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For these reasons, it is relevant to examine the tissue penetration of ciprofloxacin in the bronchial epithelial lining fluid, alveolar macrophages, and peripheral lymph fluid. As shown here, ciprofloxacin concentrations do remain above the Bacillus anthracis MIC for the full 12-hour dosing period.

Now that I have discussed ciprofloxacin from a pharmacokinetics perspective, I'd like to speak with you about ciprofloxacin from an efficacy and safety standpoint. It is the most widely used and studied fluoroquinolone, and Bayer has conducted over 850 ciprofloxacin trials.

There have been over 140,000 adults and 3,400 children treated in these protocols. The safety and efficacy of ciprofloxacin therapy has been well established through these clinical trials and the post marketing experience.

Now, as highlighted, there are no human anthrax data in our submission. To support the anticipated efficacy in this pulmonary indication, we have conducted a review of the U.S. ciprofloxacin trials conducted in lower respiratory tract infections which can serve as a reasonable predictor of efficacy against anthrax.

This analysis includes a review of 34 controlled studies, many of which were conducted in severe diseases. These trials employed well known and established comparators and confirmed the efficacy of ciprofloxacin therapy in lower respiratory tract infection.

Clinical success, defined as cure plus improvement, was demonstrated for 86 percent of ciprofloxacin treated patients in this pool. Patients treated with comparator drugs had an 85 percent clinical success rate.

In addition, we have also reviewed the clinical trial safety database from all patients enrolled in ciprofloxacin protocols. We have found that there were over 1,000 patients, including 104 children, who have received ciprofloxacin for 60 days or longer. The most frequent indications for these patients are listed here.

This slide reviews for you the safety database which includes adverse event rates from ciprofloxacin in controlled patients from comparative trials, those who received cipro from 30 to 59 days, and those who received ciprofloxacin for 60 or more days.

The data show that for the comparative trials that regardless of severity or drug relationship, 31 percent of patients reported an adverse event versus 33 percent of the patients receiving comparator drugs.

The most common adverse events reported for ciprofloxacin therapy were nausea and diarrhea. Of the over 1,000 patients who received ciprofloxacin for over 60 days, we note the 29 percent reported an adverse event and that the frequency of events was similar to those who received shorter durations of ciprofloxacin therapy.

To shift now to ciprofloxacin use in pediatrics, Bayer has data available on over 3,400 patients who have received therapy for a variety of indications, the most common of which is cystic fibrosis. For the 104 patients who received ciprofloxacin for over 60 days, there were no reported serious adverse events.

In comparative pediatric studies conducted, again, primarily in cystic fibrosis patients, the incidence of nausea, vomiting, and rash is somewhat higher for ciprofloxacin treated patients. However, these patients reported fewer arthralgia and joint disorder complaints than those in the comparator group.

An overall review of the global clinical trials database for pediatrics is presented here. Data from all ciprofloxacin patients from clinical trials, those who received 30 to 59 days of therapy, and those who received 60 or more days of ciprofloxacin treatment are shown. The adverse event rate is quite similar for all groups regardless of treatment duration.

Now, as mentioned earlier, Bayer is presently conducting two clinical trials in pediatric patients. We designed these studies in partnership with the FDA.

The first study is a randomized, double blind comparative trial in patients with complicated urinary tract infections.

The second trial is a long term, post dosing observational study in children treated with ciprofloxacin for any indication.

Both trials are currently in the enrollment phase.

Even though Bayer has never promoted ciprofloxacin to pediatricians, we know that it is used to some degree off label in this community, despite the well known quinolone class labeling warnings. Data show that about 14,000 ciprofloxacin prescriptions are written annually in the U.S. for patients under the age of ten. This represents about 0.1 percent of all U.S. ciprofloxacin scrips.

An additional 28,000 prescriptions are written for patients between the ages of ten and 14 years old, and 140,000 scrips or about one percent of the U.S. total use are for patients between the ages of 15 and 17.

All told, we estimate that approximately four and a half million courses of ciprofloxacin therapy have been administered to pediatric patients worldwide since approval.

And I'll now discuss briefly the post marketing safety experience for ciprofloxacin. Ciprofloxacin has been available for prescription use for 13 years. My next overhead will present raw numbers for adverse events reported to Bayer from anywhere in the world, regardless of relationship to ciprofloxacin therapy or any concomitant medications.

These numbers should be viewed in the context of the over 250 million prescriptions dispensed in over five billion individual doses taken worldwide. About half of this exposure has occurred in the United States.

The ten events reported most frequently for all formulations over 13 years are reported here. As you can see, rash is the most commonly reported event, more than twice that of the next event, tendon disorder. For any of these listed events, the frequency of reporting is less than five per one million treatment courses.

