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Center for Drug Evaluation and Research

Pharmacy Compounding Advisory Committee

May 7, 1999

Advisory Committee Conference Room, 1066

Food and Drug Administration

5630 Fishers Lane

Rockville, Maryland 20852

Proceedings By:

CASET Associates, Ltd.

10201 Lee Highway, Suite 160

Fairfax, Virginia 22030

(703) 352-0091



Randy P. Juhl, Ph.D., Chair

Igor Cerny, Pharm.D.

Judith Martin Riffee, R.Ph.

William J. Rodriguez, M.D., Ph.D.Tony Welder, R.Ph.

Loyd V. Allen, Jr.,, Ph.D.

Carmen A. Catizone, M.S., R.Ph.

Elizabeth I. McBurney, M.D.

Sarah L. Sellers, Pharm.D.

Garnet E. Peck, Ph.D.

Christopher T. Rhodes, Ph.D.

William J. Rusho, R.Ph.

Lawrence Trissel, F.A.S.H.P.

Consumer Representative:

Rose-Ellen M. Hope R.Ph.

Industry Representative (non-voting):

David Liebman, R.Ph.

Industry Representative (non-voting):

Joan M. LaFollette, R.Ph.

Consultants to the Committee (Voting):

Kenneth B. Giddes, B.A., M.B.A. (Patient Representative) (Voting on hydrazine only)

Guest Experts of the Committee (Non-voting):

Sid Gilman, M.D.

Janice Dutcher, M.D.

Guest Speakers:

E. William Rosenberg, M.D.

Christopher T. Bever, Jr., M.D.

Donald Sanders, M.D.

Andrew R. Blight, Ph.D.

Ronald Cohen, M.D.

Sharon Hamm, Pharm.D.

Dr. David Jacobus



Call to Order 1

Dr. Randy Juhl

Mild Silver Protein 2

Dr. Wiley Chambers

Open Public Hearing 12

Discussion and Vote on Mild Silver Protein 21

Monosodium Aspartate 22

Dr. Norman Stockbridge

Open Public Hearing 32

Discussion and Vote on Monosodium Aspartate 36

Cyclandelate 38

Dr. John Feeney

Open Public Hearing 53

Discussion and Vote on Cyclandelate 55

Betahistine Dihydrochloride 56

Dr. John Feeney

Open Public Hearing 62

Discussion and Vote on Betahistine Dihydrochloride 62

Hydrazine Sulfate

Dr. Saul Malozowski 65

Dr. Charles L. Loprinzi (via video tape) 72

Ms. Mary McCabe 84

Discussion and Vote on Hydrazine Sulfate 93

PROCEEDINGS [8:30 a.m.]

Agenda Item: Call to Order

DR. JUHL: We will begin. Welcome to day two of the Pharmacy Advisory Committee -- Pharmacy Compounding Advisory Committee. We will continue on today with a review of drug products or drugs that have been nominated for inclusion on the pharmacy compounding bulks list.

I think we will go around the table and have everyone introduce themselves. We have a few new faces at the table. So, if we can start, Judy, with you.

MS. RIFFEE: Good morning. I am Judy Riffee. I am faculty, College of Nursing, University of Florida.

MS. LA FOLLETTE: Joan LaFollette, Bristol-Myers Squibb.

DR. SELLERS: Sarah Sellers, pharmacist, North Carolina.

MR. CATIZONE: Carmen Catizone, representing National Association of Boards of Pharmacy.

MS. HOPE: Rose-Ellen Hope, consumer rep.

MR. RUSHO: William Rusho, University of Utah.

MR. TRISSEL: Lawrence Trissel, the University of Texas, M.D. Anderson Cancer Center.

DR. JUHL: Randy Juhl, University of Pittsburgh, School of Pharmacy.

DR. CERNY: I am Igor Cerny, executive secretary.

DR. MC BURNEY: Elizabeth McBurney, dermatologist from Louisiana.

