Warfarin manufacturer change and INR levels

[Thoughtfulsinner]

We just changed warfarin manufacturers at Walgreens and I was wondering if there is any evidence that shows a change in INR level do to this? Some patients are complaining that their physicians are needing to decrease their warfarin dosages because of this change.

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[Praziquantel86]

No.

 

[Aznfarmerboi]

I would say yes... since Warfarin is a narrow therapeutic index drug. This means the way the drug is release over time can affect INR.

 

[Praziquantel86]

I would say yes... since Warfarin is a narrow therapeutic index drug. This means the way the drug is release over time can affect INR.

To an extent greater than random fluctuations and nonadherence? Doubt it.

I've spent a lot of time in a Coumadin Clinic and have never had a problem switching people.

 

[ForcedEntry]

Do they prefer the blue one?

 

[VCU2011]

To an extent greater than random fluctuations and nonadherence? Doubt it.

I've spent a lot of time in a Coumadin Clinic and have never had a problem switching people.

Well seeing as how switching from one generic to another can alter the dose by up to 40% (bio equivalents have to be between 80-120% of the brand), for such a narrow therapeutic index drug I would say that there's a very good chance that the INR could be affected...

 

[wolingfeng]

Well seeing as how switching from one generic to another can alter the dose by up to 40% (bio equivalents have to be between 80-120% of the brand), for such a narrow therapeutic index drug I would say that there's a very good chance that the INR could be affected...

For some patients, it might. But for majority of patients there shouldn't be a problem. The 80-125% is an confidence interval, not as simple as percentage. Besides, when brand drug companies making their drugs from different batches, they apply the same method for testing pharmaceutical equivalence. I think for drugs that have extended release formulations are ones that are hard to mimic its PK profiles due to the complexity of mechanisms for formulation. But warfarin and levothyroxine, IMO, are just better excuses to promote brand drugs sales.

 

[Aznfarmerboi]

For some patients, it might. But for majority of patients there shouldn't be a problem. The 80-125% is an confidence interval, not as simple as percentage. Besides, when brand drug companies making their drugs from different batches, they apply the same method for testing pharmaceutical equivalence. I think for drugs that have extended release formulations are ones that are hard to mimic its PK profiles due to the complexity of mechanisms for formulation. But warfarin and levothyroxine, IMO, are just better excuses to promote brand drugs sales.

Levothyroxine yes, Warfarin.. not as much. I only have one to two patients who are still on Coumadin. My rule (I am only retail so what do I know) is to never mess around with anti-coagulation. I am sure diet, new drugs, etc, affect the INR more than brand to generic switch. However I would still take precautionary measures and do required test works until the patient is stablized on the generic.

But then I have never been in an anticoagulation clinic so I take Praz..'s word for it.

 

[MountainPharmD]

Do they prefer the blue one?

That is only for thier generic Xanax or Hydrocodone!

 

[npage148]

The bioequivalence guidelines for AB rating a generic are exactly the same as the guidelines that the brand product uses when there need to demonstrate bioequivlanace to itself. So, the brand product will have the same amount of variability as the generics to the brand by law. So, I don't believe that the INR changes are not due to that. They probably and extra salad or a extra glob of mayonnaise that week.

The when you say the log value of Cmax and AUC of the generic needs to be w/in 80 and 125%, it's the 90% confidence interval needs to be w/in that bound. So in reality, the true mean of the Cmax or AUC is actually much tighter, typically w/in 5%.

 

[WVUPharm2007]

Levothyroxine yes, Warfarin.. not as much. I only have one to two patients who are still on Coumadin. My rule (I am only retail so what do I know) is to never mess around with anti-coagulation. I am sure diet, new drugs, etc, affect the INR more than brand to generic switch. However I would still take precautionary measures and do required test works until the patient is stablized on the generic.

But then I have never been in an anticoagulation clinic so I take Praz..'s word for it.

Do you honestly think that an instant release medication is going to vary that much? It's ridiculous. Switch. It's not going to make any difference. Hell, at my hospital I review INRs every day. And we use whichever brand was the cheapest/ASB had in stock that week. And, what do you know, under a monitored and controlled situation, there has never been an issue of a generic magically making the labs come back all jacked up.