Now, as one reviews this data when the age of the patient is known, you can see that the distribution of adverse events is generally similar regardless of the patient's age. Remember that the estimated denominator for the under age 18 group is four and a half million treated patients.

From this database we can say that there does not appear to be a signal for excess joint related adverse events in pediatric patients treated with ciprofloxacin.

Finally, a review of the most frequently reported serious events is shown here. The frequency of serious reports is low for all events, and these events are consistent with the currently approved ciprofloxacin product labeling.

So now to summarize, ciprofloxacin has been available for 13 years, and over 250 million treatment courses have been completed by patients throughout the world.

The pharmacokinetic data shared today supports expected efficacy in the indication of anthrax post inhalation exposure prophylaxis.

Our extensive clinical trials and post marketing experience have shown that ciprofloxacin therapy is safe and effective, including treatment durations up to and exceeding 60 days.

Bayer Corporation, at the encouragement of government agencies, has submitted this labeling application to respond to a public health need. And given the seriousness of the indication and the extraordinary hazards that an anthrax release would entail, the risk-benefit ratio supports ciprofloxacin therapy for this indication.

This concludes my prepared remarks. I and my Bayer colleagues would be happy to answer any questions on ciprofloxacin.

CHAIRMAN RELLER: Are there any questions on the material that Andrew Verderame presented? David.

DR. SOPER: You have a pretty extensive experience now with pediatric exposure. What about pregnant women? Clearly there probably has been opportunity over the years for pregnant women to have been administered cipro. Do you have similar sorts of outcome data on them?

MR. VERDERAME: I would address that to Dr. Felix Monteagudo, who is our Vice President for Drug Safety.

DR. MONTEAGUDO: Felix Monteagudo. I'm in the Drug Safety Group from Bayer.

We really do not have any well controlled studies looking at the use of ciprofloxacin in pregnancy. However, we have had cases where women have taken ciprofloxacin during the pregnancy at various stages of pregnancy, and looking through the data, we have no suggestion of any teratogenic potential arising out of that.

Now, looking at that, clearly, in terms of the indication with anthrax, one would have to look at the benefit-risk ratio that would ensue out of that and possibly the consideration of the consensus document that came out of the JAMA article last year.

CHAIRMAN RELLER: Dr. Archer.

DR. ARCHER: What about data on QT prolongation, particularly in children, and is there any indication that if it were even a small risk that prolonged exposure for like 60 days would increase that risk?

DR. MONTEAGUDO: We have, as you heard from Mr. Verderame's presentation, we have about 250 million prescriptions for this product over about 13 years, and if we were to look at the database that we have, we have only had four cases of Torsade de Point with ciprofloxacin over this entire period of time, and this would lead us to believe this very small incidence in the background of such wide exposure would lead us to believe that this is not a signal for our particular product.

With the specifics regard that you say about children and prolonged duration of therapy, we would not have any additional data to that regard.

CHAIRMAN RELLER: Dr. Chesney.

DR. CHESNEY: Two questions. The first one: have you looked at the cipro MICs for organisms that are resistant to other drugs and are they the same?

The second question is: has there ever been a cipro resistant strain identified?

And the third one: how long does it take for the spore to become the vegetative state in vitro?

MR. VERDERAME: If this is okay with you, there are other speakers who are going to cover all of those topics. We at Bayer are ciprofloxacin experts. We're not necessarily anthrax experts, and I'd rather that be experts answer those questions.

CHAIRMAN RELLER: Thanks.

Yes, Dr. Deitchman.

DR. DEITCHMAN: I'm cursed with a name that everyone stumbles over.

MR. VERDERAME: Me, too.

(Laughter.)

DR. DEITCHMAN: I appreciate your showing the information from the adverse effects database. Recognizing that we don't know much about under reporting in this data, I'm not sure how fair it is to estimate rates, but in reading some of the articles, such as the one by Segev, it is my impression that that database encompasses patients that received a variety of dosages, including some as low as 250 milligrams BID.

Since the indication that we're looking at here would be 500 milligrams BID for most adults, what does the data look like if you break it out by the higher dose experience?

MR. VERDERAME: It's all very similar.

DR. DEITCHMAN: And secondly, how quickly do you achieve MICs following the initial dose? And should there be consideration of a larger loading dose for the initial dosing?

MR. VERDERAME: I'll address that to Dr. John Lettierie.

DR. LETTIERIE: John Lettierie from Clinical Pharmacology Group at Bayer.

Cipro is very rapidly absorbed. So you reach a concentration of 0.06 within a half hour or so, 15 minutes to a half hour.

DR. BROOK: Itzhak Brook from AFRRI.

