Generic vs. brand name medications - differences in potencies/fillers?

[Cotcha Yankinov]

A common anecdote is "I was taking xyz medication for 5 years but when I switched to generic I started getting awful headaches. When I returned to the old formulation/name brand, the headaches ceased."

I have heard that generic's potency is allowed to deviate a little bit (20% or something?), and that they also use various fillers.

Its conceivable that a deviation in potency could put somebody into a bit of withdrawal, and for SSRIs I think this could explain some of the "side effects" seen with people who switch to generics, but just how much deviation (if any) is actually allowed?

Is this perhaps a somewhat isolated issue to do with particular batches of generics?

How valid is the "fillers/lactose" explanation?

Thanks for any thoughts.

 

[WSH]

I have heard that generic's potency is allowed to deviate a little bit (20% or something?), and that they also use various fillers.

Its conceivable that a deviation in potency could put somebody into a bit of withdrawal, and for SSRIs I think this could explain some of the "side effects" seen with people who switch to generics, but just how much deviation (if any) is actually allowed?

A reduction of potency of 20% would only decrease SSRI transporter occupancy from the usual 80% (4 times the IC50) to ~76% (3.2 times the IC50), and I can't see this slight difference causing "withdrawal".

 

[Cotcha Yankinov]

So if a particular SSRI dosed at 25mg occupies 80% of SERT then a 20mg dose would only occupy 76%?

Lets take somebody who is stabilized for years on 25mg of a benzo. Then they switch to a generic that technically only has 20mg of the same benzo. Shouldn't we intuitively expect some withdrawal?

 

[WSH]

So if a particular SSRI dosed at 25mg occupies 80% of SERT then a 20mg dose would only occupy 76%?

We can actually use a real world example, because the 25mg dose that you came up with is very usual, let's choose paroxetine:

The IC50 of parox is 5mg, so therefore the 25mg dose is 5x the IC50, so we can calculate the occupancy of ~83.33%.

A 20mg dose would only be 4x the IC50, and any school kid could calculate the occupancy of exactly 80% (they wouldn't even need a calculator, but for the one above where the result was ~83.33% i would give them a calculator [i also used one ]).

So the difference is only 83.33%-80%=3.33% or in my above post 80%-76%=4%, which are low-single-digit-values which would be very surprising to produce any withdrawal symptoms!

 

[Cotcha Yankinov]

Interesting, thank you.

Regarding intuitively expecting withdrawal symptoms when going from 25mg to 20mg of a benzo, I guess there could be a half life component to having withdrawal symptoms in the sense that a very fast 3-4% decrease in concentrations could be very different from a very slow decrease.


I suppose another piece of evidence against the "reduced potency -> withdrawal symptoms" hypothesis is that I first heard about this with zolpidem (with headaches etc being reported with particular generics).

If the symptoms were due to reduced concentrations, we should expect people to have such symptoms every morning.

Unfortunately this all seems to leave the filler/lactose hypothesis, but maybe some percentage of people really are intolerant to some fillers?

 

[CFC]

I have heard that generic's potency is allowed to deviate a little bit (20% or something?), and that they also use various fillers.

I'm not sure that's a reliable way to interpret bioequivalence and the confidence interval in practice as there's also a permissable deviation for the original patent holder's drug and between individual batches and manufacturing facilities.

Perhaps if we could give everyone the same coloured drug in the same packaging - regardless of source - they would be less likely to claim a difference?

 

[sekio]

There aren't that many different fillers used in pills (cellulose, starch, silica, PVPP), and effectively all of them are picked because they are inert and handle well. Stuff like PVPP is actually added because it swells rapidly in water causing the pills to disintegrate into mush.

I never bought the argument that "different fillers" actually effect the release rate of generic drugs. In fact I'd be willing to bet most generic drugs have the same "fillers" as the originals. After all there's only so many ways to formulate a tablet that sticks together and doesn't fall apart in a bottle, yet dissolves in water., there's probably one formulation that pharma houses pick and stick with.

 

[serotonin2A]

There aren't that many different fillers used in pills (cellulose, starch, silica, PVPP), and effectively all of them are picked because they are inert and handle well. Stuff like PVPP is actually added because it swells rapidly in water causing the pills to disintegrate into mush.

I never bought the argument that "different fillers" actually effect the release rate of generic drugs. In fact I'd be willing to bet most generic drugs have the same "fillers" as the originals. After all there's only so many ways to formulate a tablet that sticks together and doesn't fall apart in a bottle, yet dissolves in water., there's probably one formulation that pharma houses pick and stick with.

I don't think fillers are the main issue. One relevant issue is that some drug salts can form polymorphic crystals, which can have different dissolution rates, solubilities, PK properties.