It's all crazy talk I tells ya...crazy talk...

 

[npage148]

You would see a problem with the Cmax value of the generic if the release and disintegration of the IR tablet was an issue. Since they are AB rated, the Cmax is not different than that of the brand and you would expect no problems.

 

[evilolive]

I remember hearing somewhere in class that Coumadin maintains stricter manufacturing practices than what the FDA requires for their bioequivalence, so their therapeutic range is narrower than the 80-125% interval. Maybe that might make a difference?

 

[ForcedEntry]

I remember hearing somewhere in class that Coumadin maintains stricter manufacturing practices than what the FDA requires for their bioequivalence, so their therapeutic range is narrower than the 80-125% interval. Maybe that might make a difference?

Don't confuse therapeutic range with confidence interval.

 

[npage148]

As far as I know, the FDA does not apply different guidelines to Narrow TI drugs. They DO relax the bioequivelance standards for highly variable drugs

 

[Praziquantel86]

Well seeing as how switching from one generic to another can alter the dose by up to 40% (bio equivalents have to be between 80-120% of the brand), for such a narrow therapeutic index drug I would say that there's a very good chance that the INR could be affected...

You're misinterpreting the statistics. The 80-100% refers to the confidence interval (as others have indicated), not a flat percentage. As was also pointed out, this is the same test applied from lot to lot for brand manufacturers.

If you think about it, what drug wouldn't be seriously affected by a 40% change in dose? Hundreds of medications are supplied with dose intervals less than 40% apart. There would have been an uproar a long time ago if this were the case.

 

[evilolive]

Don't confuse therapeutic range with confidence interval.

mm, my point was that it might lead to a narrower therapeutic range as a result of stricter manufacturing practices and thus the confidence interval. All you have to do is be within the 80-125% to satisfy the standards, no? I think the whole debacle came over barr laboratories a few years ago?

 

[WVUPharm2007]

mm, my point was that it might lead to a narrower therapeutic range as a result of stricter manufacturing practices and thus the confidence interval. All you have to do is be within the 80-125% to satisfy the standards, no? I think the whole debacle came over barr laboratories a few years ago?

Let's be realistic. These companies can manufacture tablets to the nanogram. Do you honestly think there is a 2% difference in the tablets from one manufacturer to another that wouldn't exist from one manufacturers lot to a seperate lot? Let alone 20%? These generics manufacturers aren't a bunch of wacko, fly by night snake oil salesmen. It's a molecule. It's measured to very exact standards. They are equivalent. Anything you read otherwise is propaganda.

 

[MountainPharmD]

Let's be realistic. These companies can manufacture tablets to the nanogram. Do you honestly think there is a 2% difference in the tablets from one manufacturer to another that wouldn't exist from one manufacturers lot to a seperate lot? Let alone 20%? These generics manufacturers aren't a bunch of wacko, fly by night snake oil salesmen. It's a molecule. It's measured to very exact standards. They are equivalent. Anything you read otherwise is propaganda.

You are assuming the highest standards are adhered to by every manufacturer. Your recent post concerning Mylan in WV is a case in point. Read about some of the generic companies in India and how suspect things are their. How often do you think the FDA gets to inspect generic manufactures in India?

The recent mass recalls of all Ethex products as well as the Digitek recall at best could be classed as rare anomalies. At worst it highlights an industry wide quality control problem that is not being caught by FDA inspectors or company quality control processes. The case you brought up in WV with Mylan seems to fit into the latter. Do you think Mylan is the first company to have something like this happen?

High speed systems may be capable of punching out millions of tablets and measuring them to the nanogram if they are functioning properly and employees are not overriding system checks and balances. Who knows what is going on in foreign countries where many generic companies reside.

 

[Priapism321]

I would say yes... since Warfarin is a narrow therapeutic index drug. This means the way the drug is release over time can affect INR.

Show me the data....and when/if you do, I will show you the better data that tells the real story.

 

[Priapism321]

Well seeing as how switching from one generic to another can alter the dose by up to 40% (bio equivalents have to be between 80-120% of the brand), for such a narrow therapeutic index drug I would say that there's a very good chance that the INR could be affected...