I have a question about the use of ciprofloxacin in endemic anthrax, which is very prevalent in Thailand, Turkey, Africa, and Russia. Do you have any information about the use of those, of ciprofloxacin, in those countries of course not for inhalation mostly, but for cutaneous or gastrointestinal?

CHAIRMAN RELLER: I should like to ask that we come back to this question later when we've heard the presentations about anthrax, its epidemiology and pathophysiology.

Are there any other questions regarding the safety, pharmacodynamics, pharmacokinetics of ciprofloxacin?

Yes.

DR. ARCHER: Just a question about drug accumulation with cipro, once again, over long periods of time, like 60 days. Is there any evidence that it actually accumulates in lung tissue, for instance, which might be an advantage if you're trying to prevent spore germination with time?



MR. VERDERAME: Again, Dr. John Lettierie.

DR. LETTIERIE: I'm not aware of any data on lung accumulation specifically. It does not accumulate in plasma to any significant degree.

DR. ARCHER: How about other tissues, liver?

DR. LETTIERIE: No, I'm not aware. There's no prolonged -- there's no accumulation.

DR. ARCHER: No accumulation.

CHAIRMAN RELLER: Yes, Dr. Deitchman.

DR. DEITCHMAN: I have a practical question. I'm sort of concerned as some of my CDC colleagues who manage the stockpile. What's been the experience, if any, with the use of diluents if you needed to crush tablets to prepare a suspension for oral use? This might be a practical issue in a community prophylaxis situation.

CHAIRMAN RELLER: I'd ask Dr. Posner to answer that, please.

DR. POSNER: I actually don't have the answer to that question, but what I could say is that ciprofloxacin, I believe, is one of the few antibiotics that we do have an oral suspension available. So it actually is available in an approved marketed oral, non-tablet form. But I don't know the answer specifically to the question about crushing tablets and how it can be diluted.

MR. VERDERAME: And, Dr. Lettierie, can you add something?

DR. LETTIERIE: There is at least one published report of giving crushed tablets to children, and they did attain adequate plasma concentration.

CHAIRMAN RELLER: I'd like to remind everyone that after lunch there will be an open public hearing session, and at this time I should like to thank Mr. Verderame for his succinct, but complete presentation.

MR. VERDERAME: Thank you.

CHAIRMAN RELLER: We now will move into the discussion of anthrax, its epidemiology, pathophysiology, and clinical manifestations.

Dr. Martin Hugh-Jones will be our first invited speaker on these topics.

DR. HUGH-JONES: Thank you, Mr. Chairman.

It's a privilege to be here. Good morning, ladies and gentlemen.

The first half of my talk will be the sort of basic background of what anthrax is, and then the second half will be aspects of the Sverdlovsk epidemic, as we discovered when David Walker and I were there and in retrospect.

Next slide, please.

This is, as I tell my graduate students, Bacillus anthracis is a Swiss army knife as far as an organism goes. It's very straightforward. It's agile on its feet, and what it does it does very well.

It's been known for a long, long time, clinically described first in the 1830s. It's a Gram-positive organism. You can see from this it has a nice capsule around it.

The vaccines were first developed in the 1870s by Greenfield in London and Toussaint in Paris. Pasteur then had a public demonstration Toussaint's vaccine, not his own, I may add, in '82, and it was very successful, and there are a whole series of livestock and human vaccines.

In general, the livestock vaccines are live vaccines and the human ones tend to be dead, except the Russians, in fact, use a live vaccine as they do for brucellosis, as well.

Next please.

It's derived from the Bacillus soil organism. It's Gram positive, and it survives by killing. It has no reason to hang around in the body. Its whole purpose is to kill and do it as quickly as possible, and then form spores, which are capsulated and have a very good survival for decades of years sometimes.

I've got a very large collection in some of our material that's come out of desk drawers, say, in Maputo where it was first isolated from a partridge in '42, and it's still growing very nicely. Thank you.

(Laughter.)

DR. HUGH-JONES: It's a junior relative of the B. cereus/thuringensis group, and recent molecular biology puts it into a group here of a subset, as you might say, which are pathogenic, which cause disease, but it's just a junior member of a larger series, and its pathogenicity depends on its two plasmids, pX01 and pX02.

Next slide.

We've been involved with a study with Northern Arizona University in Los Alamos in the molecular strain definition, and what we've been using is variable number tandem repeats. We have presently -- we have been using eight, but we've now, in fact, expanded it to 36, and these are just sequences which repeat, and without getting too complicated into this and so all of you can understand the level that I understand it, it's a bar code. Just think of it as a bar code.

And we can read these. At first it would take us six months. Now it takes is less than six hours to do that work, and it does a very nice job, and it works extremely well.

