Sildenafil from different manufacturers

[scutty brown]

Read page 15/27 for the European Medical Agencies parameters and limits for bioequivalence.
External Link/Members Only

"1.1 Background
Two medicinal products containing the same active substance are considered bioequivalent if they are
pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent)
after administration in the same molar dose lie within acceptable predefined limits. These limits are set
to ensure comparable in vivo performance, i.e. similarity in terms of safety and efficacy."

Page 15/27:
"Parameters to be analysed and acceptance limits
In studies to determine bioequivalence after a single dose, the parameters to be analysed are AUC(0-t),
or, when relevant, AUC(0-72h), and C max. For these parameters the 90% confidence interval for the ratio
of the test and reference products should be contained within the acceptance interval of 80.00-
125.00%. To be inside the acceptance interval the lower bound should be ≥ 80.00% when rounded to
two decimal places and the upper bound should be ≤ 125.00% when rounded to two decimal places."

You will see the FDA and UK agency with similiar tolerances.
External Link/Members Only

you don't understand that document
It exists to aid definition of equivalent dosages of different versions of the same pharmaceutical active e.g. differing salts such as citrate, nitrate, sulfate, hydrochloride. Differing salts have differing uptake rates so need   differing dosage to hit the same level in the blood plasma
For manufacturing reasons sildenafil is only sold as the citrate so discussion about bioequivalence is irrelevant

[FiveKnuckles]

Doc,  yes I did read that link that debunks the 80-125 myth and states the differential is closer to 90-110%. (max 10%)
You also mentioned the 80-120% variable in generics/bioequivilence in post #25.   
So if you accept from memory there's a variance in active ingredients, how can you state that generics are 100% the same as the master product?  The generic product just needs to show the same level of substance within the blood at certain intervals within a co-efficient to be deemed the same, which is different to people arguing the product is 100% identical

They will all contain the same active ingredient sildenafil but the inactive ingredients may differ slightly. That said from memory the acceptable range of active ingredient is something like 80% to 120%.

you don't understand that document
It exists to aid definition of equivalent dosages of different versions of the same pharmaceutical active e.g. differing salts such as citrate, nitrate, sulfate, hydrochloride. Differing salts have differing uptake rates so need   differing dosage to hit the same level in the blood plasma
For manufacturing reasons sildenafil is only sold as the citrate so discussion about bioequivalence is irrelevant

Another link to read from the University of Illinios that suggest generics do not perform 100% to the master product.
External Link/Members Only

[scutty brown]

In regards to the fatty foods beforehand thing, would i be ok if i wait 2 hours (roughly how long it takes to empty your stomach) after eating fatty food then take the pill or is it still best to avoid?

only you can answer that based on your own experience, but personally I find I need to avoid ANY heavy meals for 3-4 hours before taking the meds

Also, ive never had problems using the Teva brand but tbh ive never tried anything else to compare it to apart form those shitty knockoff indian ones

Teva is a licenced Israeli distributor, no problems there - though they probably source at least some ingredients from India, just as they all do.
FWIW most Indian production is fine, just not licenced here. And that's because UK/Europe is too small a market to worry about compared with Indian domestic use and the likes of Brazil, Nigeria, South Africa, Malaysia. However a small percentage is fake, and there's the danger

[Doc Holliday]

They will all contain the same active ingredient sildenafil but the inactive ingredients may differ slightly. That said from memory the acceptable range of active ingredient is something like 80% to 120%.

Yes that was incorrect and should have read the bioequivalence range (ie the blood level range of active ingredient) is within that range. I shouldn't rely on my memory any more! That said thanks to your article the 80 to 125% is a 'myth' anyway and I was wrong on that score all along.

[Blackpool Rock]

Where to start with this then 

There shouldn't "Theoretically" be any difference between the original Viagra and the generic copies, as people have stated the active ingredients are the same and they are effectively comparable however there will be batch to batch variation.
However the same applies to the genuine Viagra and the generic copies, i'm not worried about the reputable generic medicines but i couldn't have the same confidence in some of the shit manufactured in India / China etc

I think Doc referred to someone buying Nurofen instead of generic Ibuprofen and effectively wasting their money and this is correct as each tablet will officially contain 200mg of Ibuprofen as the active, the same is true of Sildenafil

Check the Product licence number on a pack of brand name tablets then check the licence number of the supermarket own brand ones, often it's the same thing but 5-10 times cheaper

As for each tablet containing "exactly" the same amount of active ingredient that's impossible due to normal manufacturing tolerance however the active in each tablet will need to fall within a specification or allowable tolerance

