Nepal develops more effective drug for typhoid

[Anil Tuladhar]

Above is the message which is being circulated around the world regarding the trial of Gatifloxacin on 390 typhoid patients in Patan Hospital by a team of our Nepali Doctors.

But I am horrified to read about Gatifloxacin and its side effects. This drug was withdrawn from the USA market on 1st May 2006 due to its serious and life-threatening side-effects. It's very puzzling that a drug that has been withrawn from the US market because of its life threatening side effects will be matketed as a " big breaktrough" in Nepal. I thought it is my duty to inform all of us concerned and those involved in patient care and lets not make our own people guinea pig of the drug companies.

Please visit following sites for the detailed information:
Gatifloxacin - Wikipedia, the free encyclopedia
Tequin Adverse Side Effect News and Information

[Pal]

thanks for this info.... Im sure this message will reach to the researchers

[Angel]

Dear Tuladhar,

Its very good that you brought up this issue. I talked to Dr. Buddha Basnyat the man behind this research. He has provided me the article published in PLOS One [CLICK HERE to read the article]. He has following words with me


Dear Angel,

Please read the article if you have not done so. The point about the dysglycemia and possible life threatening complications is discussed in the article. There seems to be no danger in the younger population in whom our enteric fever is pretty much confined. Importantly, this aspect of the withdrawal by the USA was reviewed by our ethics board and our drug board (DDA) quite extensively only after which we received permission.

This was not a question of making guinea pigs of people, and please let us not try to spread baseless fear.

Oxford University was also involved in this study and they too have very stringent human rights record and are very politically correct. Indeed it was also passed by their ethical review board.

I urge you to read the article which I have attached and also let the good Dr Tuladhar be informed about it. There was zero conflict of interest.

Please feel free to ask any questions. Please note this drug is extensively used in India, Vietnam ( where it is the drug of choice for typhoid) and I believe is available in the UK.

Best wishes,

Buddha Basnyat, M.D.
Home
6-2-449 Baluwatar
GPO Box 3596, Kathmandu, Nepal
Phone:977-1-4418 774 (Home)
Email:rishibas@wlink.com.np

Office
Nepal International Clinic
GPO Box 3596,Laldurbarmarg 47
Kathmandu, Nepal
Phone: 977-1- 4434 642, 4435 357 (Office)
Fax:977-1-4434 713
Email:nic@naxal.wlink.com.np
Website :Nepal International Clinic

I hope this information will be helpful. Incase you need more info please email him for further detail.

Regards

[BoilingIce]

Thanks Anil for informing everyone and thanks Angel for the clarification. But i wud like to draw attention of the researchers that there hasnt been enuf information given to the patients while including the subjects. It happened to one of my relative.

[Anil Tuladhar]

This is the message I received just now from Nepal pharmacy Council.

Dear All
If your concern is for GatiIfloxacin than I want to inform you that this drug not yet approved for therapeutic use in Nepal.
May be some body is exposed in India. Department of Drug Administration, Drug consultative Council, Ministry of Health and Nepal Pharmcy Council are not convinced for any therapeutic benifit of GatiIfloxacin.
For the registration of this GatiIfloxacin any of the referal hospital's Drug and Therapeutic Comittee (DTC) have to send a proposal with full justification to DDA. Now I it is quite impossible.
So we are at least safe aganist any toxicities of GatiIfloxacin.

But I read the Alert Anti-typhoid drug! It is true. We have to use any of the AntiTyphoid drug with preacuation.

Thank you

Dr. D P Khanal
Member
Nepal Pharmacy Council

[Anil Tuladhar]

Thanks Angel for forwarding our concern to the senior investigator and posting his reply and also forwarding me the original article. I am no way trying to belittle their hardwork and effort on this study and provide cheaper drug for one of the commonest infectious disease in Nepal. It is a superb paper as far as looking into the outcome measures.

I am writing this out of my genuine concern regarding Gatifloxacin, which is banned in USA, definitely not licensed in the UK and withdrawn from European Marketin 2004 (Pharma Japan 2004, ISSU 1886, page 9).

I would be most grateful if any of the authors be kind enough to comment on our following concerns:

1. What was the safety reason for which this study was prematurely terminated (though not mentioned in the original paper)? Please read following link:ISRCTN75784880 - An open randomised comparison of Gatifloxacin versus Cefixime for the treatment of uncomplicated enteric fever

2. I would be reassured if you could clarify whether this study was approved by Oxford Tropical Research Ethics Committee. Please refer to the above link once again.