DR. RODRIGUEZ: Bill Rodriguez from Children's Hospital, National Medical Center in Washington, D.C. and George Washington University.

DR. ALLEN: Loyd Allen, International Journal of Pharmaceutical Compounding, the USP representative.

MS. OGRAM: Lana Ogram, co-chair, FDA.

DR. CHAMBERS: Wiley Chambers, deputy director, Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products.

MS. AXELRAD: Jane Axelrad, associate director for policy in the Center for Drugs and co-chair of the Pharmacy Compounding Steering Committee.

DR. BEHRMAN: Rachel Behrman, deputy director, Office of Drug Evaluation 1.

DR. JUHL: Thank you.

Agenda Item: Mild Silver Protein

Our first drug this morning is mild silver protein. And Dr. Chambers will give a presentation on behalf of the Agency.

DR. CHAMBERS: Good morning.

My name is Wiley Chambers. I am an ophthalmologist with the Division of Anti-Inflammatory, Analgesics and Ophthalmic Drug Products. I am going to talk about mild silver protein.

Mild silver protein has been marketed in the past. It was developed prior to 1938 so that it came into effect or it was used prior to the enactment of the Food, Drug and Cosmetic Act of 1938. It was marketed under the names Argyrol and Protargol and came in a variety of different formulations, including formulations that were marketed as OTC products in a 10 percent solution, both in 15 and 30 ml containers, an Rx product that was 20 percent solution marketed with EDTA in a 1 milliliter dropperette.

While it was being marketed, and to my knowledge it is not currently marketed, it was marketed by Cooper Laboratories and when Cooper Laboratories sold all their products to IOLAB, IOLAB continued to market it for a period of time until IOLAB stopped marketing products and the product was not picked up following the marketing by IOLAB.

The indications that it was marketed under included the treatment of eye infections, preoperatively for eye surgery and as a dye as part of the preop surgical procedure.

There is no question it has been well-known that silver ion is perfectly capable of killing microorganisms. It is also perfectly capable of killing cells and tissues. It was, therefore, considered to be a useful anti-infective agent as long as it was possible to kill the microorganisms without damaging the surrounding tissue.

One of the ways to make it a little bit safer so that it would not damage any of the surrounding tissue was to bind it in a protein complex and that was what the creation of mild silver protein was, was a binding of the silver ion in a mild -- in a protein complex. This made it less harmful to tissues, but, unfortunately, also made it less effective.

It has been studied in a number of different ways, including back in 1937, this slide shows a comparison of the concentration in the number of organisms surviving. Obviously, the fewer the number of organisms surviving, the more effective the product is. And this is a comparison of a number of different products that were available in 1937.

As can be seen on this slide, Argyrol was not one of the more affective products even in 1937. It was used fairly widely during that period of time and because it was continuing to be used, additional studies were done at different points in time. In 1986, another comparison was published in the literature with a variety of different products. Again, the lower the number, the better off it is. And as you can see, mild silver protein with an MIC90 at 200 is far less effective than even thiomersal.

There are also clinical studies in which the product has been evaluated, published in the Archives of Ophthalmology was a comparison between an untreated eye and using mild silver protein, both before irrigating and after irrigating. As you can see, the results are very similar between untreated and treated and, in fact, if you do the wash afterward to wash the mild silver protein out, either in the controlled or uncontrolled, you increase the number of organisms that are found in the eye.

A number of investigators looking back in the literature did not understand why they were continuing to use mild silver protein at their institution and people in New York decided to put together a trial to find out what the true incidence was of endophthalmitis, which is the particular disease that they were trying to prevent.

Endophthalmitis is what destroys eyes. So, it is why we use prophylactic antimicrobials prior to surgery. They looked at a comparison between povidone-iodine, which was being touted as a product that potentially should be used and silver protein, which was the standard at the time.

