Psychopharmacology: Brand versus Generic

http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070124.pdf

Read and understand this and you'll have your answer. There is no PK difference between AB rated brands and generics. Plus the guidelines that dictate brand generic BE are exactly the same as those used to demonstrate formulation equivalence when a brand name manufacturer changes something in its formulation or manufacturing process.

What happened with Teva's wellbutrin generic is that they got lazy and asked the FDA is they could use the results from their 150mg dose BE study and extrapolate to the 300mg tablet. FDA said ok, whatever and in the end both got screwed when it turned out they were not BE. You can bet that that will never happen again for a sustained release product BE application

http://www.fda.gov/Drugs/DrugSafety...ormationforPatientsandProviders/ucm322161.htm
http://www.fda.gov/Drugs/DrugSafety...ormationforPatientsandProviders/ucm322160.htm
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm

No one is ever allergic to brand. No one ever says I have to have a generic because it works better than brand. No one is ever complaining about brand on those websites. Statistically speaking, someone should have a problem with branded meds and be begging for the generic to hit the market due to non-active ingredient related side effects. This is rarely the case. The points me to think the issue with generics is due to something other than pharmacokinetics (i.e. perceived effectiveness of meds).

It's not like generics are being made with 0 oversight and regulation. I've had patients tell me brand only X and the generic didn't work. The generic was made in the same building with the same ingredients just pressed into different shapes. The bupropion thing is an outlier.

Planes2Doc said:

I'm currently a medical student with a huge amount of interest in psychopharmacology. I've been debating brand versus generic medications with fellow students. Generally, people are inclined to say that there is no difference between brand and generic medications. Yes, generics must have the same amount of active ingredient, but the fillers can be different.

Based on patient experiences and what I've come across on internet message board, I see that patients can have extremely varying experiences with psychiatric generic versus brand medications.

This is especially prevalent among Bupropion XL users. Apparently the time release mechanisms differ among the drugs despite having the same amount of active ingredient. There are an insane amount of complaints you can read from a lot of people. When these patients who have severe issues with generics switch to brand Wellbutrin XL (Bupropion HCl) or Aplenzin (Bupropion HBr), it becomes like a night and day difference. The huge number of complaints, as well as Teva's former generic, Budeprion, getting pulled off the market shows that this is definitely not placebo.

Looking at ADHD message boards, it looks like patients (not abusers) have differing experiences with popular drugs, like amphetamines and methylphenidate. For example, in the case of instant release Focalin (dexmethylphenidate), there are many complaints about Teva's generic causing bad side effects. Patients prefer the Novartis brand medication and claim that Teva's technically gives Focalin a "bad name."

With these things in mind, what are your opinions as pharmacy students and hopefully current PharmDs? I couldn't think of a better place to ask this question.

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Patients are idiots. Look up the nocebo studies in patients with migraines. It will blow your mind. I've had patients tell me that the Greenstone brand sertraline made them sick versus the Pfizer brand. Turns out they are made in the same factory. It's a psychosomatic response. And too many uneducated practitioners and patients are falling into this idiocy. The wellbutrin thing was an outlier and an embarrassment to the FDA

Another study to look up... The Effect of an Apparent Change to a Branded or Generic Medication on Drug Effectiveness and Side Effects. Psychosom Med January 2013 75:90-96

The nocebo effect is an emerging study interest. Its about time. My uninfluential ass has been asking for research into the subject since forever.

The problem isn't the medications; it's all in the patients mind.

I had this problem with Protonix, both generic and brand come in the same shape, color, bottle shape, with the same inscription (Protonix40 now P40 for generic), and even matching barcodes. YET a patient told me it doesn't work as well.

Then again with lipitor, and many others I can't remember AND will continue indefinitely until the human race makes another jump in evolution.

To end your medical study, there is NO difference and to the FOOL who answered yes.. GO back to prepharmacy forums you troll.

amox said:

To end your medical study, there is NO difference and to the FOOL who answered yes.. GO back to prepharmacy forums you troll.

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That wasn't a "yes" - reread their post.

I believe there may be a difference, especially in older generics that were approved prior to the current testing requirements. Hell, generic pyridium can't even technically exist because the brand name was approved prior to the requirement that it be tested to have a baseline to which to compare generics.

That being said, the differences are almost never clinically significant (meaning 1-2 in a million of the people who "have issues" with generics have a physiological justification, rather than psychological). I flat out do not believe the patients who need brand name concerta because the (identical) generic "doesn't work". The people that I do believe are the ones who note unusual differences. I had a patient who told me generic elavil caused them to have bizzare dreams. Messing with neurotransmitters causing altered activity while in an unconscious state? I buy it. Must be different release characteristics relative to their dosing/sleeping schedule. If they told me it flat-out doesn't work, I'm less apt to think it's an actual difference.

