a pharmacist at work behind the counter of a pharmacy, mistake, atenolol shortage, ethical question

Most (but not all) pharmacists routinely tell patients that generic drugs are identical to brand name medications. That is hardly surprising. This is what pharmacy students are told during their education process. It is also what the FDA states on its website:

“A generic drug is identical–or bioequivalent–to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Although generic drugs are chemically identical to their branded counterparts, they are typically sold at substantial discounts from the branded price.”

What Does “Identical” Really Mean?

Now we don’t know about you, but when we see the word identical we assume that means exactly the same as. Here is how Dictionary.com defines the word identical:

1. Similar or alike in every way
2. being the very same
3. agreeing exactly

Related Words for: identical
Indistinguishable, one and the same, selfsame

Medical Dictionary
1. Exactly equal and alike
2. Of or relating to a twin or twins developed from the same fertilized ovum and having the same genetic makeup and closely similar appearance; monozygotic.

In our opinion, the FDA’s use of the word identical, when describing generic drugs, is misleading. First, the inactive ingredients (colors, binders, fillers, etc) do not have to be “alike in every way” to the brand name product. In fact, they are often quite different. These so-called inactive ingredients or “excipients” may influence how the product affects patients. For example, a patient who is allergic to a particular color may develop a rash when switched to a generic product.

Different Formulations Between Brand and Generic Drugs:

The formulation may also differ dramatically from the brand name. Many pharmacists may be unaware that the physical characteristics or release properties of a brand name drug often stay under patent even after the active ingredient becomes available generically. This is especially problematic for slow-release or long-acting medications. Generic manufacturers may have to come up with different technologies to deliver the active ingredients. This means that the products are not always “indistinguishable or one and the same.”

To see this for yourself, visit the FDA’s website and report on the antidepressant bupropion XL.

If you look at the graph the FDA provides for Budeprion XL 150 you will discover that the mean plasma concentration of the two drugs is certainly NOT identical! The generic formulation (which uses a matrix technology to release the active ingredients) produced peak blood levels in 1.5 to 2.5 hours, whereas the brand name product (using a membrane technology) produced peak blood levels around 5 hours. This kind of information for other generic formulations is not always easy to access.

What Does “Bioequivalent” Mean to the FDA?

Pharmacists have been taught that generic drugs must be bioequivalent to brand name medicines. The FDA defines that as “an equal rate and extent of drug absorbed [from] the bloodstream.” We’re back to the meaning of the word “equal” or “identical.” The FDA’s understanding of these words is quite different from most other people.

Many pharmacists do not know how the FDA actually goes about approving generic drugs. For one thing, the FDA never releases the bioequivalence curves to health professionals or the public. We have already pointed out above that the rate of absorption for a drug like Budeprion XL 150 can be quite different from the brand name Wellbutrin XL 150.

The FDA relies primarily on two measurements to determine rate and extent of drug absorption. One is the maximum concentration of drug in the bloodstream (Cmax). This occurs at one point in time over 24 to 48 hours. The other is called the area under the curve (AUC) and it represents the total amount of drug absorbed over the length of the trial (usually a day or two). If these two numbers (Cmax and AUC) are “close enough,” the FDA says the drugs are bioequivalent and the generic gets a green light.

The Problem with the FDA’s Generic Drug Approval System:

Here’s the big mistake with this approach. It does not actually compare hour-by-hour rate of absorption. Let us share an analogy. Imagine two seemingly identical 2016 Honda Civics. The difference, not detectable to the naked eye, is the engine size. One has a 158 horsepower engine (Car A). The other has a special 385 horsepower engine (Car B). The cars must travel from Washington DC to New York City. They will be judged by two metrics to determine if they are “identical” cars. The first will be the time it takes them to reach NYC. The second will be how far they traveled in actual miles (a substitute for AUC).