3. Were the subjects given sufficient information (including the major side effects) before being enrolled for the study? One of the posting in this thread mentions it otherwise. There wasn't enough clarity in the "Participants" section in this regard.

4. Though senior investigator mentions in his reply in this thread, it would have been more informative to the readers and the participants in the trial to be aware of Gatifloxacin's status in many countries since the drug was withdrawn only after the study had been terminated.

5. I would be most interested to know if Oxford University Ethics Committee would find it ethical in approving similar study involving Gatifloxacin in the UK.

Originally Posted by Angel

Dear Tuladhar,

Its very good that you brought up this issue. I talked to Dr. Buddha Basnyat the man behind this research. He has provided me the article published in PLOS One [CLICK HERE to read the article]. He has following words with me


Dear Angel,

Please read the article if you have not done so. The point about the dysglycemia and possible life threatening complications is discussed in the article. There seems to be no danger in the younger population in whom our enteric fever is pretty much confined. Importantly, this aspect of the withdrawal by the USA was reviewed by our ethics board and our drug board (DDA) quite extensively only after which we received permission.

This was not a question of making guinea pigs of people, and please let us not try to spread baseless fear.

Oxford University was also involved in this study and they too have very stringent human rights record and are very politically correct. Indeed it was also passed by their ethical review board.

I urge you to read the article which I have attached and also let the good Dr Tuladhar be informed about it. There was zero conflict of interest.

Please feel free to ask any questions. Please note this drug is extensively used in India, Vietnam ( where it is the drug of choice for typhoid) and I believe is available in the UK.

Best wishes,

Buddha Basnyat, M.D.
Home
6-2-449 Baluwatar
GPO Box 3596, Kathmandu, Nepal
Phone:977-1-4418 774 (Home)
Email:rishibas@wlink.com.np

Office
Nepal International Clinic
GPO Box 3596,Laldurbarmarg 47
Kathmandu, Nepal
Phone: 977-1- 4434 642, 4435 357 (Office)
Fax:977-1-4434 713
Email:nic@naxal.wlink.com.np
Website :Nepal International Clinic

I hope this information will be helpful. Incase you need more info please email him for further detail.

Regards

[Khushboo]

Thanx a lot for drawing our attention towards it.

The researchers shouldnot play with anyones life, hope this post might open their eyes regarding this.

[Angel]

Originally Posted by Anil Tuladhar

Thanks Angel for forwarding our concern to the senior investigator and posting his reply and also forwarding me the original article. I am no way trying to belittle their hardwork and effort on this study and provide cheaper drug for one of the commonest infectious disease in Nepal. It is a superb paper as far as looking into the outcome measures.

I am writing this out of my genuine concern regarding Gatifloxacin, which is banned in USA, definitely not licensed in the UK and withdrawn from European Marketin 2004 (Pharma Japan 2004, ISSU 1886, page 9).

I would be most grateful if any of the authors be kind enough to comment on our following concerns:

1. What was the safety reason for which this study was prematurely terminated (though not mentioned in the original paper)? Please read following link:ISRCTN75784880 - An open randomised comparison of Gatifloxacin versus Cefixime for the treatment of uncomplicated enteric fever

2. I would be reassured if you could clarify whether this study was approved by Oxford Tropical Research Ethics Committee. Please refer to the above link once again.

3. Were the subjects given sufficient information (including the major side effects) before being enrolled for the study? One of the posting in this thread mentions it otherwise. There wasn't enough clarity in the "Participants" section in this regard.

4. Though senior investigator mentions in his reply in this thread, it would have been more informative to the readers and the participants in the trial to be aware of Gatifloxacin's status in many countries since the drug was withdrawn only after the study had been terminated.

5. I would be most interested to know if Oxford University Ethics Committee would find it ethical in approving similar study involving Gatifloxacin in the UK.

Here is the reply from Prof. Basnyat I just got a mail from him...



Yes dr Tuladhar please read the article as many of the answers are in the article. I would also invite you to write in PLoS one website because this is an open access journal and they invite your comments there and everyone related to the article could read your comments.