There was a study from 2009 or so (which might have been posted already, I didn't check the links) where patients were given pain medication. Some got Tylenol, and some got Tylenol and were told it was a very expensive new analgesic. Apparently price factored heavily into effectiveness. When people perceive value for subjective measures, they get it.

Without objective measures, there's no real way of knowing. When you find patients who have DEXA scans backing up their claims that anti-osteopenia meds "don't work as well as the brand name" I'll start to put some faith into the "generics are garbage" theory...or just blame it on cortisol because of the unfounded stress they have about taking a generic.

amox said:

The problem isn't the medications; it's all in the patients mind.

I had this problem with Protonix, both generic and brand come in the same shape, color, bottle shape, with the same inscription (Protonix40 now P40 for generic), and even matching barcodes. YET a patient told me it doesn't work as well.

Then again with lipitor, and many others I can't remember AND will continue indefinitely until the human race makes another jump in evolution.

To end your medical study, there is NO difference and to the FOOL who answered yes.. GO back to prepharmacy forums you troll.

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Anecdotal, I know, but I had a patient swear I was putting generic atorvastatin (Lipitor) into the brand bottles.

The basic story is the patient was given atorvastatin and demanded that she only wanted Lipitor (since it's the only thing that works for her although I have no clue how you accurately quantify this with a cholesterol medication). This was at the time when they were identical pills made from the same company before other companies were able to make their own generic. After telling her they were the same pill, she demanded to see the bottle. Her 'proof' was the seal wasn't on our open stock bottle of brand medicine so we put the generic medication in there to fool her. Even after showing her various web images of the pills, she still would not believe us. I had to call around to various stores to find one that had an unopened brand bottle so she could finally convince herself.

That was indeed a fun day. Medications, brand or generic, are allowed a tolerance of a certain percent over or under, so realistically no two pills are exactly identical regardless of what you get. For people who are so convinced that brand is better I like to point out the lack of brand Tylenol or Benadryl due to bad manufacturing practices while there's plenty of generic available.

zelman said:

That wasn't a "yes" - reread their post.

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There was a yes, take a look at the poll results, not the posts.

Planes2Doc said:

Certain medications, like Adderall XR, if I'm not mistaken, are all made by Shire. The generics are just rebranded. But not every generic is obviously made by the original manufacturer. There's definitely complaints about certain instant release medications not being as effective, or causing side effects. I'm not sure it's all perception either.

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Where's the data (excluding the wellbutrin outlier)? I went to pharm school and now am in med school. I hate seeing my peers buy into this brand is better than generics bs. The point I was trying to make is that patients complain about the branded generic not working and it indicates nocebo effect rather than a pharmacokinetic issue. People complain. People are stupid. Both of these qualities intersect in this debate.

The thing is with psych drugs, the patients are already sensitive to changes. Placebo/nocebo makes a huge effect. You tell them their getting sertaline rather than Zoloft and the think it won't work because it's not the same. I think the psychiatric issues may play a role in this population not liking changes to generic. Even if the generics don't have the same pharmacokinetic profile, a good practicioner can monitor and adjust doses so that the patient doesn't have inadequate levels of the drug.

FlavyFlav said:

There was a yes, take a look at the poll results, not the posts.

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Oops. My bad.

Planes2Doc said:

In fact, this is why I think Sanofi Aventis went so far as to develop Aplenzin. Why re-invent the same medication that is already off-patent and still has a brand formulation by GSK?

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To cash in on a 450mg equivalent version.

Planes2Doc said:

Since it is considered a different drug all together, insurance companies have to cover it due to no generic being available.

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Since when? Last I checked, insurance companies can do whatever they want.

Planes2Doc said:

I guess Wellbutrin was a huge outlier, and it's probably not the best idea to assume that generics are automatically inferior. Nevertheless, the FDA should still investigate a drug when hundreds of complaints are coming in instead of blaming the issue of only being in "peoples' heads."

The magnitude of the FDA's mistake in the whole Wellbutrin issue has been enormous. There are massive complaints for all the generics, and it wasn't just for Teva's either. In fact, this is why I think Sanofi Aventis went so far as to develop Aplenzin. Why re-invent the same medication that is already off-patent and still has a brand formulation by GSK? Since it is considered a different drug all together, insurance companies have to cover it due to no generic being available. The FDA really screwed the pooch on this one.

