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Thursday, April 18, 2013

Are generic drugs bioequivalent and interchangeable?

Use of generic drugs has the potential to reduce annual consumer spending on prescriptions by billions. A study published in the New England Journal of Medicine and discussed in the New York Times Economix blog in 2012 looked at Medicare Part D expenditures and correlated them with drug prescribing patterns. The regions of the United States with the highest Medicare expenditures were those where more name brand drugs were prescribed. But, are generic drugs as safe and effective as name brand drugs?

Generic medications become available after brand name drugs go off patent (usually 10 to 14 years after coming to market). The pharmaceutical industry maintains that the high cost of brand name drugs relates to the research and development required to innovate and bring new products to market. Advertising and promotion are also, no doubt, a major factor.

A generic drug is a drug that has been determined to be the bioequivalent of a brand name drug in terms of its active ingredient. Standards for proving bioequivalence are defined by the FDA and are similar to standards used in Canada, Japan and Europe. Here's what the FDA website says about bioequivalence: "One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption-or bioavailability-of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug."

The following graph illustrates the bioavailability of two drugs, Drug A and Drug B. The statistics may be difficult to understand, but to be determined bioequivalent the 90% confidence interval of the ratios of the mean bioavailability, or "area under the curve" (AUC), of the two drugs and their peak concentrations (Cmax) must be in the ranges of 80% to 125%. In more concrete terms, analyses of numerous studies of bioequivalence have shown that differences in blood concentrations of the active ingredients of branded versus generic drugs are generally less than 4%.


Once a generic drug is deemed to be bioequivalent by these statistical standards it is not required to go through the same extensive clinical safety and efficacy trials, as a newly innovated brand name drug applying for its initial patent.

What are some pitfalls of using generics? The inactive ingredients in generics compared with branded drugs are not required to be the same. Therefore allergies to these fillers and inactive compounds can be an issue. Also, special consideration should be taken when changing from a branded drug to a generic drug, or when changing between generics, if the drug has a narrow therapeutic index. Some drugs with narrow therapeutic indices include thyroid medications, anti-epileptics and warfarin.

Here are some examples of issues that come up with generics.

The adhesive contained in a fentanyl transdermal patch differs depending on whether the patch is generic or brand name. Some of my patients have developed allergies to the adhesive in the brand name patch (as opposed to the generic,) others complain that the generics don't stick as well.

Along the lines of narrow therapeutic index, I can recall two separate instances in which a patient was changed to a new warfarin generic drug product. In each case the patient's PT and INR (coagulation test) had been stable for months, but after the change their levels of anti-coagulation became too high. This took some detailed history-taking to figure out. One review of the literature suggested that generic warfarin and Coumadin products are equally effective and safe and uphold the FDA's criteria for bioequivalence, yet the authors still suggested that patients limit switches amongst warfarin products and brand and monitor anti-coagulation after making changes.

If a product is deemed bioequivalent then it is also deemed "interchangeable" and pharmacists are not required to inform physicians when they change a patient from brand to generic, or when they change from one generic to another.

Another patient, who reports a high level of drug sensitivity, noticed that a particular generic of nortriptyline used for chronic insomnia was more effective for him than others.

Thyroid medication is known to vary amongst the generics and Synthroid brand in terms of clinical effects. While the FDA has deemed these various products to be bioequivalent and interchangeable many endocrinologists disagree. In attempt to address this issue in 2004 a Joint Statement was issued by the major endocrinology professional societies making recommendations on the topic.

The most recent controversy regarding generics has to do with biological drugs, or "biologics." Because of the inherent complexity of these innovator drugs, which are derived from living cells, the concept of "biosimilar" has replaced bioequivalent for the generic products being developed. As reported last week in the New York Times, the pharmaceutical industry is currently engaged intense lobbying to prevent biosimilar generic biologics from coming to market as competition to the numerous, ultra-expensive biologics whose patents will be expiring in the near future.

The science behind the FDA approval process for generic drugs is rigorous. My advice, it can be smart to try a generic. There is no evidence that these products are of lower quality, or less effective than name brand products—though they are not required to go through clinical efficacy trials. However, be wary of minor fluctuations in the clinical effects of your medications when switching between name brand and generic, and amongst different generics, and be aware that your pharmacist may change your generic from one manufacturer to another without your knowledge (the pill should look different).

What is your experience with generic medications versus name brand products?

Juliet K. Mavromatis, MD, FACP, is a primary care physician in Atlanta, Ga. Previous to her primary care practice, she served on the general internal medicine faculty of Emory University, where she practiced clinical medicine and taught internal medicine residents for 12 years, and led initiatives to improve the quality of care for patients with diabetes. This work fostered an interest in innovative models of primary care delivery. Her blog, DrDialogue, acts as a conversation about health topics for patients and health professionals. This post originally appeared there.

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Blog log

Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Auscultation
Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Richmond, Va., with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

DrDialogue
Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

FutureDocs
Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

KevinMD
Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

Prescriptions
David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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