This statement is very far from being accurate about the bioequivalence standards in this country.

 

[powertoold]

Warfarin's half life is > 2 days, and if we compare two IR formulations, it shouldn't make a difference even if one IR releases 30 minutes faster than the other. In the end, you'll get a similar concentration curve.

 

[npage148]

Also think of this, BMS would LOVE to show that using only brand name Coumadin leads to better INR control. They would pump out study after study and promote it endlessly. But unfortunately they can't show it because the generic is fine.

 

[WVUPharm2007]

You are assuming the highest standards are adhered to by every manufacturer. Your recent post concerning Mylan in WV is a case in point. Read about some of the generic companies in India and how suspect things are their. How often do you think the FDA gets to inspect generic manufactures in India?

The recent mass recalls of all Ethex products as well as the Digitek recall at best could be classed as rare anomalies. At worst it highlights an industry wide quality control problem that is not being caught by FDA inspectors or company quality control processes. The case you brought up in WV with Mylan seems to fit into the latter. Do you think Mylan is the first company to have something like this happen?

High speed systems may be capable of punching out millions of tablets and measuring them to the nanogram if they are functioning properly and employees are not overriding system checks and balances. Who knows what is going on in foreign countries where many generic companies reside.

Bull****. I don't buy a few isolated cases as a reason to ignore common ass sense. And EVEN IF the above was the case, then there would be just as much variance within individual product lines as among competing brands, so that's a bull**** argument in and of itself.

Also, India is an industrialized nation. They have a very sophisticated chemical producing industry. This isn't Jim Bob in the basement making methamphetamine. Until you prove that Dr Reddy's doesn't use modern machinery (and they do), that's being classified as a classic bull**** argument, too.

 

[MountainPharmD]

Bull****. I don't buy a few isolated cases as a reason to ignore common ass sense.

You can run around screaming bull**** with your head up your ass all you want. Is it a few isolated cases or the tip of the iceburg and foreshadowing of greater probelms yet to be discovered in the industry? You have made up your mind. I am not so sure.

Also, India is an industrialized nation. They have a very sophisticated chemical producing industry. This isn't Jim Bob in the basement making methamphetamine. Until you prove that Dr Reddy's doesn't use modern machinery (and they do), that's being classified as a classic bull**** argument, too.

I never said anything about the equipment they use. I simply suggested if Mylan in the good ole' US of A is bypassing quality control procedures what are they doing in other countries where the FDA cannot easily go and inspect?

Your argument that all manufactures have fancy machines therefore what could go wrong is ridiculous. Again, I reference your post concerning Mylan in WV, the Ethex recall and the Digitek recall. You can call these "isolated incidents" if you want. I think it's a sign of bigger problems that are not being caught because the FDA is under funded and is not inspecting as frequently as they should. Also these companies do not care and just want to make as much money as possible.

Here is a quote from The Telegraph from Calcutta India. Read the rest of the article it is quite interesting.

New Delhi, July 31: Poor regulatory monitoring of drug manufacturing practices, opaque state regulators and public apathy may be factors fuelling the fairly steady levels of substandard medicines in India, medical experts have said.

Pharmacology experts believe the current regulatory environment in India is conducive to laxity in drug manufacturing practices which has the potential to contribute to substandard drugs. "When you have an unsupervised environment, some companies are likely to drift towards low (manufacturing) standards," a senior official in the World Health Organisation said, requesting anonymity.

But questions over manufacturing standards practiced at even some leading Indian companies have tumbled out through US inspections of facilities that manufactured drugs intended for export to the US.

Over the past year, the US Food and Drugs Administration (FDA) has sent warning letters to at least two companies — Ranbaxy and Lupin — saying that inspections at their facilities in India had revealed significant deviations from the US current good manufacturing practice regulations. Both letters, made public by the FDA on its website, list out point-by-point observations by the US inspectors.

http://www.telegraphindia.com/1090801/jsp/frontpage/story_11308519.jsp


http://www.factsandcomparisons.com/News/ArticlePage.aspx?id=8294

http://www.cigna.com/customer_care/healthcare_professional/pharmacy/digitek_recall.pdf

You can keep tucking yourself into bed at night wispering "They have fancy macines its okay what could go wrong" as you drift off to sleep. I on the other hand think there is a problem.