Both cars leave DC at 2 am and both arrive in NYC at 6 am (four hours total driving time). Their average speed is the same, ie, 63 mph. They traveled the same number of miles. But there is a tremendous difference in how they got there. Car A with the small engine drove straight to NYC, never exceeding the speed limit. Car B with the 385 HP engine went at 120 miles per hour for two hours (it had a fancy radar detector to avoid speed traps). Then car B stopped for a leisurely breakfast for 45 minutes and resumed the trip at a more modest 95 mph. Again, both cars covered the same distance and achieved the same average speed over the four-hour trip (63 mph).

Clearly the two cars traveled the distance very differently. The cars were not identical! But without seeing the data from speedometer you would never know that one traveled the speed limit and the other hit 120 mph for long periods of time. The same thing is true for generic medications. By not allowing health professionals or patients to see the actual bioeqivalence curves we cannot see the true rate of absorption on an hour-by-hour basis. This may be especially problematic for long-acting, timed-release formulations. Tis time for the FDA to allow the American public to see the data for themselves. “Trust by verify!”

Manufacturing Quality of Imported Generic Drugs Remains Worrisome:

Here is something else a pharmacist might not realize. According to the FDA, 80 percent of the active and inactive ingredients in our pharmaceuticals come from abroad. It is estimated that 40 percent of the finished pills come from abroad including countries such as India, China, Brazil and Mexico. It is also very clear that the FDA does not have the resources to inspect all or even many of the manufacturing plants producing either the raw materials or finished products millions of Americans take every day. That means that there is no verification system that the pills are exactly what they say they are.

We have seen manufacturing problems with some of the most prestigious drug companies in the U.S. (Johnson & Johnson and GSK). These problems occurred at plants where the FDA visits on a regular basis. Do we really believe that chemical companies in China that are not inspected are producing perfectly identical generic drugs at cutthroat prices?

Perhaps it is time for pharmacists to acknowledge that there are no guarantees when it comes to generic drugs. Pharmacists must be the patients’ allies and advocates. When patients experience problems with certain generic formulations, pharmacists should offer a sympathetic ear and report the problems directly to the FDA’s website (MedWatch). Perhaps if pharmacists insisted that the FDA do a better job both approving and monitoring generic drugs, patients would have more confidence in these money-saving pills. Pharmacists should also insist that the FDA make all generic bioequivalence curves available for public scrutiny. Without that data they have no way of verifying that the products they are selling are indeed “identical.”

Learn much more about generic drug problems and mistakes that health professionals make in our book, Top Screwups. You will be amazed out how serious the problems really are. But there are many things that patients and their families can do to prevent health care harm.

Revised: June 8, 2016

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  1. Linda J.
    Arlington, Texas

    Thank you for all information on generic drugs..this analysis of the differences of one generic vs. Another, makes me know I am not crazy. I had taken Atenelol made by Mylan for 7 yrs. With no problems. Recently my prescription of Atenelol caused severe stomach cramps, nausea continually, severe bloating and belching. This Atenelol was manufactured by Teva. Now thank you, I know how to be proactive with the Pharmacists who say Generics are just the same..no they are Not!!

  2. Wendy

    I was on brand medication for years and now my insurance won’t cover it and I am so sick oh hearing pharmacist saying the generic is exactly the same! I went to the generic and stayed on it for 6 months. I gained 30lbs and feel like I am not on anything and I have other side effects and am going off the generic. I have reported this to the FDA but I know it will be dismissed. These generics are NOT the same and it’s all about MONEY. Until someone of importance stands up and gets the FDA to tell the truth and help patients it will never change! All these drugs come from foreign countries and who knows what is really in them. Very disappointed in the way healthcare has caused this to happen

  3. Mary

    Try being an epileptic and being dependent on name-brand Depakote. The first kind of generic I took made my legs shake something freaky; the second time it was given to me I ended up in the hospital for a week following a bad seizure.

    You would be nuts to not take it if it’s possible. Depakote is exhorbitant. I’ve been in debt paying for it all my life. But it’s more expensive to go back in the hospital because I don’t want to pay for the name-brand.