As you can see, the percentage of positive endophthalmitis cases was considerably lower when using povidone-iodine than it was with silver protein. From the side effect perspective -- this doesn't project, I think, quite as well as the handout did but there is the possibility of silver staining even with a single administration, although it is not particularly common to occur with a single administration of this. It is much more common after repeated administrations.

But as you can see in this picture, the slight gray, bluish gray area in the conjunctiva is the result of repeated administration of mild silver protein. This also does not project as well as the handout, but there is depositing in the lacrimal sac and that will trace then through the skin of a grayish area.

If you look on a slit lamp and look at the cornea itself, you can detect the deposition of the silver protein in the cornea. And if you look on electromicroscopy, look at the basement membrane, you can see the thick black line that is along there is not a normal process. That thick black line is the deposition of silver protein.

This is not the first time that this product has been reviewed. As was discussed a couple of different times, the agency does not frequently completely rule out products at any point in time. We do periodically relook at products and that is what is being done here. There was an OTC review of this product between 1973 and 1979. At that time, the external OTC panel reviewed the data that was available. Some of the slides that I presented were presented at that time and the authors at that time had given me permission to go in and reuse those articles.

From a safety perspective, the panel concluded that there were not toxicity concerns as an OTC product, provided that everybody was warned of the potential deposition of silver. The efficacy to the best that they were able to determine was not supported in any way and they looked and were unable to find any data to support the efficacy. So, the overall conclusion was that it might be useful but it requires clinical studies to show that it was useful.

The literature review that I have done, as well as reviewing the Agency files have not found anything since this time to support the efficacy.

There are a number of alternatives that have been developed and this is a partial list of a number of the anti-infectives that are all currently approved and are available to treat the same types of infections that mild silver protein was originally developed for.

Goodman and Gilman provided a summary of the efficacy and safety that they determined for mild silver protein and I have quoted just a couple of excerpts from the end of Goodman and Gilman's discussion on mild silver protein. They also did not conclude that there was any efficacy, but noted that these products -- and I will -- as listed within the book, ";Fortunately, the colloidal silver preparations are now in a deserved oblivion."; That was at least the conclusion that the textbook made.

I will be happy to take any questions.

DR. JUHL: Questions for Dr. Chambers?

DR. MC BURNEY: I have a question.

Dr. Chambers, are there any conditions in which you could consider using this silver preparation that these other preparations would not be effective?

DR. CHAMBERS: I am not aware of any conditions that the other products are not clearly more effective.

DR. RODRIGUEZ: Having grown up in another area of the world, did you come into the use of Argyrol for, quote, unquote, strep throat?

DR. CHAMBERS: For strep throat?

DR. RODRIGUEZ: That is right.

DR. CHAMBERS: I did not review anything other than the eye indications.

DR. RODRIGUEZ: It used to be used as a painting solution on the tonsils to, quote, unquote, take care of strep throat with similar results.

DR. CHAMBERS: Thank you.

MR. TRISSEL: In looking at the two papers that you presented in here, there seems to be a conflict in the relative efficacy in relation to merthiolate or thiomersal. In one study it shows it is better. In the other study it shows it is much worse.

At least as you have characterized it, I would argue that the second study in 1986 actually compares -- is really a comparison of equivalent activity doses rather than one being better than another. But merthiolate and thiomersal are the same things, right?

By your characterization in one place it would be better and in the other place it would be worse. So, it would be conflicting information.

DR. CHAMBERS: I am sorry. Which are you referring to?

MR. TRISSEL: The 1937 article by Thompson, Isaacs, et cetera, merthiolate is worse by the comparison they have here, is the worst in the category, as I understand this table, right?

DR. CHAMBERS: Correct.

MR. TRISSEL: And Argyrol is the next to the worst.

DR. CHAMBERS: Correct.

MR. TRISSEL: In the next paper in 1986, thiomersal by your characterization is better because it is used in a lower dose, but -- and what I am saying is that I wouldn't characterize this second study in 1986. It is really a study of what doses are equally effective among these different agents.