 

[WVUPharm2007]

Yeah, but the entire argument is bunk. Why? Because if every damn manufacturer out there has shoddy quality control, then it wouldn't matter if you kept them on one product or not. Because that one product would show incredible variance in and of itself. So **** it, use the generic. Why does it matter? And how would you know which one was the evil, dastardly manufacturer and which was the pure, Jesus-like manufacturer. I don't doubt that people may get lazy, but I can't go around practicing assuming that they are. It's bull****.

Plus, they ARE isolated incidents. And if a random ass Indian manufacturer is showing poor manufacturing practices, the FDA should step in. It's ******ed to go around all day assuming every damned generic was produced by the aforementioned Jim Bob in his basement. Go find employment with Abbott. They would enjoy your bull****.

Then there is my actual experience with the numbers. In actual practice, we use different brands every day in the hospital. At my hospital, the pharmacists monitor INRs daily. And under those controlled conditions, we've never noticed peoples' INRs dropping off whenever a new lot or brand is used. Never. They were using an unknown generic at home...their INR is 2.5....they come in and use like 2 different products over 2.5 weeks...take the weekly INR for stable patients...yup...INR is still 2.5...and it happens every day. Has your experience monitoring daily/weekly INRs with patients using variable products been any different?

Oh...right...

 

[MountainPharmD]

Yeah, but the entire argument is bunk. Why? Because if every damn manufacturer out there has shoddy quality control, then it wouldn't matter if you kept them on one product or not. Because that one product would show incredible variance in and of itself. So **** it, use the generic. Why does it matter? And how would you know which one was the evil, dastardly manufacturer and which was the pure, Jesus-like manufacturer. I don't doubt that people may get lazy, but I can't go around practicing assuming that they are. It's bull****.

Plus, they ARE isolated incidents. And if a random ass Indian manufacturer is showing poor manufacturing practices, the FDA should step in. It's ******ed to go around all day assuming every damned generic was produced by the aforementioned Jim Bob in his basement. Go find employment with Abbott. They would enjoy your bull****.

Then there is my actual experience with the numbers. In actual practice, we use different brands every day in the hospital. At my hospital, the pharmacists monitor INRs daily. And under those controlled conditions, we've never noticed peoples' INRs dropping off whenever a new lot or brand is used. Never. They were using an unknown generic at home...their INR is 2.5....they come in and use like 2 different products over 2.5 weeks...take the weekly INR for stable patients...yup...INR is still 2.5...and it happens every day. Has your experience monitoring daily/weekly INRs with patients using variable products been any different?

Oh...right...

My argument is bunk yet yours is valid because you have 2 months of "experience" monitoring INR levels. I was monitoring and adjusting INR levels when I was an intern 8 years ago genius. It was fun for a week and then became just another boring task like reconciling MAR discrepancies. You've done it for 2 months and woo hoo now you are an expert? Come at me with 10 years of your anecdotal "evidence" and I still would not care. Did you read any of the links I posted?

I do not think generics are bad. I think there are some serious flaws in the regulatory oversight of drug manufacturers. I believe the latest incidents are foreshadowing of greater problems to come. You haven't run into any problems with warfarin? You probably won't. The single greatest factor to effect a patients INR is the patient. When they take it or if they even remember to take it everyday, thier diet ect. Same statement applies to generic Synthroid.

You are extrapolating your very limited experience with warfarin and trying to apply it to the entire generic drug industry. I used to think about the same as you when I was young and new. I have read enough articles and participated in enough class I manufacture recalls to be a little skeptical of the generic drug industry right now..

 

[WVUPharm2007]

My argument is bunk yet yours is valid because you have 2 months of "experience" monitoring INR levels.

No, mine is valid because off all the stuff I mentioned before I talked about anecdotal experience - which I use to augment evidence-based findings. Which you conveniently ignored.

I was monitoring and adjusting INR levels when I was an intern 8 years ago genius. It was fun for a week and then became just another boring task like reconciling MAR discrepancies. You've done it for 2 months and woo hoo now you are an expert? Come at me with 10 years of your anecdotal "evidence" and I still would not care.

