Generic vs brand name zolpidem/Ambien

ObieWan · Mar 29, 2018

I take zolpidem to help me sleep and I enjoy it's recreational effects. I have noticed that there seems to be some differences in how effective the generics are ( I have never tried Ambien ). I take 10-20mg about 2-4 nights a week. Some of the generics seem to considerably less effective than others. I am not someone who believes that the brand name is best and usually I could care less. Anecdotally there are many, many people who report the same thing, so I think this is a real thing. I need to get more and I was wondering if it's worth it for me to get Ambien/Stilnox vs generic zolpidem? The brand is more expensive and less available.

I guess only I can address "is it worth it?" My real question is- WHY DOES THIS HAPPEN ? There are some very intelligent people on here, much more so than me. I know that they all contain the same 10mg of zolpidem tartate. Does this happen because less of the drug is absorbed? The PK and BA *should* be nearly the same for both, but maybe it's not. Maybe for example, in a section of the small intestine under certain circumstances, more of the drug passes by and less is absorbed. This could be rectified by taking the tabs sublingually instead of ingesting them. The majority of health care professionals dismiss this as being a real phenomenom, but I disagree. However I can't come up with a plausible reason for this happening.

Interested in other research studies? Find more drug studies.

Scrofula · Mar 29, 2018

Are these generic zolpidem from an actual pharmacy? Because if they are, there will be no difference.

If you purchased them from outside an actual pharmacy, you have no idea if there's even a molecule of zolpidem in them; you have no way to know they "all contain 10mg zolpidem tartrate". Especially if you've never tried actual Ambien before. I could powder up some Benadryl and press it into a pill that resembles a generic zolpidem, and probably puts you to sleep faster.

Generic drug manufacturers have to show equivalency to name brand. I'm pretty sure besides, there's a lot of data for every possible excipient and combination possible.

Now, even if it was straight-from-the-dealership brand-new Grade A top-brand Ambien™, you might have a different experience on different nights. I mean, is every time you've had a beer exactly the same as the previous? If you ask around, half the people on the planet complain about sleep problems, and it shouldn't be too surprising if even with pills known to cause tolerance, you occasionally have a hard time falling asleep. Or trancing-out Tiger Woods style.

ObieWan · Mar 29, 2018

Your answer was well thought out Scrofula.

These are all from European pharm companies sealed with lot#s and NDC #s in blister packs. They are not sold through pharmacies, but arrive through an online marketplace. So that is eliminated (at least for argument's sake).

Yes I see the point that you are making that its impossible to narrow it down to 2 or even 6 factors that will affect the user's experience. I just thought there may be trends or correlations that have surfaced or

a smart person has played with somewhere.

I hear many who have switched to Teva's brand incessantly complain that it is not as effective. When I switched to Bristol from I forget what I was having before it was not working as well. Am I blaming it on the pill? *I think so*. I can't recall any other influences in my life at that time. Somebody help me please $:\$ please, please.

What left do I have to do but take Stilnox for a month and then try taking Bristol again. Any comments?

Scrofula · Mar 29, 2018

Careful, OP, you start specifying brand differences like that it can start to sound like you're soliciting them.

There is always a good workout in the evening, possibly copulatory; and then wash down your Benadryl with a beer. Better than any failed benzo.

Cotcha Yankinov · Mar 29, 2018

See what Serotonin2A wrote in this thread
http://bluelight.org/vb/threads/816...es-fillers?highlight=generic+brand+medication

I think there can be genuine differences between some brand name and some generic medications

ObieWan · Mar 29, 2018

Scrofula said:
Careful, OP, you start specifying brand differences like that it can start to sound like you're soliciting them.

There is always a good workout in the evening, possibly copulatory; and then wash down your Benadryl with a beer. Better than any failed benzo.

It's not like that at all. Was just hoping for some brand recognition as well as illustrating a point. I knew it would be difficult to make this post without breaking or stretching any rules or regs.