    Almost nobody in my town carries the drug. The drug store that should had been told to order name brand didn’t bother; just filled the generic. Like it wouldn’t matter. The doctor called a second time without success; this went on until I ran out today. I have spent two days finding a store that carried name-brand Depakote. Why, oh why, can’t any major drug store at least keep 6 or 10 name brand pills around? I know I am not alone with this problem. Depakote isn’t like aspirin. You’ve got to have the real thing.

  4. Robert
    Rhode Island

    Recently my blood pressure medication was changed from Benecar to a generics. Two generics were given one month apart. The first generic I did notice slight differences, next month I got a generic from Walmart, Wow, I developed a number of reactions. These varied from continuous vertigo to extreme fatigue and rapid weight gain just to name a few. I was also having trouble breathing. I am 74 years old and still very active and athletic bike riding, hiking and being outdoors. This drug changed my life and degraded the quality of my life.

  5. Annette

    Whenever I take a generic drug, within a day or two, I break out in terrible hives and swelling. This has happened even when I mistakenly took a generic believing it to be brand, so it is not something in my mind as many have indicated. My problem is that no pharmacy in Florida carries brand name antibiotics and they have indicated that they cannot even order them. I am left unable to take any antibiotics. I recently had a dental issue and the dentist assured me that penicillin was a “brand” name. I took the pills for two days and I developed hives and terrible swelling. When my dentist saw this, she told me to immediately stop taking it. I have paid huge co-pays to get brand names and have had to fight with every doctor and every pharmacy to get them to believe that I cannot tolerate the fillers used in generics. It is bad enough that on top of huge health insurance premiums that I have had to incur thousands of dollars to get brand name, but now I cannot even get brand names at all.

  6. Alan

    A delay of the time to peak does not necessarily reflect an alteration in efficacy in a maintenance medication. The peak plasma concentration is important primarily for the dose-dependent side-effects. Hence, the reason we look at the Cmax and not so much the Tmax. We are primarily interested in equilibrium plasma levels remaining within the therapeutic range.

    Given that Wellbutrin XL is a 24 hour formulation, the Tmax is much less important than with an IR product (where the drug is immediately available for absorption via Fickian diffision after quick dissolution). In fact, this is one of the main benefits of extended release formulations (reduced dose-dependent side-effects) along with reduced dosing frequency which improves adherence. 1.5 vs 5 hours seems huge but it is not clinically significant in this case. Again, this is because efficacy is not reflected in the Tmax with this medication. Efficacy is reflected in the equilibrium plasma curve remaining within the therapeutic range.

    I will concede that Tmax is more important in acute medications taken as needed and in medications with a very narrow therapeutic index. If a patient suffers from severe anxiety and/or panic attacks, they will often be given alprazolam (Xanax) because of its rapid absorption. In this case, the Tmax may be far more important because time is of the essence in treating such issues.

    Additionally, there is reason to be concerned with medications that have a narrow therapeutic index such as warfarin, levothyroxine and phenytoin. Slight alterations in warfarin absorption can alter the INR very quickly and phenytoin has kinetics in which the peak concentration can run out of control very quickly. Thus, in cases of narrow therapeutic index, it is common practice not to switch between manufacturers unless absolutely necessary or if requested by the patient with their full knowledge of the potential issues. Where I live, a pharmacist may freely switch between manufacturers of these drugs but I personally do not switch manufacturers.

    Additionally, your car analogy doesn’t really work. A matrix or membrane formulation will not simply speed up and slow down in the way a car can. Instead, in an aqueous environment of relatively stable pH (as the body is), it will be released at a fairly predictable rate and will be absorbed in the small intestines at an even more predictable rate (within a single individual).