Ok...yet a bunch of random news articles and a few theories backed by ziltch evidence-based studies isn't anecdotal? Ok, whatever. Guess what...the only evidence-based trials show that they are equivalent. Plus my anecdotal observations leads me to believe that you are freaking crazy. I'm not insane enough to think that my isolated experience is the be all end all...but when it matches up perfectly with the only evidence-based data out there...I'm sorry...but you don't convince me of anything...

Did you read any of the links I posted?

No. Because you're not posting any sort of evidence. Why care.

But because you whined I read them. I don't get your point. So a few generic manufacturers made a few bad batches. I don't care. Branded manufacturers make bad batches, too. Are you seriously so obtuse that you think that branded drugs never experience recalls? Gimme a break.

I do not think generics are bad. I think there are some serious flaws in the regulatory oversight of drug manufacturers. I believe the latest incidents are foreshadowing of greater problems to come. You haven't run into any problems with warfarin? You probably won't. The single greatest factor to effect a patients INR is the patient. When they take it or if they even remember to take it everyday, thier diet ect. Same statement applies to generic Synthroid.

Ok...so then what the hell is your entire point? "Oh no generic manufacturers are EVUL!!!.....but I'm sure there aren't any clinically important effects...ahem...in fact I don't think they are bad..."

You are extrapolating your very limited experience with warfarin and trying to apply it to the entire generic drug industry.

**** you and your appeal to authority logical fallacy bull**** about limited experience. That **** doesn't fly in formal debate and it doesn't fly with me. Evidence or stfu. Nobody cares about the theories the voices in your head formulate in between bagging Doritos and Diet Coke.

I used to think about the same as you when I was young and new.

Hey, everyone becomes a little slow and senile with age. It's ok.

I have read enough articles and participated in enough class I manufacture recalls to be a little skeptical of the generic drug industry right now..

So you're anecdotal evidence good...mine bad? Ok, crazy hypocrite person. The problem with your assumption is that you will find just as much controversy in branded manufacturers, too. Old Timer had some good links in a thread a while back. Nobody is saying lazy people working at manufacturers don't **** **** up. But, again, it's not a good idea to base evidence-based medicine on the wild assumption that some arbitrary generic is manufactured by Jim Bob in his basement meth lab.

So in summary...no, I don't agree with you. No, I don't have a reason to agree with you. No, you're not going to change my opinion. So just give up. Because you know damn well I'm a crazy hilljack with no life and I'll keep doing this all week. I live in BFE and I've got nothing better to do.

 

[SpirivaSunrise]

Show me the data....and when/if you do, I will show you the better data that tells the real story.

Enjoy your trip?

 

[ForcedEntry]

 

[MountainPharmD]

So in summary...no, I don't agree with you. No, I don't have a reason to agree with you. No, you're not going to change my opinion. So just give up. Because you know damn well I'm a crazy hilljack with no life and I'll keep doing this all week. I live in BFE and I've got nothing better to do.

Give up? Oh, I am just getting started! I have a 12 hour shift today so it is on. They cut our internet access off at work. We had to submit pharmacy/work related websites for approval. I managed to sneak SDN in as a pharmacy reference site. This is the only cool thing I can access for 12 hours today. Again, it's on like Donkey Kong.

 

[WVUPharm2007]

Give up? Oh, I am just getting started! I have a 12 hour shift today so it is on. They cut our internet access off at work. We had to submit pharmacy/work related websites for approval. I managed to sneak SDN in as a pharmacy reference site. This is the only cool thing I can access for 12 hours today. Again, it's on like Donkey Kong.

I got in trouble at work because the IT department noticed that the bandwidth used by the pharmacy increased 3500% whenever I was working...lmao...

 

[MountainPharmD]

I got in trouble at work because the IT department noticed that the bandwidth used by the pharmacy increased 3500% whenever I was working...lmao...

Awesome....first time I have sat down since 8:30 this morning. You may have to wait another day Mr. Mike.

I am waiting to get busted. I can't believe I was able to sneak this website in. It is on the approved list for now.