Scrofula · Mar 29, 2018

Yes, there are tolerances that will be allowed, to keep in line with reality, and depend on the drug. The mass of the drug in question is not going to have more than like 1% deviation, though. For complex delivery systems, you could theorize that maybe temperature and moon phase affects the propellant in an inhaler (laws about CFCs affect it quite a bit).

But polymorphic crystals in the salts in a tablet of zolpidem rendering one of them only half effective or non-effective?

I hate when titanium dioxide and magnesium stearate mix under the pressures in the core of Jupiter to form Excipient9 crystals, not only reducing absorption but reversing it completely, and causing fatal insomnia in all who encounter it.

ETA: OP, if you really believe there's a substantial difference, in only a specific drug, the people to contact are lawyers.

Hodor · Mar 29, 2018

Cotcha Yankinov said:
See what Serotonin2A wrote in this thread
http://bluelight.org/vb/threads/816...es-fillers?highlight=generic+brand+medication

I think there can be genuine differences between some brand name and some generic medications

I agree with what sekio posted in that thread though (and what Scrofula posted here): It is fairly unlikely that a pharm company would just put in 20% less of the active ingredient; whatever they'd save on materials would be more than made up for by the money they'd have to spend on lawyers to prevent themselves from getting sued into oblivion (or losing their license altogether).

Yes, there may be minor differences in the make-up of a pill (ex.: I remember name-brand Topamax having a thin layer of coating that kept you from noticing the taste on your tongue in the time it took you to swallow it, whereas generic topiramate didn't), but I seriously doubt that is enough to render a pill significantly more or less effective. In the end, all pharm companies have access to pretty much the same kinds of binders (and their cost is basically nil), and I doubt these introduce anywhere near the variance that is caused by other factors such as the contents of your stomach or your physical and mental state as you take it...
The power of the placebo effect has been proven time and time again, and I strongly suspect that this is what is happening here.

Cotcha Yankinov · Mar 29, 2018

Hodor said:
I agree with what sekio posted in that thread though (and what Scrofula posted here): It is fairly unlikely that a pharm company would just put in 20% less of the active ingredient; whatever they'd save on materials would be more than made up for by the money they'd have to spend on lawyers to prevent themselves from getting sued into oblivion (or losing their license altogether).

I think what some people have said is that there is allowed to be a +20%/-20% deviation in generics, so -20% sounded like it would be fully lawful to do

Some PhDs were postulating in an MED thread that some of the differences between batches of MDMA may have to do with polymorphic variation as well

For what its worth, I hold Serotonin2A's opinions in very high esteem, a psychopharm PhD from industry, they would be the ones to know

The other thing I'll mention is that I notice people around here love to jump on the "its all placebo" and "its all anxiety" bandwagon - I appreciate that mainstream society has a rather lacking understanding of the two aforementioned things but I think sometimes people on BL may go overboard claiming placebo when there just really is a crappy generic batch. I looked into the matter a while ago with ambien and the common story was

"My ambien worked fine for a year, then all of a sudden it stopped working, I then remembered my doctor had just switched me to a generic version when I had been getting brand before." I guess my point is that its somewhat validated because people don't necessarily go into the brand -> generic switch thinking "Oh lord this is going to be a shitty generic", from what I remembered most people only figured out that they had just switched after the fact and then isolated that as the culprit

And what I remember is that people were usually complaining about one generic in particular.

We hold our regulations in very high esteem but its possible that crappy generic batches slip through

Cotcha Yankinov · Mar 29, 2018

Scrofula said:
But polymorphic crystals in the salts in a tablet of zolpidem rendering one of them only half effective or non-effective?

I'm not too versed on the polymorphic variation deal and I totally understand the skepticism but I shall quote those smarter than me

To quote LucidSDreamer (I believe he's an O-chem PhD, not to invoke pedigree, just saying he's not Joe Blow)

"^Different polymorphs absolutely have different rates of absorption. I've seen examples where certain polymorphs of a compound have drastic improvement serum levels obtained.

This difference in absorption is what makes it possible to patent a polymorph of a drug that is already patented...it happens alot."