DR. CHAMBERS: Correct. This is -- they are looking at slightly different avenues. They are looking at slightly different bugs. I mean, this is only a comparison of Neisseria on the 1986 slide, but the orders of magnitude that they are compared to other agents that we have available --

MR. TRISSEL: But it is just a dose equivalency and it doesn't necessarily mean one is superior to the other. You would have to take into account the relative toxicities as well.

DR. CHAMBERS: Absolutely and I would put much more weight on the clinical studies that were done afterwards than I would on the in vitro studies that were done earlier on.

MS. RUSHO: In the study by Isenberg, where the colonies actually increased, doesn't that indicate two things; number one, the solution was not sterile and, number two, it was ineffective?

DR. CHAMBERS: When you wash the eye afterward and it was not well-known before the study was published, what you do is you potentially wash other areas of the eye that were not necessarily covered by the initial drops that you put in -- now, in the conjunctiva. So, that was probably what leads to the increased count. And everybody is trying to wash just the areas where they thought they had already cleansed, but as shown by the data, that is not necessarily the case. It leads to the conclusion that you should not be trying a wash after you attempt to go in and cleanse the area. That is probably the biggest message that that study shows.

MS. RIFFEE: I just have a comment. I appreciate Goodman and Gilman's comment about oblivion, but there is a silver -- a colloidal silver solution that is now being promoted in a non-prescription area among health food stores. I did a seminar and was presented a whole batch of literature on it.

So, just in case we think silver is not out of the picture, it looks like it is coming back in and this is for internal use. And I have none of that material with me, but just as a comment.

DR. CHAMBERS: I am not questioning that products resurface multiple different times. And we discuss the products and what is known about them at the time. Absolutely.

Agenda Item: Open Public Hearing

DR. JUHL: No further questions or comments, let's move to the open public hearing on mild silver protein. We have two speakers listed; Gina Ford -- is Gina here? I don't see her here. Then Rosemary Jacobs. Rosemary, welcome.

MS. JACOBS: My name is Rosemary Jacobs. I am a private citizen. I am not sponsored by anybody. You will read rumors on the Internet that will tell you I am sponsored by the pharmaceutical associations, by the medical associations and by the government. That is not true. If it is true, they must be sending homeopathic checks because I haven't gotten any money from anybody.

Now, I have condition, which is called argyria, a-r-g-y-r-i-a. Argyria is gray skin caused by the ingestion of silver. Argyrol, which the doctor mentioned before, was sold in a Hispanic community in Florida until at least 1996. Argyrol was introduced into commerce in the United States by Dr. Alfred C. Barnes in Philadelphia in 1902. Argyrol was the best known brand of mild silver protein.

It has caused many cases of argyria when taken internally. I have ads that are -- I was born in New York in 1942. I have ads from medical journals that are older than I am in which Argyrol was fraudulently advertised as non-toxic. I have articles from medical journals warning doctors and pharmacists about the fraudulent ads.

Now, Argyrol was used for many purposes. There were many, many kinds of silver medicinals on the market. But remember, folks, there was a time we didn't have antibiotics. People were very sick. There wasn't much they could do. They were using all kinds of noxious substances to try and save people from these horrible diseases. Silver was one of them.

I know I don't have much time. So, I will be glad to answer questions privately later. I have a Web page, where I have got a lot of my information up, but I have got a lot more to put up. I have got citations from the medical literature, which I have been reading for about 30 years now.

I was given nose drops that contained silver by an eye, ear, nose and throat specialist in New York when I was a child. I was 11 years old. I was to take them intermittently as needed for allergies, which I did, and my skin turned gray. I am now splotched. I was originally a solid gray but in the late seventies, I was dermabraded and then I went from solid gray to splotchy gray.

There are other people with argyria living today in the United States. Many people with argyria become reclusive and I am a mild case. I am not a timid person. If anything, I am obnoxious. I feel as though I am speaking for everybody.