Hopefully something like this will never happen again, since it ultimately ends up hurting countless people and hurts the reputation of physicians and pharmacists. Also as practitioners, it's important to listen to our patients. Sometimes there might be a difference, even though we're told that it shouldn't be so.

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Doryx, Solodyn, Colcrys, Aricept 23, new Vicodin, Xodol, Kadian, Avinza, Latisse, most of the topical acne meds, etc

They put out medicines already branded and in generic form just to make more money because the "new" brand medicine must work better. Yea, they have different official indications, but it's not like the generic can't be used for that. Drugs are used off patent all the time and usually this new indication is something that the drug has been used for for a while. It's because people insist on having brand name and companies profit off of it.

Btw, insurance companies don't have to do anything. You need to learn about prior authorizations. Some insurance companies won't cover this "new" stuff because there's cheaper branded medicine and if they do, they make the patient and prescriber jump through a lot of hoops to get it.

You gotta drop the bupropion outlier. It was a huge **** up, but it's the exception rather than the rule. That's like saying every doctor is crazy since one went around stitching his initials into people. It's not the case.

It's all in the patients' heads and please docs write generic or be prepared to do prior authorizations all day long. Make your lives easier, and ours too. Plus, Lord Obama is about to tell you guys how to practice medicine anyway, and patients having access to brands with their insurance covering it is not happening.

GamecockPharmD said:

Plus, Lord Obama is about to tell you guys how to practice medicine anyway,

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It's about time. Most doctors could use a bit of evidenced based medicine shoved down their gullets. At least the I won't have to listen to doctor tell me why a patient needs and ACEI, ARB, and clonidine to control their htn.

npage148 said:

It's about time. Most doctors could use a bit of evidenced based medicine shoved down their gullets. At least the I won't have to listen to doctor tell me why a patient needs and ACEI, ARB, and clonidine to control their htn.

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You forgot the Tekturna. Might as well nuke the **** out of that RAAS system. The clonidine is a nice added touch, particularly if the patient is elderly.

All4MyDaughter said:

You forgot the Tekturna. Might as well nuke the **** out of that RAAS system. The clonidine is a nice added touch, particularly if the patient is elderly.

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Does this really happen? Seriously?! Yikes.

radio frequency said:

Does this really happen? Seriously?! Yikes.

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No, they just add 50 of atenolol

Obviously there is a difference (sometimes) in their shape/color/formulation, but there is no difference in how well they work. There just isn't.

Still, the placebo effect is huge, so if someone believes the name brand works better, it probably is going to work better for them--but that is from the placebo effect, not because the brand actually works better.

What I don't get is, why don't all insurance companies charge something like a $75.00 co-pay for brand name drugs that have a generic available? That would help people get over the placebo effect pretty quick (it's amazing how a patient who just swore up and down that they are "allergic" to the generic, and that it "doesn't work".....will suddenly decide that they can try it again, when they realize their new insurance is going to charge them $35.00 for the brand vs $5.00 for the generic.

But if the pt's insurance covers the brand, and they want to have it, oh well. I've learned its a waste of breath trying to explain to them that there isn't a difference.

BidingMyTime said:

Obviously there is a difference (sometimes) in their shape/color/formulation, but there is no difference in how well they work. There just isn't.

Still, the placebo effect is huge, so if someone believes the name brand works better, it probably is going to work better for them--but that is from the placebo effect, not because the brand actually works better.

What I don't get is, why don't all insurance companies charge something like a $75.00 co-pay for brand name drugs that have a generic available? That would help people get over the placebo effect pretty quick (it's amazing how a patient who just swore up and down that they are "allergic" to the generic, and that it "doesn't work".....will suddenly decide that they can try it again, when they realize their new insurance is going to charge them $35.00 for the brand vs $5.00 for the generic.

But if the pt's insurance covers the brand, and they want to have it, oh well. I've learned its a waste of breath trying to explain to them that there isn't a difference.

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I'd rather they just charged the generic copay plus the cost difference. Let the free market work its magic.

There are too many uneducated providers out there.

npage148 said:

It's about time. Most doctors could use a bit of evidenced based medicine shoved down their gullets. At least the I won't have to listen to doctor tell me why a patient needs and ACEI, ARB, and clonidine to control their htn.

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Ace and ARB together is reasonable even though the data out there isn't iron clad. Double RAAS blockade does lower BP more and reduce proteinuria. One theory is that body is an adaptable system. You block ACE, it compensate by up regulating renin or receptors, hence dual blockade of a pathway works.