There's another chem PhD (username G-Chem) who was saying something similar but I can't find quotes atm

https://symbiosisonlinepublishing.com/pharmacy-pharmaceuticalsciences/pharmacy-pharmaceuticalsciences11.php

- "Polymorphism: The phenomenon Affecting the Performance of Drugs"

Scrofula · Mar 29, 2018

Do you have a reference that doesn't come from "symbiosis online publishing"?

I mean, if this is a real phenomenon affecting drug absorption, there should be thousands of references about it.

ETA: not to mention, polymorphisms affecting drug performance probably refers to the genetic kind.

And the FDA deviation tolerance really is that big, but refers to AUC. Loosely based on being within so much of the reference confidence intervals.

One thing to keep in mind, is the huge difference between people, and time of day, and what they ate, and their pharm stats. People want to know what the bioavailability of buprenorphine is when intranasal v. buccal, and see something like 42% to 38%, and assume intranasal is better. What they don't see is that figure coming from an n=4 study, with standard deviation so high it covers the whole range 0-100%.

For a stat like Cmax, with oral tablets, the variation in an individual will be +/- 20% over the course of a week. So confining requirements to what seems to be a pretty broad allowance, is probably the minimum that's realistic.

So point is, you're not going to notice any difference between brand and generic, except what you imagine.

Cotcha Yankinov · Mar 30, 2018

I do understand the skepticism but there seems to be a body of literature regarding polymorphic variation of chems and the differing properties from my quick search, some with PK data but even just physical property data has implications for PK factors. Of course, a bit difficult to search through pubmed as anything with "polymorphism" just brings up genetics

Scrofula said:
For a stat like Cmax, with oral tablets, the variation in an individual will be +/- 20% over the course of a week. So confining requirements to what seems to be a pretty broad allowance, is probably the minimum that's realistic.

https://www.ncbi.nlm.nih.gov/pubmed/24075980 (University of Copenhagen)

"Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats"

"The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively. The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats.

The amorphous salt exhibited a significantly faster Tmax compared to the solution and amorphous and crystalline free acid. Cmax for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster Tmax compared to the amorphous and crystalline free acid."

So in that particular case there was no change in AUC, but still, polymorphic variation can result in PK differences

I'd personally like to see this thread moved over to NS&P to see if anybody would like to chime in
CY

Scrofula · Mar 30, 2018

Thanks for the links, I appreciate it.

One problem though, is that dissolution rates at multiple pH is already a requirement for generic drugs. And, you still have to consider the bioequivalence requirements.

Company A may use a synth that produces amorphous drug, while Company B uses a different synth that produces a crystal form. But if neither formulation rescues the original NDA, they won't be approved for sale. And if both of them do, it means it won't matter what crystal state your drug is in.

And move granted.

Cotcha Yankinov · Mar 30, 2018

It seems we actually get to see what the FDA wrote on this matter, from F. Holcombe PhD (Director Division of Chemistry II, Office of Generic Drugs, FDA)

"Some drug substances exist in several different crystalline forms (“polymorphs”), due to a different arrangement of molecules in the crystal lattice, which thus show distinct differences in their physical properties. The same drug substance may also exist in a noncrystalline (amorphous) form. These various forms differ in their thermodynamic energy content, but not in composition.

As the Guideline points out, the polymorphic form of a drug substance can affect the dissolution and bioavailability of drug products. Thus, it is possible that a difference in physical form of the active ingredients might prevent a proposed generic drug from being bioequivalent to the reference listed drug (thus barring approval of the ANDA)."

https://www.ncbi.nlm.nih.gov/pubmed/14962589# - from the FDA

"Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand."

It appears that the FDA may be falling asleep on the job. https://www.ncbi.nlm.nih.gov/pubmed/12860486 -

"Few publications compared the bioequivalence and efficacy of brand-name and generic psychoactive drugs. Those that were identified revealed differences in the efficacy and tolerability of brand-name and generic psychoactive drugs that had not been noted in the original bioequivalence studies.

Specifically, l study found that plasma levels of phenytoin were 31% lower after a switch from a brand-name to a generic product. Several controlled studies of carbamazepine showed a recurrence of convulsions after the shift to a generic formulation.