  7. Sam

    I agree generics are not the same as brand. I’m a very healthy person. I had to take an antibiotic after dental surgery and I was given the generic form unknowingly. I had a horrible painful reaction to my kidneys. I was then given the brand, and I was fine without discomfort. A few years later I needed to take the same antibiotic again. I was given the generic. I told the pharmacist I could not take it because the last time it hurt my kidneys. The pharmacist argued how generic and brand are the same, and my insurance won’t pay for brand. I tried the generic again and immediately my kidneys were hurting. My doctor had to fax an explanation to the insurance company as to why I could not have that form of generic, and I had to have the brand. If I had to use that antibiotic, it was a fight every time, or out of my pocket a couple hundred dollars. I have top insurance and I still go though loops, they still want to pay only for generic, not brand.

  8. Peggy

    Until the “identical” Generic drugs are all made in the good old USA, I will not take any of them. Reading about all the side effects of all medicine, I will do without the Brand names as long as possible. I was brought up on home cooked food, vegetables and fruit and very little processed foods. Consequently, I still eat that way and at 75 years old and am doing very well.

  9. Judy

    Shouldn’t these types of articles be put on all national news networks and papers, so everybody can see how the FDA is either uninformed or just does not care?

  10. Tom

    80% of BCBS policies as of 2016 (at least in Texas) have inserted “member pays the difference” feature in their pharma benefits. If there is a generic and you want/need the brand, insurance pays close to zero. A 50mg Topamax tab will run you about 10 bucks or about $300/month.

    As, has been mentioned on this site previously, some meds do have an authorized generic which usually has the exact same active and inactive ingredients as the brand due to partnership with the brand manufacturer. FDA just updated that list. If you see your med on there, tell your pharmacy to fill it with that maker. They may have to order or say they don’t have access due to their wholesaler. Just call another pharmacy or three. Do it all the time.

    As to the India etal., manufacturing issues. You can look up where your drug is being made and tell your pharmacy no India or Ranbaxy etc. You need the “other one” made in the USA. There’s usually like four or five choices depending on med.

    Also, sometimes you can find the brand in Canada, but there again check where it’s being made.

  11. C
    Greensboro, NC

    Many generics work, but some don’t. Synthroid is one that doesn’t work for me. Some others as well don’t work as well. I certainly don’t want drugs manufactured in other countries.

  12. Jeri

    My husband is taking multiple drugs prescribed by his internist and also his cardiologist and his urologist. Prescriptions are filled by a company that provides a 90-day supply as required by our medical insurance provider.
    My concern, which I have voiced to the provider, is that on several occasions, another generic is sent in place of the previous GENERIC received. This can be very confusing to the patient, usually elderly, and perhaps a lesser quality drug is provided. I, too, am concerned about the labs where these drugs are manufactured and prefer those made in the USA. When allowed, we pay the difference to get them but it is not always approved.

  13. Anne

    A number of folks have commented on adverse reactions due to generic drug switching. Here are some things that you can do as a patient that will help your pharmacist to help you:

    1. Have the prescriber write the script as DAW (dispense as written) for the specific generic brand that works best for the patient. WHY? Many (if not all) state pharmacy boards prohibit pharmacy changes to DAW scripts, and are required to fill them as written.

    2. If you have a reaction to a specific generic brand, make sure that the pharmacist documents that generic brand and drug as “Contraindicated” in your profile.

    3. Do the same at the prescribers’ office.

  14. Mark

    I think you are being a bit conservative on English definitions. Go back to a college of pharmacy & relearn something. Only narrow therapeutic index drugs can objectively have a difference in therapeutic outcome when it comes to generic vs. Brand.

    Besides, there isn’t enough room in most pharmacies to shelf BRANDS, many of which of no longer manufactured, again, because there is no incentive when competing with generics. Yes, excipients can be different but is not significant enough to affect plasma drug concentration. Enough with the BS conspiracy & overpaying for BRAND meds

  15. thomas

    After Reading much online, and talking with two older pharmacists, one retired after years in the business, and my own experiences, generics are not the same. Bulk orders from large chains usually shop the best price and there is no AA ratings in the FDA orange book on one in particular I looked up, showing there have been reported problems, although rectified at some popint. Without more FDA guidelines, percentage variances 20% high /low on main ingrediants, and with questions on fillers used having an effect, no, generics are not all equal.

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