Let's say a tablet contains 10 separate ingredients, each individual ingredient or raw material will have it's own specification which also has an allowable tolerance either side of the target.
Every raw material will be randomly sampled on arrival and tested to the spec, if it's outside the spec then it's rejected, if it's within then it's passed for use.
Some ingredients degrade over time so the potency / strength etc may be different if part of a batch is used a week after arrival then the remainder in the next batch in a years time.
All ingredients will have an expiry date after which then will need to be retested to ensure they are still within spec.
Many things can affect the degradation of a raw material including the storage conditions such as temperature and humidity, was it stored at ground level or at the top of the warehouse racking where it's 10 degrees hotter, was it stored by a door that opens and closes all day long, was it in the middle of the warehouse or stored for 6 months through the winter next to a cold wall etc

If a raw material is derived from natural origin such as a plant that's grown then the variance can be a lot wider than synthetic ingredients, where was it grown Africa; Asia or Europe, what was the exact make up of the soil, when was it harvested in spring summer or autumn, had it been hotter cooler wetter etc etc etc

To get the MHRA medicine licence approval the manufacturer will need to submit 3 validation batches, the method of manufacture will need to be specified so if the instruction says to add A and B then mix it for 5 minutes in a specific mixer with specific mixing blades and X revolutions / minute then heat it to 40 degrees and mix for 2 minutes then that's what you have to do, there's no allowance for someone doing it differently.

All of the processes are validated however variations do still occur from batch to batch and within each batch but within an agreed tolerance which is checked / tested by random sampling.
I was told many years ago by someone who worked for a Pharmaceutical manufacturer that the Paracetamol ingredients were mixed in a "V" cone mixer for about 2 hours as it took that long to ensure all of the ingredients were sufficiently mixed to give consistency, apparently if you continued to mix it for longer then some of the ingredients weirdly started to separate out again 

When the tablets are made the machine will dispense a slightly different weight of powder into the die meaning the active will vary from tablet to tablet etc etc


 

[Doc Holliday]

Another link to read from the University of Illinios that suggest generics do not perform 100% to the master product.
External Link/Members Only

I have only just read that link and once again it seems positive towards generics? Where does it say they do not perform as well?

[FiveKnuckles]

I have only just read that link and once again it seems positive towards generics? Where does it say they do not perform as well?

You're missing the point of this discussion somewhat.  The OP mentioned that he noticed a difference in effectiveness between the generic brands.   The first two paragraphs in that link sums up that generics "may or may not have the same effect in the body".   Is Daphne E. Smith Marsh writing nonsence?

Do you believe 'Bioequivilence' exist in generic drug manufacturing or do you believe that generics are 'Pharmaceutical equivilent' and will perform exactly like the brand?

If bioequivilence exist, then it implies different generics just need to meet blood level parameters for the stated pill dosage.  So a 100mg sildenafil taken will feed into blood at 'nearly' the same rate as the brand name product.  Your Mylan, Torrent, Teva will therefore have small variations compared to the brand it replicated. 


Pharmaceutical equivalence as define by the European Medical Agency
Medicinal products are pharmaceutically equivalent if they contain the same amount of the same
active substance(s) in the same dosage forms that meet the same or comparable standards.
Pharmaceutical equivalence does not necessarily imply bioequivalence as differences in the excipients
and/or the manufacturing process can lead to faster or slower dissolution and/or absorption.


So whether your generic is Bioequivilent or pharmaceutically equivalent, there will be differences in dissolution and absorption of the product into the blood.   


The points Blackpool Rock mentioned, I also agree will give a small variation on the finished product.

[Doc Holliday]

You're missing the point of this discussion somewhat. 

I haven’t missed the point. The OP asked are all generics equally effective as he had noticed a difference.

The answer is, if they are licensed then yes they are equally effective in comparison to both the original branded and patented medication and other licensed generics. The generics may be branded generics such as Teva etc or unbranded generics. As Scutty pointed out some of the unlicensed ones may also be as effective.

To be licensed they have to be both pharmaceutical equivalent and bioequivalent, the latter within a narrow parameter. That parameter is actually much narrower than in my original incorrect post.

All the evidence you have linked to confirms this comparable effectiveness including the last article.

The article rightly points out that just because both products are pharmaceutical equivalent ie contain the identical type and quantity of active ingredient (which they do) this does not necessarily mean this will result in the same bioequivalence ie the same blood levels of the active drug. This could be because the inactive ingredients may differ and potentially affect blood levels achieved.

Therefore this has to be tested and if the bioequivalence is shown to be equal (within a statistically acceptable range) the generic is granted a licence and deemed equally effective.

[FiveKnuckles]

The article rightly points out that just because both products are pharmaceutical equivalent ie contain the identical type and quantity of active ingredient (which they do) this does not necessarily mean this will result in the same bioequivalence ie the same blood levels of the active drug. This could be because the inactive ingredients may differ and potentially affect blood levels achieved.

Therefore this has to be tested and if the bioequivalence is shown to be equal (within a statistically acceptable range) the generic is granted a licence and deemed equally effective.