After a sudden recurrence of seizures when generic valproic acid was substituted for the brand-name product, an investigation by the US Food and Drug Administration found a difference in bioavailability between the 2 formulations. Statistically significant differences in pharmacokinetic variables have been reported in favor of brand-name versus generic diazepam (P < 0.001). Finally, a case report involving paroxetine mesylate cast doubt on the tolerability and efficacy of the generic formulation."

If a brand product was overdosed by +20% and a generic underdosed -20%, I suppose 31% difference could be seen but I'm not ready to say its just due to the +-20% deal

What is probably happening is that there is an original synth that the generic producer uses to get bioequivalence approval, and then if the FDA doesn't stay on the ball about re-checking bioequivalance in vivo with subsequent batches, the manufacturer could either purposefully switch to a different polymorphic form for financial reasons, or their manufacturing standards could slip

There actually seem to be some papers where authors are citing differences between brand and generic drugs, interestingly

https://www.ncbi.nlm.nih.gov/pubmed/27026878
https://www.ncbi.nlm.nih.gov/pubmed/14693311

CY

Scrofula · Mar 30, 2018

Yes, the FDA block you quoted pointed out that crystal or amorphous differences can exist with certain drug formulations. They'd have slightly different relevant physical properties, and might be a reason a new generic drug application may fail bioequivalence.

Cotcha Yankinov · Mar 30, 2018

Part of what I was trying to point out in the second half of my post is that the FDA may be falling asleep on the job after the manufacturers initially prove bioequivalence, I certainly doubt they do in vivo PK testing for every lot. So they may test purity et cetera, but in vivo generic testing is what really matters, and that's what those papers seem to say there are problems with (there are various others I didn't bother linking)

Scrofula · Mar 30, 2018

And what I stand by, is that even if such a thing was happening, multiple rare events colliding with any kind of frequency, I'll still close a thread where the OP whines that she's all out of Brand X fent patches. If only she had the Brand Y patches that are clearly superior! O who could have Brand Y patches?

The forum would be nothing but people asking and offering which brand is superior for whichever drug, just shoot them a PM for reviews. A forum dedicated to a few anonymous internet usernames ranking different drugs by personal anecdote, nothing to support them. Not what ODs ostensibly about. And in the remote chance that someone asks and legitimately is affected by lax regulatory standards of bioequivalence at the same time the crystal shape actually differs and even matters, and renders it so reduced as to be nearly useless, the proper people to talk to are lawyers anyway. I'll risk it.

As if we didn't already have conspiracy threads about methadone and suboxone and liquid v film v SL tablet. There's a rule against ID'ing whatever bizarre cutting agent is in your dope for the same reason. Pure speculation. Sure kid, you and you alone got the methadone that rearranged its crystal shape to be ineffective, on purpose. It was that one bouncer-looking counselor, who personally hates you for being so edgy.

If it went that way, I'd give up and just say they all were contaminated with isopropylbutylamine.

Cotcha Yankinov · Mar 30, 2018

One thing I'd keep in mind is that we should differentiate between the original bioequivalence data, and the performance of generics at a later date, especially batch to batch. For starters, patients have been unknowingly switched to generic, with deterioration following thereafter

https://www.ncbi.nlm.nih.gov/pubmed/17664246/
https://www.ncbi.nlm.nih.gov/pubmed/11726006

https://www.ncbi.nlm.nih.gov/pubmed/27576318 - St. Elizabeth's Medical Center, Boston

"Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed."

https://www.ncbi.nlm.nih.gov/pubmed/25830930/ - Serum Olanzapine levels dropped after switching to that particular generic batch
https://www.ncbi.nlm.nih.gov/pubmed/11305844 - University of Texas finding differences in Clozapine PK from brand to that generic

https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm322161.htm

- "The U.S. Food and Drug Administration (FDA) has reviewed new data that indicate Budeprion XL 300 mg (bupropion hydrochloride extended-release tablets), manufactured by Impax Laboratories, Inc., and marketed by Teva Pharmaceuticals USA, Inc., is not therapeutically equivalent to Wellbutrin XL 300 mg.

