Jennifer S. Haas, MD, MSPH; Kathryn A. Phillips, PhD; Eric P. Gerstenberger, MS; Andrew C. Seger, PharmD
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Pharmacologie - HÃ´pital Dupuytren - Limoges - France
June 16, 2005
Are generic-drugs so cost-effective ?
We read with interest the paper of Haas et al on the benefits of substituting generic drugs for brand-name drugs. We agree with most of the authors' statements. However we would like to stress the following points:
The authors assume both the quality and the composition of generic and brand-name drugs are equivalent. From our pharmacovigilance experience in France and in Mauritania we do not think this could apply everywhere.
Â· Poor quality of generics could have obvious consequences when the chronic treatment of a serious condition such as epilepsy is at stake (1).
Â· Excipients found in generics but not in brand-name drugs such as macrogol, starch, indigotine, carmine indigo or povidone can induce cutaneous allergic reactions.
Â· The change in excipient content when shifting from a brand-name to a generic drug may modify and most of the time reduce bioavailability. With such substitutions, we observed : hyperglycemia with gliclazide, blood pressure increase with diltiazem and verapamil.
If a generic-linked adverse reaction occurs, hospitalisation may ensue, a correcting treatment may be needed, and a return towards the brand-name drug is often the only way to continue the treatment safely. All these situations might induce an extra cost.
Two other costly situations should be mentioned :
- Some pharmacists would at times mistakenly substitute an immediate release generic for a slow-release brand-name drug. We experienced such a case with mebeverine which induced a vascular collapse.
- In the elderly specially, compliance which is usually poor is depressed by every impeding factor and in particular by any change in the drug they were used to. Substitution might be poorly understood which could lead to overlapping of generic and brand-name drugs and so to toxicity, or to interruption of the treatment (2).
All these changes which could potentially induce adverse effects generate costs up to now widely unevaluated. So the benefit drawn from generic-drug use although indisputable might be lower than is usually considered.
1. Laroche ML, Traore H, Merle L, Gaulier JM, Viana M, Preux PM. Quality of phenobarbital solid-dosage forms in the urban community of Nouakchott (Mauritania). Epilepsia 2005; 46 (8): 1-4.
2. Merle L, Laroche ML, Dantoine T, Charmes JP. Predicting and preventing adverse drug reactions in the very old. Drugs Aging 2005; 22: 375-92.
Jennifer S. Haas
Brigham and Women's Hospital, Harvard Medical School, Boston, MA
July 19, 2005
In response to Dr. Laroche
Dr. Laroche raises several issues about the potential risks of switching to a generic formulation. We agree that a generic drug may have different inactive ingredients, such as coloring agents, than the branded product. Uncommonly, an inactive ingredient may cause an allergic reaction. This is true for brand name drugs as well generics. In reviewing the literature, we found only a handful of case reports about allergic reactions to inactive ingredients, most commonly coloring agents.
In the United States, generic formulations are examined and approved by the Food and Drug Administration (FDA) as being bioequivalent to a brand-name drug in safety, strength, and quality [1, 2]. We cannot speak to the generalizability of our findings to other countries, which likely have different utilization patterns of both brand name and generic products.
We agree that errors in drug dispensing are common and costly , but we know of no literature that suggests that they are more commonly associated with generic products. We believe that health care professionals, including physicians and pharmacists, should inform all patients about generic substitution to avoid interruptions in treatment or over-use and monitor patients with chronic conditions. We do not believe that these issues would result in substantial change in the potential savings in drug expenditures associated with widespread generic substitution in the United States.
1. Nightingale SL. From the Food and Drug Administration. JAMA. 1998;279(9):645. 2. (National Institute for Health Care Management Foundation). A Primer: Generic Drugs, Patents and the Pharmaceutical Marketplace. 2002. 3. Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med. 2003;348(16):1556-64.
Joshua D. Safer
Boston University School of Medicine, Boston, MA
July 21, 2005
Substituting Brand Name Levothyroxine Preparations with Generics Would Increase Treatment Costs
Haas, et al. (1) make a provocative point about potential financial savings with broader prescribing of generic pharmaceuticals. However, a blanket policy of generic prescribing would result in increased costs when dealing with agents with narrow therapeutic indexes such as levothyroxine.
