to trade name topical glucocorticoids? Arch Derm, 1987; 123:9, 1312-1314.

Univ. of Chicago Drug Information, telephone conversation.

For insurance companies who will not cover brand name drugs when a generic is available, a blood test to determine concentration may be necessary for those using low dose antibiotics to provide data to require payment for the brand name drug.

To assure continuity for the patient, the physician should indicate on the prescription no substitutions or dispense as written (daw).