1. What was the safety reason for which this study was prematurely terminated (though not mentioned in the original paper)? Please read following link: ISRCTN75784880 - An open randomised comparison of Gatifloxacin versus Cefixime for the treatment of uncomplicated enteric fever
As the article clearly states the trial was stopped because gati was found to be so effective in comparison to cefxime that the data safety monitoring board thought it was unethical to continue the trial based on priori defined numbers. This was not for safety reasons.

2. I would be reassured if you could clarify whether this study was approved by Oxford Tropical Research Ethics Committee. Please refer to the above link once again.
Yes again may I suggest you please read the article carefully. It is the first sentence in the Methods section.

3. Were the subjects given sufficient information (including the major side effects) before being enrolled for the study? One of the posting in this thread mentions it otherwise. There wasn't enough clarity in the "Participants" section in this regard.
Yes.


4. Though senior investigator mentions in his reply in this thread, it would have been more informative to the readers and the participants in the trial to be aware of Gatifloxacin's status in many countries since the drug was withdrawn only after the study had been terminated.
The drug company pulled the drug out in the USA whilst the trial was going on and in the discussion we do indeed talk abou the NEJM article that caused the company to pull the drug out in the USA. Where typhoid is rampant ( eg in India and Vietnam) this drug is indeed used quite a lot as I mentioned earlier. Again as I clearly mentioned earlier and also as is mentioned in the article the side effects in the NEJM study were confined to an elderly population with usually renal failure.

5. I would be most interested to know if Oxford University Ethics Committee would find it ethical in approving similar study involving Gatifloxacin in the UK.
I have no idea.

[Ajay]

I didnt get

it was unethical to continue the trial based on priori defined numbers.

Could anyone clearify this, please?

[anilpandit]

Well, I believe it is the most effective and cheap medicine available todate. I say this becuase that's what the data says and I was primarily invovled in treating the patients.

There are several clarifications I want to make about the issues that have come up in this forum.

First of all we should read and be updated and verify what we have heard from other sources. It reminds me of good old saying of "Kag le kan lagyo vandai ma kan ko pachadi dau dunu hudai "

The drug is not banned in the US!!! And FDA still continues to approve it. They haven't withdrawn it. Only the Bristol Myer Siquib, a patent right company withdrew its sale only from North American market because of fear of litigations. That's being hysteric.Once agian, what ever treatment modalities US doctors follow is not appropriate all the time.

What ever side effects of hypo and hyperglycemia reported so far were primarily in the patients with diabetes. We didn't have any patient with diabetes enrolled in our study. We gave Gatifloxacin to 390 patients and none of them had any serious side effects. As every knows so called dangerous hypo/hyperglycemia would warrant these patients to be admitted in the hospital because they become so sick. None of the patients became sick requiring admission rather those on gati improved quicker and better. Only complications we had was in cefixime group.

Well what ever discussion we doing right now is largely based on the retrospective audit of prescriptions in elderly patients whose mean age group 78 years(NEJM, march 2006). They had diabetes and were on oral hypoglycemic agents also. Really can't draw any definite conclusions from that study. We need prospective double blind study to answe this questions.
There are association of dysglycemia with gatifloxacin and association is different from causation. One should give us convincing evidence that gati causes dysglycemia.

Trails are stopped early due to various reasons. One being if a drug is found to be very very effective than other compared drug. Then the trial is stopped in the middle because the difference in out come was so huge that you dont' need to reach the target sample size to have statistically significant results

I anyone need to read or know about gati an FDA, I would suggest you all to do some homework on gati. Read March 2006 NEJM article, go to FDA website and what really FDA says about it. It doesn't say don't use gati. Even with cipro and oflox DDA gives warning of cartilage toxicity, how many of us don't use cipro/oflox in children. FDA hasn't approved any flouroquinolones below 18 years of age. Now does it mean that we are poisoning our kids here in nepal because we are prescribing flouroquinolones in pediatrics as well as in young adults who are between 13 and 18 years of age !!! Did u guys get what I mean?
Being the first author of the article, I would end my discussion saying that I would take gatifloxacin if I get typhoid. I would treat my brothers, father and mother with gatifloxacin if they get typhoid and don't have diabetes.

Anil Pandit, MD
Maryland General Hospital
University of Maryland Medical System
Baltimore, Maryland.