In my opinion, its not really a question of whether its a reasonable combo, rather a question of outcomes and cost-effectiveness compared to alternatives.

xiphoid2010 said:

Ace and ARB together is reasonable even though the data out there isn't iron clad. Double RAAS blockade does lower BP more and reduce proteinuria. One theory is that body is an adaptable system. You block ACE, it compensate by up regulating renin or receptors, hence dual blockade of a pathway works.

In my opinion, its not really a question of whether its a reasonable combo, rather a question of outcomes and cost-effectiveness compared to alternatives.

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This. In fact, in heart failure, it's a recommended combo for add-on treatment when ACEi/BB/loop is not properly controlling symptoms, even at target doses.

Carboxide said:

This. In fact, in heart failure, it's a recommended combo for add-on treatment when ACEi/BB/loop is not properly controlling symptoms, even at target doses.

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Wait, I thought the trials demonstrated increased mortality when a combo ACEI and ARB was initiated with a BB. Also, that you wouldn't want to use target dosage when combining an ACE and an ARB. You also have to worry about additive side effects, especially if there is renal failure or hyperkalemia to worry about.

I would think adding spironolactone would be next in line if your ACEI/BB/Loop wasn't cutting the mustard. I would be very hesitant to add an ARB to that regimen.

FlavyFlav said:

Wait, I thought the trials demonstrated increased mortality when a combo ACEI and ARB was initiated with a BB. Also, that you wouldn't want to use target dosage when combining an ACE and an ARB. You also have to worry about additive side effects, especially if there is renal failure or hyperkalemia to worry about.

I would think adding spironolactone would be next in line if your ACEI/BB/Loop wasn't cutting the mustard. I would be very hesitant to add an ARB to that regimen.

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This. The evidence for ACEI/ARB combination in hypertension is very weak and this is no longer recommended. There is limited evidence for the combination in some heart failure patients but there is better evidence for adding spironolactone. This is discussed in the March issue of Pharmacist's Letter, for those who have access.

Fenofibrate, Antara, Fenoglide, Lipofen, Lofibra, Tricor, Triglide... Wonder which on works the best.

Going back to that lipitor, I heard of a lot of companies buying generic bottles that were cheaper and using the brand bottle for scanning if the patient requested brand. Was quite profitable for a little, still can be done if Watson brand is available.

I learned ACEI + ARB was only in severe cases, but do-able if needed. It's sort of like using HCTZ + Loop, blocking the pathway in two separate locations will have benefits but only with minimal efficacy and increased adverse effects. Mostly clinician based as there is much more evidence supporting different agents.

amox said:

Going back to that lipitor, I heard of a lot of companies buying generic bottles that were cheaper and using the brand bottle for scanning if the patient requested brand. Was quite profitable for a little, still can be done if Watson brand is available.

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No can do. Misbranding.

I learned ACEI + ARB was only in severe cases, but do-able if needed. It's sort of like using HCTZ + Loop, blocking the pathway in two separate locations will have benefits but only with minimal efficacy and increased adverse effects. Mostly clinician based as there is much more evidence supporting different agents.

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This is from Pharmacist's Letter. Subscribers can log in to see the references and full version:

ACEI plus ARB combos DON'T improve CV outcomes in patients with hypertension, vascular disease, diabetes, or after a heart attack...and they can lead to syncope or renal impairment. There's also no proof they reduce progression of kidney disease. One exception is systolic heart failure. Adding an ARB to an ACEI may modestly reduce mortality or hospitalizations for these patients. But it's more effective to add an aldosterone antagonist (spironolactone, etc) instead of an ARB to an ACEI for systolic heart failure. For example, an aldosterone antagonist plus ACEI prevents 7 more deaths per 1000 patients per year than an ARB plus ACEI.

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All4MyDaughter said:

No can do. Misbranding.



This is from Pharmacist's Letter. Subscribers can log in to see the references and full version:

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Right. I'd definitely do spironolactone or eplerenone before an ARB add-on...but some patients need more than that, too.

Carboxide said:

Right. I'd definitely do spironolactone or eplerenone before an ARB add-on...but some patients need more than that, too.

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Not according to EMB.

npage148 said:

Not according to EMB.

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The Heart Failure Association agrees with me..

http://www.heartfailureguideline.org/angiotensin_receptor_blockers/76

As does the AHA.

"The addition of an ARB may be considered in
persistently symptomatic patients with reduced LVEF
who are already being treated with conventional therapy."

http://circ.ahajournals.org/content/119/14/1977.full.pdf

Those documents are 3 and 4 years old which means they were built on data at least that old. Lots of new info about arbs has been gathered since then

npage148 said:

Those documents are 3 and 4 years old which means they were built on data at least that old. Lots of new info about arbs has been gathered since then

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I think the AHA guidelines are lukewarm on the issue of ACEI + ARB anyway. They freely admit the evidence (at the time of publication) was mixed.