If you combine different excipients, different polymorphic forms, and variations in the amount of drug in single dose units (eg, brand name pills may be over-dosed, and generics underdosed), you end up with a situation where people may notice differences between brand name and generic drugs.

 

[WSH]

Regarding intuitively expecting withdrawal symptoms when going from 25mg to 20mg of a benzo, I guess there could be a half life component to having withdrawal symptoms in the sense that a very fast 3-4% decrease in concentrations could be very different from a very slow decrease.

Benzos are agonists at their sites (which are not the orthosteric sites, but allosteric sites, i know), and agonists generally don't require the occupancy of antagonists (which is typically 80%, not only for transporter antagonists/blockers, but also e.g. for d2-antagonist antipsychotics, see the rule of 80%).

So if we assume that the therapeutic occupancy of benzos is ~10% (which is a guess), then the therapeutic dose would be ~0.1x the ki -> 9.09% occupancy, and your reduction of 25% would be 0.075 the ki -> ~6,98% occupancy (here you definitely need a calculator, well, at least I did)

So that's a 2.11% reduction, even smaller than the previous 3% and 4%! However, 4% from 80% is 5%, whereas 2% from 10% is 20%, which could cause a withdrawal!

PS: There are many number and calculations in my reply, did you understand everything? And do you understand how to calculate occupancies? For example, what is the occupancy of 11x the Ki?

 

[MDPV_Psychosis]

Is it actually true that the active ingredient in generic pills is allowed to deviate that much? 20% seems awfully high... Unless you mean plus or minus 10%... But even that sucks if you ask me. I don't see why things wouldn't be regulated at no more than plus or minus 5%, or even lower.

 

[CFC]

Is it actually true that the active ingredient in generic pills is allowed to deviate that much? 20% seems awfully high... Unless you mean plus or minus 10%... But even that sucks if you ask me. I don't see why things wouldn't be regulated at no more than plus or minus 5%, or even lower.

Bioequivalence (which is what we're discussing here) is usually determined via PK variables such as Cmax, Tmax and AUC, though on rare occasions pharmacodynamic endpoints may be accepted. In most developed countries, an acceptable range for a new generic is 80-125% of proprietary brand (90% CI).

I would caution against reasoning that this certainly accounts for meaningful differences between brands and generics, though, since different batches of either product may also vary to an equivalent degree.

Edit: >>here's<< a simplified read

 

[Solipsis]

Sorry I have no information, but that is an excellent question! ,OP

(If you think 20% seems awfully high, I'm not sure that you understand it's not the amount of product per amount of binding/fillers necessarily I think, but the consistency. How many types of binders and fillers there are? OK categorically it's pretty limited, but still enough to give you enough permutations. The question is about pharmacokinetic properties of those I think, which is a different matter.)

 

[MDPV_Psychosis]

Yes, my apologies for my poor reading comprehension. I get it now by rereading everyone's posts. How embarrassing...

 

[Cotcha Yankinov]

So if we assume that the therapeutic occupancy of benzos is ~10% (which is a guess), then the therapeutic dose would be ~0.1x the ki -> 9.09% occupancy, and your reduction of 25% would be 0.075 the ki -> ~6,98% occupancy (here you definitely need a calculator, well, at least I did)

So that's a 2.11% reduction, even smaller than the previous 3% and 4%! However, 4% from 80% is 5%, whereas 2% from 10% is 20%, which could cause a withdrawal!

Ahhh I see, so there are essentially large enough diminishing returns on dosage such so that a reduction in potency at high occupancy levels does not result in a significant change in occupancy.. Interesting, thank you

 

[what5next]

Fillers etc

Interesting, thank you.

Regarding intuitively expecting withdrawal symptoms when going from 25mg to 20mg of a benzo, I guess there could be a half life component to having withdrawal symptoms in the sense that a very fast 3-4% decrease in concentrations could be very different from a very slow decrease.


I suppose another piece of evidence against the "reduced potency -> withdrawal symptoms" hypothesis is that I first heard about this with zolpidem (with headaches etc being reported with particular generics).

If the symptoms were due to reduced concentrations, we should expect people to have such symptoms every morning.

Unfortunately this all seems to leave the filler/lactose hypothesis, but maybe some percentage of people really are intolerant to some fillers?

You are spot on regarding the fillers... check the generic Wellbutrine class action won in favor of patients... much ado about the non regulation of the fillers/lactose_binders interaction with active ingredient... this is my first night_am posting anything, and I just posted info in detail on this subject in the Ambien thread... I hope this lost a over to you correctly! )

 

[what5next]

And I'm going on zero sleep at hour 37, so pardon the typos

 

[sekio]

The release systems used in XR medications are more than just "binders/fillers", they are specifically engineered mixtures of compounds designed to release the drug at a gradual rate, whereas the lactose or starch or whatever in an IR pill is effectively just there to add weight and does not retard dissolution of the pill.