    Straight from the Doc.

So when the little head points towards a specific generic brand, i trust it felt a little something 

[big-al93]

  Straight from the Doc.

So when the little head points towards a specific generic brand, i trust it felt a little something 

Instead of highlighting the part you think makes your point read the full post, in particular the  sentence under it!!  Once pharmaceutical equivelence is proved, a license is only granted if bioequivelence can also be proved.

Therefore a licensed generic has been proven to be the same and work the same as the branded drug, within an incredibly tight tolerance. Any percieved difference between brands is simply that. So if you feel more comfortable with a specific brand, keep buying it, but it really makes no difference.

[FiveKnuckles]

Instead of highlighting the part you think makes your point read the full post,

read back to post #15 and #19 where inactives are said to have no impact on the product.

if binders and bulking agents used by different pharma companies have the potential to affect blood levels achieved, then Sildenafil having a very low half-life can't be considered the same by all generic manufacturers.  If the bulking agents in Torrent blocks the effectiveness for me, then I switch to another brand. 

Post #43 as quoted below is therefore misinformation.
"The whole point of generic drugs is that the brand does not matter - it's just a label on a box.
Often what goes in that box is sourced from the same global pool of suppliers"

If you read the link on debunking the 80-125% myth, it is suggested that generics can deviate 10% to achieve bioequivilence approval.  (although a 2 year study found 3.5%).
Say generic-A has 110% blood dope v Generic-B with 90% dope, that 20% spread when switching generic brands, along with binders MAY have some impact?   


As I said earlier, I have a preferred generic sildenafil brand that works for me.  I better bow out 

[Doc Holliday]

Instead of highlighting the part you think makes your point read the full post, in particular the  sentence under it!!  Once pharmaceutical equivelence is proved, a license is only granted if bioequivelence can also be proved.

Therefore a licensed generic has been proven to be the same and work the same as the branded drug, within an incredibly tight tolerance. Any percieved difference between brands is simply that. So if you feel more comfortable with a specific brand, keep buying it, but it really makes no difference.

Yes it's not rocket science is it. As I said much earlier it can be very difficult if not impossible to persuade some people that licensed generics are equally as effective and I fully accept that. A placebo effect can be strong, especially with something like sildenafil where cerebral level involvement is highly variable yet crucial to their success. However what he has tried to do is google the subject to try and find scientific evidence to support this. As Scutty says he has read stuff he has no real understanding of, but has picked up on certain statements within documents and articles as evidence, but ignored the rest of the text.

All the links he provided when read in entirety counter his belief. I use the term 'belief' because that is what it is and I fully respect him to hold that belief, something much of the pharmaceutical industry is more than happy with.

On that basis it should, I suppose, come of no surprise that, as you pointed out, he chose to highlight just the one sentence in my post without the context of the whole post. For that reason I cannot make my mind up whether this is deliberately obtuse or just trolling? Then I remembered our paths have crossed before in another thread and I am leaning towards the latter.

So for that reason .. I'm out.

[FiveKnuckles]

As Scutty says he has read stuff he has no real understanding of, but has picked up on certain statements within documents and articles as evidence, but ignored the rest of the text.

Doc you've just fallen down the big hole scutty dug at post #50.     He didn't understand the document i linked him or picked up pieces 

you don't understand that document
It exists to aid definition of equivalent dosages of different versions of the same pharmaceutical active e.g. differing salts such as citrate, nitrate, sulfate, hydrochloride. Differing salts have differing uptake rates so need   differing dosage to hit the same level in the blood plasma
For manufacturing reasons sildenafil is only sold as the citrate so discussion about bioequivalence is irrelevant

[daviemac]

Doc you've just fallen down the big hole scutty dug at post #50.     He didn't understand the document i linked him or picked up pieces 

Looks like you just can't help yourself.

I better bow out 

You are going round in circles and repeating yourself. Accept you might just be wrong and leave it at that.

[timsussex]

Last night I saw a TV ad for Viagra connect - which are stated to be film coated.

Film coating is usually to make tablets easier to swallow but can influence absorption site and rate

So are they different to the generic or is this just a bit of clever marketing/patenting ?

[Blackpool Rock]

Last night I saw a TV ad for Viagra connect - which are stated to be film coated.

Film coating is usually to make tablets easier to swallow but can influence absorption site and rate

So are they different to the generic or is this just a bit of clever marketing/patenting ?

The film coating is to make them easier to swallow, basically ensure a smooth surface but crucially no dust on the tablet from the manufacturing process.
Theoretically it may make the tablet take longer to digest however the coating will actually be dissolved in seconds when it hits stomach acid / fluid at 37 degrees

[scutty brown]

AFAIK the "film coating" is the foil strips they're packaged in (as opposed to loose in bottles)