Haas, et al. calculate that the annual savings from preferential use of generic levothyroxine in the United States would be 10 million dollars. This represents less than 1/10 of 1% of the total savings achieved with generic substitution of non-narrow therapeutic index drugs where therapeutic monitoring after substitution is unlikely to be a concern.
Haas et al. fail to consider the increased costs associated with re- evaluating and re-titrating the tightly dosed levothyroxine patients as recommended by the Endocrine Society, American Thyroid Association and American Association of Clinical Endocrinologists . Despite recent efforts, thyroid hormone preparations from different manufacturers are not interchangeable. Differences in bioavailability of up to 12.5% have been documented between preparations designated therapeutically equivalent (2). In a retrospective study of well controlled thyroid hormone replacement patients changed from one product to another, more than 25% of the patients required a new dose of levothyroxine with the new manufacture's version of the product (2).
There are 89.7 million levothyroxine prescriptions written annually, representing approximately 7 million patients (3). If each patient received a product change only once annually and 25% required dose changes, at least 1.9 million patients would be inappropriately treated until the next medical exam. At the next exam, the 1.9 million patients would require dose changes followed by blood testing to confirm the appropriateness of the new dose and then repeat interactions with the prescribing physicians for clinical review.
At Boston Medical Center, the additional retail charge for this process would be $562 per patient. If the actual reimbursement is estimated to be 60% of the retail charge, the total annual cost of the additional titration would come to 640 million dollars. The cost does not take into account harm that may befall patients until their inappropriate doses are discovered (e.g. the hospitalization of vulnerable cardiac patients whose doses become too high).
Although there may be savings achieved with greater use of generic pharmaceuticals in many instances, there must be a separate plan for pharmaceuticals with narrow therapeutic ranges, like levothyroxine. Were the logic of Haas et al applied, the impact on thyroid hormone replacement would be to increase costs significantly.
1. Haas JS, Phillips KA, Gerstenberger EP, Seger AC. Annals of Internal Medicine. 2005;142:891-897.
2. Public Meeting for Levothyroxine Sodium Therapeutic Equivalence, May 23, 2005, Washington, DC. Available at http://www.fda.gov/cder/meeting/ levothyroxinePresentations.htm.
3. IMS National Prescription Audit, March, 2005. Available at http:// www.asapnet.org/Long_ASAPJune05.ppt.
MORTON H. FIELD
July 22, 2005
To The Editor,
The article by Haas, et al1 begins an interesting dialogue concerning the pharmaceutical industry in the U.S. As salutary and informative as their article is, they have omitted an important cost aspect of drugs in this country"”the effect of counterfeit drugs on health expenditures.
Estimates of counterfeit drugs in the U.S. suggest that 7% of all drugs consumed are not as labeled. This is true of all drug sources and outlets"”Internet, retail pharmacies and mail order houses. "Counterfeit" includes repackaged drugs with incorrect contents by virtue of dishonest repackaging, substituting an incorrect drug, a correct drug with a dosage different from that stated, and out-dated drugs repackaged with different expiration dates.
I have encountered substitutions that resulted in significant and dangerous changes in patient stability with thyroid, diabetic and cardiac drugs. These substitutions force me to monitor much more closely the drug effects in a patient using generics. This monitoring requires frequent blood level checks and assessment of the drug's effectiveness. Occasionally a hospitalization results from drug "failure" often blamed on patient "non-compliance". Faulty accusations can result in a serious breach in physician-patient trust if a counterfeit drug problem is not suspected.
The occurrence of "counterfeit drugs" can be traced, in part, to the FDA's refusal to require "provenance" in the "paper trail" of pharmaceuticals from manufacture to dispensing.
In my experience these costs are a factor of 10 to 100 times the purported savings of $45.00 ($78.00 Medicare ) per patient per year.
Morton H. Field, MD, FACP
1 Haas, Phillips, Gerstenberger and Seger. Potential Savings from Substituting Generic Drugs for Brand Name Drugs. Annals of Internal Medicine, 2005:142: 891-897
Haas JS, Phillips KA, Gerstenberger EP, Seger AC. Potential Savings from Substituting Generic Drugs for Brand-Name Drugs: Medical Expenditure Panel Survey, 1997–2000. Ann Intern Med. 2005;142:891-897. doi: 10.7326/0003-4819-142-11-200506070-00006
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Published: Ann Intern Med. 2005;142(11):891-897.
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