I realize that this article addresses only anti-seizure medication, but the implications for all generics are there:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018179/
"Further variability in drug concentrations is allowed by the bioequivalence standards because generic drugs are tested against the brand name drug but not against each other. Current standards permit a difference in bioavailability between generic formulations that is greater than the difference between the generic and brand name drugs."
"Bioequivalence" and "bioavailability" are not synonymous. Just because an analysis of a drug outside of the human body shows that it has the same amount of active ingredients, does not mean that these ingredients will be released in the same manner in a person's system.
In addition, variance of "filler" products presents allergic reactions/sensitivity problems, as well as variance of how the drugs are metabolized.
I have found that the "-20% +20%" peramitter is misleading, positively or negatively, depending on whether the source is associated with the FDA. However, even a 10% in BIOAVAILABILITY can have a huge impact with some medications. For example, I am diagnosed with ADHD, and am prescribed 20 mgs of adderall 2X a day. If that dose could possibly mean I'm actually taking 18 mgs 2X a day, or 22 mgs 2X day, that would be a significant difference, especially if the fillers have an affect on absorption. With a schedule II prescription that is impossible to fill early, the difference between a dose lasting 1.5 hours and 3 hours could mean the difference between being able to function for 30 days and not. I have had my share of prescriptions for all kinds of medications, but I swear, I have noticed a significant difference between 20mgs of one "amphetamine salt" generic and 20 mgs of another. One formulation had my heart beating out of my chest and my eyes uncontrollably darting around, while another lasted half the time it is supposed to.
To respond to claims of "placebo" effect or patients being "stupid," I must point out that it makes no sense for a patient to find issues with a form of medication that is cheaper. If it could work, we would want it to. I was taking one particular generic formulation of adderall for 2 months before it finally occurred to me that the change in manufacturers could be the cause of my muscle spasms and anxiety. I didn't WANT that to be the cause. Preferably, I'd go to the pharmacy and pay a small amount for the exact same drug every single month. Imagining side-effects is not preferable.
Another piece of anecdotal evidence, I have noticed that between two different bottles of generic amphetamine salts, the pills will dissolve at different rates in my mouth before i swallow them. Again, why would this be something I even subconsciously imagined or desired? Obviously, this indicates a different rate of absorption.
Finally, I would like to see evidence for how generics are monitored and tested. I know for a fact that their original formations are not as tested as the brands', but I'm also interested in the oversight of generic drug companies facilities. How many bathers of a generic drug are randomly analyzed in a year???

That whole bioequivalenc thing is actually between individual lots, too. Not just brand-generic. So one month's batch could be different in a way you are making up in your head, too. I suggest reading a great journal article about this in The Annals of Pharmacology from 2009. Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug Administration.

A quote:

In our survey of generic drugs approved over a 12-year period, the average difference in the rate and extent of drug absorption between generic and innovator products was 4.35% and 3.56%, respectively.

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It also explains how that whole 20% variance thing isn't something to really worry about.

SouthCarolina316 said:

I realize that this article addresses only anti-seizure medication, but the implications for all generics are there:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018179/
"Further variability in drug concentrations is allowed by the bioequivalence standards because generic drugs are tested against the brand name drug but not against each other. Current standards permit a difference in bioavailability between generic formulations that is greater than the difference between the generic and brand name drugs."
"Bioequivalence" and "bioavailability" are not synonymous. Just because an analysis of a drug outside of the human body shows that it has the same amount of active ingredients, does not mean that these ingredients will be released in the same manner in a person's system.
In addition, variance of "filler" products presents allergic reactions/sensitivity problems, as well as variance of how the drugs are metabolized.
I have found that the "-20% +20%" peramitter is misleading, positively or negatively, depending on whether the source is associated with the FDA. However, even a 10% in BIOAVAILABILITY can have a huge impact with some medications. For example, I am diagnosed with ADHD, and am prescribed 20 mgs of adderall 2X a day. If that dose could possibly mean I'm actually taking 18 mgs 2X a day, or 22 mgs 2X day, that would be a significant difference, especially if the fillers have an affect on absorption. With a schedule II prescription that is impossible to fill early, the difference between a dose lasting 1.5 hours and 3 hours could mean the difference between being able to function for 30 days and not. I have had my share of prescriptions for all kinds of medications, but I swear, I have noticed a significant difference between 20mgs of one "amphetamine salt" generic and 20 mgs of another. One formulation had my heart beating out of my chest and my eyes uncontrollably darting around, while another lasted half the time it is supposed to.
To respond to claims of "placebo" effect or patients being "stupid," I must point out that it makes no sense for a patient to find issues with a form of medication that is cheaper. If it could work, we would want it to. I was taking one particular generic formulation of adderall for 2 months before it finally occurred to me that the change in manufacturers could be the cause of my muscle spasms and anxiety. I didn't WANT that to be the cause. Preferably, I'd go to the pharmacy and pay a small amount for the exact same drug every single month. Imagining side-effects is not preferable.
Another piece of anecdotal evidence, I have noticed that between two different bottles of generic amphetamine salts, the pills will dissolve at different rates in my mouth before i swallow them. Again, why would this be something I even subconsciously imagined or desired? Obviously, this indicates a different rate of absorption.
Finally, I would like to see evidence for how generics are monitored and tested. I know for a fact that their original formations are not as tested as the brands', but I'm also interested in the oversight of generic drug companies facilities. How many bathers of a generic drug are randomly analyzed in a year???