FDA has changed the therapeutic equivalence rating for this product in the Agency’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) from AB to BX, signifying that Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg.

Impax has requested that the Agency withdraw approval of budeprion XL 300 mg extended-release tablets. Impax and Teva have stopped shipping the product and are issuing detailed information to their customers."

What's funny is that I think Teva was often the manufacturer in question when I was reviewing the crappy generic Zolpidem thing a while ago, now we actually have a report from the FDA saying that a generic produced by Teva wasn't bioequivalent

I understand the skepticism, and I think "Generic-Fear" as a whole would be bad for our society, but I really do think there can be bad batches of generics

Apparently the initial bioequivalence study needed for an ANDA typically uses around n=60 with young healthy patients. With what the FDA are calling "high variability" drugs, some are saying that a more stratified test population would be better for determining bioequivalence among many patients.

https://www.ncbi.nlm.nih.gov/pubmed/18446515 (FDA on high variability drugs)
https://www.ncbi.nlm.nih.gov/pubmed/22972221

I still think the issue is the occasional bad batch, and that the original bioequivalence data may differ if a much later lot was used (hence using only the initial bioequivalence data is kind of odd, that's exactly when you would expect manufacturers to put out their best product). But I highly doubt the FDA has the manufacturers repeat in vivo PK testing very often (if at all) after an initial approval

Article from 2014
https://www.peoplespharmacy.com/201...ting-generic-drugs-huge-victory-for-patients/

Coolwhip · Mar 31, 2018

Not to say it doesn't apply here, but I imagine that data more aptly applies to generic formulations of extended release drugs.

OP, were the pills the same size, same color?

Were you stomach contents the same each night? Did your previous nights sleep quality differ? Amount of activity in the day? Sugar intake? Coffee intake?

I think Scrofula's post is a great answer and probably the most correct one, but there are so many factors at play which can change a drugs effect, the greatest one probably being our own psyche.

what5next · Mar 31, 2018

Hi, quick add on to your great post.

I used to work in biotech litigation all cases centered around different drugs and their movement out of their 15 year Brand name protection period and fading into the multiple manufacturers beginning the generic run.

Initially it was believed all would be the same, and their main 'active' compound must maintain the FDA regulations put on the initial brand Patten. However, the polymer, and binders used to hold the string of compounds together ate not / or were never under the restrictions of the FDA. I know blah blah blah... but here's where this matters and why so many people have varying experiences with the generic manufactures-- even if the generic is made by the original big pharma, say Phizer, just for example. Those binders and polymers vary so widely, and while not considered an active ingredient, per say, they can and often fo have an impact on the way the active ingredient behaves when all mixed together. [If interested check the Big class action won against generic wellbutrin makers... the details there explain much better than I can illiterate here. So. Long story short each person also might have different reactions to the various mfgs. chosen polymers and binders. So when possible it is worth asking your pharmacy to order a different Mfg companies pill. Oh ps: the reason there would be a difference in the brand name vs generic produced by the same lab is that, again the Bran written Pattent formula is the only thing bound by the FDA in complete ingredients.... so that lab/big Pharma had to use the tested and approved binders/polymers-- which are usually/ nearly always across the board, more expensive than the polymers/binders used in the generics. The same lab will make the brand and use the approved ingredients, and stamp the pill Ambien, while also using the less expensive non controlled binders/polymers and stamp the generic pill zolpidem... Scofula is right about the testing being fairly extensive e for most us/eu mfg on generics, but , again, those varing polymers/binders are given a pass. So, the different reactions, check the history on the Wellbutrine- generic class action suite. The patients won hands down ad these details were exposed at trial. The different reactions were proven to be a fact and not in the minds of the users.

All of this said, just qualify, that I am going on hour #37 with zero sleep. So pardon the errors.

I logged in here to see if anyone had a solution to hold my eyelids down... using an eyemask now.

Pps: I have zolpiedum (sp), alprazolam (generic for xanax) and gabbapentin (gen. for nerontin). Stumped with Eyes Wide Open. Ugh.

Generic vs brand name zolpidem/Ambien

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