Now, I believe, but I am not certain that the doctor that gave me the medicine was ignorant. He was a good person. He was a caring person. I also know he didn't make a cent when my mother bought the drug. The pharmacist, I believe, compounded it and I believe the pharmacist realized the danger and never warned my mother.

I know the companies that are advertised -- the drug companies that advertise silver drugs knew exactly what they were doing. They were lying to make a buck. Now, with Argyrol -- as I said, Argyrol was used for many things and there are three kinds of argyria, generalized or systemic, which I have, which covers large portions of the body, usually the face. There is localized argyria. Argyria has been caused by every form of silver used therapeutically.

It has also been caused by elemental silver. Then there is argyrosis, which is the silver deposits in the eye. Argyrol has caused many, many documented cases of argyrosis. I think as the doctor pointed out, there was one case recently in Canada, where just one application of the drops to the eye have caused deposits in the eye. That is unusual. Usually, it requires repeated doses.

And also from reviewing the literature, it would look as though there is a very, very wide range of individual susceptibility to silver, to silver toxicity. I know that is for generalized argyria. I don't know if that would be true for the eyes, too, but I would just have to assume that probably it is.

Now, as you probably all know, silver nitrate was used in the eyes of neonates and according to the literature, it seemed very effective in stopping blindness, but it was only effective against the bacteria from gonorrhea, which they thought that the infant got from the mother when the infant passed through the birth canal or from the hands of the people taking care of it.

Argyrol was promoted for that use, too. In 1928, the Council of Pharmacy and Chemistry for the American Medical Association reviewed the literature and kept asking the company, please, give us your data. Give us the evidence. You are advertising it for this use. Show us that it works.

Well, they never got the data. They got something -- they got testimonials from maybe six different doctors. They found one of them. The others, they couldn't find and the one had to admit that, no, they weren't using Argyrol. They were using silver nitrate in the eyes of neonates, using it once, not repeatedly.

It didn't work in vitro. It didn't work in vivo. Now, today, there is also the danger if people are permitted to compound this for ophthalmic use, there is the very grave danger that it is also going to be used systemically, people are going to be drinking it. As was pointed out, if you will get on the Internet, if you will go to the health food stores, there are people all over taking what they call colloidal silver. Colloidal silver if you -- I have asked people -- when I first heard about colloidal silver, I was stunned.

I saw an article in a magazine and I thought I was going to read about people that looked like me. I didn't. I read that this is silver in your body, protects you from every bad thing known to man. And it doesn't hurt any good thing known to man and it doesn't hurt the host himself.

I was stunned. There were lists -- they give you lists of these 650 different diseases that it prevents, including cancer. They are promoting it to prevent and cure breast cancer, which I have. You know, I tell them, excuse me, I have it. The nurse thought I was in cardiac arrest. You are telling me silver in your body prevents cancer. How can you say this?

Well, it works for me. Great. It goes on and on and on. I tell them -- the promoters have actually asked me -- I am not a scientist. I tell everybody I am not a scientist. They want me to do their toxicology studies for them. There is no animal model for argyria. You have to line up people who are going to agree to take the stuff to see how much causes argyria. Fine, guys. You have evidence that it prevents or cures a terrible illness, like cancer or AIDS. I bet you are going to have to turn people away. They will be volunteering to take the stuff.

But you don't have any evidence. Until you have the evidence, you can't do toxicology studies to get the people to sign up to agree for the studies. Okay. I did an estimate -- it is on my Web page. I think it is hysterical. I mean, you know, I can't believe that anybody would take an unregulated product -- you know, would take a risk with an unregulated product and want me to evaluate the risk for them. All I have done is gone through the literature and pulled out -- you know, if somebody took a silver nitrate stick in the mouth, so many grams caused argyria and I gave both extremes. And I think in one example somebody used three grams and became argyric, another person used 24.