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People who have never taken a PK/PD class, Volume I....

That whole bioequivalenc thing is actually between individual lots, too. Not just brand-generic. So one month's batch could be different in a way you are making up in your head, too. I suggest reading a great journal article about this in The Annals of Pharmacology from 2009. Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug Administration.

A quote:


It also explains how that whole 20% variance th

My final point in my original comment was that I have experienced a difference between different batches of the same medication produced by the same manufacturer. And again, I can't imagine how someone would be motivated to experience effects of a cheaper, easier-to-obtain medication they were "making up in their head," consciously or unconsciously. From my limited knowledge of the pharmaceutical industry, I have no bias towards companies that produce brand name or generic. Both categories of corporations seem equally evil to me.
And again, when you consider medications that are administered in low doses (2.5-20 mgs), like stimulants, any percentage of variance is potentially significant.
And also, again, I would like to see data that isn't sourced by the FDA concerning how generics are tested. You are referring to a 12-year investigation done by the FDA that confirms its own lenient policies on generic drug regulation. How many times in this study were generics analyzed for bioequivilency and bioavailability? Once a year? Twice? Every single batch of every single drug? Unless they were analyzing every single batch of every single drug for 12 years, I'm going to doubt the reliability of those results.

Carboxide said:

People who have never taken a PK/PD class, Volume I....

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I admit, I am not a doctor or a pharmacist, and I possess nothing but the anecdotal evidence of my own experiences taking every formulation of brand and generic SSRI (as well as other categories of antidepressants), ritilan/amphetamine-based medications, possibly every kind of antibiotic, and most formulations of pain meds. I never noticed a difference between generic and brand (or between different generics and batches of the same generic) until I began to be treated for ADHD.
I am also basing my assumptions (clearly inferior to those who have sat in classes and watched Power Point presentations) on 6 immediate family members who have taken various drugs for mental illness and pain killers. For the most part, differences between generic and brand were indistinguishable. But, it seems like drugs given at low doses (like stimulants) would present a more noticeable difference, because that's how percentages work.

SouthCarolina316 said:

... it seems like drugs given at low doses (like stimulants) would present a more noticeable difference, because that's how percentages work.

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That's exactly how percentages DON'T work.

Also, there was a study comparing 3 pain medications with interesting results:
Group 1 got placebo - this worked the worst.
Group 2 got Tylenol - this worked okay.
Group 3 got Tylenol, but were told that it was a very expensive new drug - this worked the best.

Just because logically you want the cheaper option to be better, doesn't mean your subconscious fears won't influence your response in the other direction.

Its called the nocebo effect. Look it up. I know its hard to accept that this might just be a manifestation of this phenomenon...but more than likely it is. Also, stimulants aren't considered by anybody anywhere to have a narrow therapeutic index. Some practitioners think some of these might have major effects with minor dosage changes. Drugs like Synthroid, Warfarin, etc. And even this is controversial as many practitioners don't think there is a major difference in these medications, either.

It's just generic psychos vs Brand Name psychos

SouthCarolina316 said:

I realize that this article addresses only anti-seizure medication, but the implications for all generics are there:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018179/
"Further variability in drug concentrations is allowed by the bioequivalence standards because generic drugs are tested against the brand name drug but not against each other. Current standards permit a difference in bioavailability between generic formulations that is greater than the difference between the generic and brand name drugs."
"Bioequivalence" and "bioavailability" are not synonymous. Just because an analysis of a drug outside of the human body shows that it has the same amount of active ingredients, does not mean that these ingredients will be released in the same manner in a person's system.
In addition, variance of "filler" products presents allergic reactions/sensitivity problems, as well as variance of how the drugs are metabolized.
I have found that the "-20% +20%" peramitter is misleading, positively or negatively, depending on whether the source is associated with the FDA. However, even a 10% in BIOAVAILABILITY can have a huge impact with some medications. For example, I am diagnosed with ADHD, and am prescribed 20 mgs of adderall 2X a day. If that dose could possibly mean I'm actually taking 18 mgs 2X a day, or 22 mgs 2X day, that would be a significant difference, especially if the fillers have an affect on absorption. With a schedule II prescription that is impossible to fill early, the difference between a dose lasting 1.5 hours and 3 hours could mean the difference between being able to function for 30 days and not. I have had my share of prescriptions for all kinds of medications, but I swear, I have noticed a significant difference between 20mgs of one "amphetamine salt" generic and 20 mgs of another. One formulation had my heart beating out of my chest and my eyes uncontrollably darting around, while another lasted half the time it is supposed to.
To respond to claims of "placebo" effect or patients being "stupid," I must point out that it makes no sense for a patient to find issues with a form of medication that is cheaper. If it could work, we would want it to. I was taking one particular generic formulation of adderall for 2 months before it finally occurred to me that the change in manufacturers could be the cause of my muscle spasms and anxiety. I didn't WANT that to be the cause. Preferably, I'd go to the pharmacy and pay a small amount for the exact same drug every single month. Imagining side-effects is not preferable.
Another piece of anecdotal evidence, I have noticed that between two different bottles of generic amphetamine salts, the pills will dissolve at different rates in my mouth before i swallow them. Again, why would this be something I even subconsciously imagined or desired? Obviously, this indicates a different rate of absorption.
Finally, I would like to see evidence for how generics are monitored and tested. I know for a fact that their original formations are not as tested as the brands', but I'm also interested in the oversight of generic drug companies facilities. How many bathers of a generic drug are randomly analyzed in a year???

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Siiiiiigh. Fine. Let's do this.

1. It's nice that you attempted to cite some literature. However, something I think you failed to realize is that your publication didn't actually address any ACTUAL MEASURABLE differences between brand and generic. All they said was "Patients and doctors think it makes a difference." This means nothing. In fact, studies done with brand to generic crossovers in very narrow therapeutic index drugs such as tacrolimus (which has a measurable level, so we can actually quantify any difference) showed that there was no difference. At all. Other studies with crossovers have shown the same thing. This is a drug that doctors and patients feel very strongly about the brand-generic crossover 'effect' so I can assure you, their feelings about psych med effects means nothing.

2. The +/- 20% thing is the technical standard. As posted above, the actual differences are much smaller ( < 5%). Even if it was that large, for the vast majority of drugs (including Adderall) there would be no noticeable difference. There would also not be a 50% difference in effect (1.5 to 3 hours as you said). Changing the dose by 20% does not necessarily change the length of effect by 20%, either. Another point I want to make is that the milligrams per dose compared to other drugs isn't really important. We dose based on potency of a drug, which can vary highly. 15 mg morphine = 5 mg oxycodone. That doesn't mean that 15 mg morphine works better than 5 mg oxycodone. They are equivalent. The number of mg does not matter.

3. When it comes to patients not having a reason to prefer brand - the problem is that this is not typically a conscious effect. In fact, besides what other people have told you above, it has actually been shown that even tablet color and size and shape can affect how people perceive side effects and efficacy.

4. This part about the dissolving is confusing me. Are you taking these buccally? You don't swallow them? Either way, that doesn't mean anything about effect or rate of absorption. Adderall is not absorbed in the mouth. It is absorbed in the upper GI tract. (I'd have to check if it's stomach or small intestines, but I'd hazard a guess that it's stomach.) When a drug like that dissolves in your mouth, it gets to your stomach via swallowing your saliva. It is then absorbed there. Whether or not it breaks down at a pH of 6.5 means literally nothing. It will be broken down very quickly in the stomach and only the active ingredient is transported into the bloodstream. The fillers are irrelevant. They aren't involved in transport. In fact, the reason why they are fillers is because they don't affect that sort of thing.

5. The reason why generic meds aren't studied for efficacy is because they have already been proven to be effective. Again, it is the active ingredient that we worry about, and there is a reason that we don't care about the fillers. Why would we spend millions retesting efficacy when we know it already? The cost of generics would be the same as brand. It would be pointless. No clue about regulation, to be honest. But considering how frequently hospital meds are on shortage due to FDA shutting down the plant to fix stuff, I'd hazard a guess that it's fairly regularly.