The same thing with fulvarphenamine(?) in all the different forms. There is this huge, huge wide range and I published it on my Web page for them to look at. The EPA also has done some studies or has something on their Web page about silver.

So, there are people that believe it, though. There are many people out there that actually believe that silver is beneficial for health and it is not toxic. You know why? Because it is natural. It can't hurt.

They are also using it to purify water. From what we can find, when I first found out about colloidal silver, the first thing I did was go to the promoters and say, please, please, guys, show me your evidence. If you can prove, you know, that it actually prevents serious illnesses, like cancer or AIDS, you know, I will go with you to FDA and present the evidence to them and say here, you have got to approve it.

If you have got evidence that you can help people and save lives, there is no government on earth that can stop you. Just give me the evidence. No evidence yet. I am still waiting.

But it is out there and the people believe it and they are using it to purify water. I have heard of cases where people like living in the Southwest instead of carrying, you know, a little bottle of the kind of supposedly purified water you buy in the store, they have their bottle of colloidal silver. They sell machines to make their own.

When I started -- I know lots and lots of dermatologists, who are experts on argyria. Nobody would speak to anybody but me. Now, I found out about this in 1995. Now I have got a lot of doctors and scientists, who are interested. Some of them are trying to test the products out there. What we are getting, we are getting just pure water or we are getting trace elements of silver. But when you think of people going around all day long out in the Southwest carrying a huge bottle of water that they think they have purified with silver, they are being exposed.

And there are also records of people with dairy herds using it in animals. They are using natural products now to cure their animals. The veterinary branch of FDA has told them that they can't do this. But milk, supposedly, is one of the primary sources of silver in the human diet. So that people could be being exposed from many areas. And for this reason, I just feel that the idea, first of all, to use any form of silver in the eye, all the evidence that I have seen indicates first that it is not effective, second that it is dangerous and then there is the potential for abuse.

They hear all the hype and the promo, the false ads. They are going to take it systemically, somebody is. I just don't see any reason why it would be put on a bulk list for compounding. I also would like to ask something of the compounders about -- compounders are compounding colloidal silver. Pharmacists are selling colloidal silver and I would like to know -- I would -- please, is there anyone here, please show me your evidence that the product is beneficial and safe. That is all I want.

If I can see evidence that you have got a product that is beneficial and safe, I will support it. I will endorse it. However, without that evidence, please tell me why you are doing it. Are you ignorant, like my doctor was? Or are you quacks, like my pharmacist was?

Thank you. Are there any questions?

DR. JUHL: Thank you very much for coming to present to the committee.

Is there anyone else who would like to address the committee from the public, who hadn't contacted us ahead of time?

[There was no response.]

Agenda Item: Discussion and Vote on Mild Silver Protein

Seeing none, we will move to discussion. Comments from the committee.

MR. TRISSEL: I wonder if I could be reminded by the Agency who sponsored this material and what was its -- I hesitate to say indication, but what was the proposed use in the community of this material because I am afraid I do not recall.

MS. AXELRAD: It was the International Academy of Compounding Pharmacists, I believe, was the nominator of the substance and I believe it was recommended for use and for the ophthalmic use as an antiseptic.

MR. TRISSEL: Was there any survey or discussion with the ophthalmology groups, whether there is any use of this -- well, obviously, someone is using it, but whether there is any recommended use of this in the ophthalmology community.

DR. CHAMBERS: I am an ophthalmologist. I have talked with a number of the people that presented at the OTC Advisory Committee. There was not any supported use at that time. There has not been any since then.

DR. ALLEN: I am not aware that it is used to any extent anyplace, at least in compounding right now.

DR. JUHL: Are we ready for the question? Again, two options, simpler today. Option 1, we recommend that the mild silver protein be added to the bulks list. Option 2, we would recommend that mild silver protein not be on the bulks list.

All those in favor of Option 1, please raise your hands. Seeing none, all those in favor of Option 2 raise your hands. It is unanimous that we recommend that mild silver protein not be added to the bulks list.

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