A bunch of you should read the FDA guidance papers on bioequivelence and the BCS/bio waiver system before you're allowed to comment anymore.

This is the FDA saying there is concern that two versions of generic concerta are not equal.

http://www.m.webmd.com/a-to-z-guide...ic-versions-of-adhd-drug-not-as-effective-fda

But AGAIN, I would like to see evidence concerning bioequivilency/bioavailability that IS NOT SOURCED BY THE FDA. Again, the FDA confirming its own lenient policies can't be definitively objective. The fact the the FDA is expressing concern about concerta might mean that the issue was just too obvious to ignore. Wellbutrin's issues obviously were not isolated.

On the difference between bioequivilency and bioavailability:
"Most drugs work their magic not in the blood but in organs, cells or tissue elsewhere, and the agency does not insist on proof that a generic formulation delivers its active ingredient effectively to the same sites that pioneer drugs do."
and
"One version of a drug might use lactose or sugar as an inactive ingredient; another might not. But incidental ingredients like these can affect the way patients dissolve and metabolize a drug's active ingredient -- faster or slower. And that, in turn, can result in variations in the two formulations' effects."

http://articles.latimes.com/2008/mar/17/health/he-genericside17

Here, the FDA's warning letter to the pharmaceutical company Corepharma. The company has since "addressed" the many issues of concern, but I think it's safe to say that pharmaceutical companies being sloppy is POSSIBLE.
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm221615.htm

Again, I can't find information on how often generic drugs and their manufacturing facilities are inspected...

Carboxide, I swallow adderall whole but noticed that between 2 bottles of pills from the same manufacturer, one batch would quickly begin to dissolve in my mouth before I drink water to swallow it. Why would the rate of dissolution in any liquid NOT indicate the rate of dissolution in the stomach? Surely it is possible that differences in active and inactive ingredients would affect the SPEED at which a medication were dissolved/absorbed, and this would have an effect on the amount of the drug in the bloodstream and it's half-life? Don't they make medications specifically designed release a small amount of the active ingredients slowly, or a larger amount more quickly? The differences in these formulations isn't the active ingredients. It seems reasonable to infer that inactive ingredients have an effect in general.

SouthCarolina316 said:

This is the FDA saying there is concern that two versions of generic concerta are not equal.

http://www.m.webmd.com/a-to-z-guide...ic-versions-of-adhd-drug-not-as-effective-fda

But AGAIN, I would like to see evidence concerning bioequivilency/bioavailability that IS NOT SOURCED BY THE FDA. Again, the FDA confirming its own lenient policies can't be definitively objective. The fact the the FDA is expressing concern about concerta might mean that the issue was just too obvious to ignore. Wellbutrin's issues obviously were not isolated.

On the difference between bioequivilency and bioavailability:
"Most drugs work their magic not in the blood but in organs, cells or tissue elsewhere, and the agency does not insist on proof that a generic formulation delivers its active ingredient effectively to the same sites that pioneer drugs do."
and
"One version of a drug might use lactose or sugar as an inactive ingredient; another might not. But incidental ingredients like these can affect the way patients dissolve and metabolize a drug's active ingredient -- faster or slower. And that, in turn, can result in variations in the two formulations' effects."

http://articles.latimes.com/2008/mar/17/health/he-genericside17

Here, the FDA's warning letter to the pharmaceutical company Corepharma. The company has since "addressed" the many issues of concern, but I think it's safe to say that pharmaceutical companies being sloppy is POSSIBLE.
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm221615.htm

Again, I can't find information on how often generic drugs and their manufacturing facilities are inspected...

Carboxide, I swallow adderall whole but noticed that between 2 bottles of pills from the same manufacturer, one batch would quickly begin to dissolve in my mouth before I drink water to swallow it. Why would the rate of dissolution in any liquid NOT indicate the rate of dissolution in the stomach? Surely it is possible that differences in active and inactive ingredients would affect the SPEED at which a medication were dissolved/absorbed, and this would have an effect on the amount of the drug in the bloodstream and it's half-life? Don't they make medications specifically designed release a small amount of the active ingredients slowly, or a larger amount more quickly? The differences in these formulations isn't the active ingredients. It seems reasonable to infer that inactive ingredients have an effect in general.

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The journal the LA Times (mis)cited doesn't seem to exist. Can anyone find "The Journal of Clinical Therapy"?

The original publication of the article cited the journal article incorrectly. The correction is here:

http://articles.latimes.com/2008/mar/24/health/he-correx24.S1

And here is the journal article:

http://www.clinicaltherapeutics.com/article/S0149-2918(13)00242-7/references