Next, please.

A few years ago all anthrax was anthrax. You couldn't tell them apart. There were some which grew better on this culture than that, killed faster than this, but really there was not much difference.

But thanks to being able to take it apart, and the team I'm a member of, we're way in advance of everybody else, I may add, we've been able to work out some very interesting things in it, and I'm not going to bore you with, as my daughter says, once I get started on anthrax, I don't stop, and I know I've only got 30 minutes, and so I'll be very brief.

(Laughter.)

DR. HUGH-JONES: But basically the B strains at the bottom are probably the very first pathogens out of this group and probably existed from Cape Town to the Horn in wildlife, and then with domestication of livestock, it managed to get into these cattle and sheep, and through changing its habits, to go around the world.

What basically it does, it takes advantage of a dormant infection so that an animal can be taken on a caravan or a ship journey and gets to somewhere else before it dies 12 months later.

Also, the A strains appear to be more flexible in the environment in which they live. The B strains need high pH, high calcium levels. The A levels are much more flexible, and there are different forms in different parts of the world, but I'm not here to tell you about that.

But it is all around the world and a fascinating bug. The way it works is pX01 produces three toxic factors. There's the protective antigen, called that because this is the basis of the human vaccine. If you use this as an antigen, it protects. Therefore, it's known as a protective antigen.

This binds to cell surface receptors, and there are about 200, 300 per cell. So it has no difficulty catching at that end.

And then furin comes along and pops the top off rather like you pop the top off a beer can, revealing an adhesion surface at the top.

These then form heptamers, i.e., seven PA groups together clustered, and those open surfaces compete for edema factor or lethal factor that the adhesion surface is where it stick on.

This structure is then drawn into the body of the cell by endocytosis, and then the heptamer structure acts as a portal into the cell itself where the edema toxin or the lethal toxin is produced.

The edema toxin does just that. It produces edema, leakage. You get a lot of fluid like in the lungs. The lungs fill up with fluid. Your kidneys; even in your brain to a certain extent. It allows a substrate for further multiplication.

The lethal factor, through a complicated process not totally understood yet, an oxidation causes the release of large amounts of cysteine and the induction of shock, and when we were in Nekatminsberg (phonetic) talking to the Director of Hospital No. 20 --

PARTICIPANT: Forty.

DR. HUGH-JONES: Forty -- no, 40 was -- well, whichever, the hospital which dealt with the initial triage, and this woman had been there for many years, and these people came in from the local community with high temperatures, substernal pain, anxiety, and she'd be taking their temperatures, taking their pulse, talking to them, and she said, "They would die in mid-sentence." And that is absolutely characteristic of this disease.

One moment you're alive. The next you are dead, and this is as true of animals as it is of human beings.

Next, please.

As I said, for us we regard this as a veterinary disease. If we've failed to control it, it then gets into the human population, and then we see a whole lot of other things.

But very quickly, basically what we see is a farmer calls us up and says an animal that was fine yesterday is dead today. Why? Sometimes you can go out and find an animal, and I have friends who have gone onto a farm and literally as they came in the farm they'd see animals fall over dead in front of them.

I've seen pictures of hippopotami dead on their feet. They died so fast they didn't fall over.

Next, please.

The acute form, yes, you find animals sick. You've got to realize that livestock normally get it from eating. We don't see the pneumonic form.

Dogs and pigs tend to be more resistant, but in this form, they die normally within about 36 hours. Horses take a big longer.

Next, please.

What I call hypoacute -- I'm afraid I had to make a work up because it's not chronic -- but you get internal lesions in dogs and pigs, and they rare die of it, to be quite frank, but they can get very sick.

Human beings at this point, you see cutaneous lesions. A lesion once seen you can never forget it. It's usually around a cut or insect bit, frequently on the hands. It's inflamed. There will be small vesicles forming, and characteristically there is no pain involved in it whatsoever, and I'll show you some pictures of what it looks like.

Next, please.

This is a case of a man in London -- no, Liverpool, and this is absolutely characteristic. It's about the size of a quarter, and there are little vesicles around the side. Once the ulcer is form, the better the ulcer is black, which is why the French call it "charbon." It's otherwise known as Siberian ulcer, and in fact, if you ever see anybody with a circular scar on the inside of their wrist, you'll know that they've had anthrax. It's absolutely pathognomonic.

Next, please.

This was a gentleman in England whose son worked in a bone meal plant, and he lent his father, who was a postman, his scarf, and he developed lesions all around his neck. It was touch and go whether he would live, but he did, in fact.

But without treatment, the skin lesion carries a ten percent fatality risk. With treatment, as long as you get it early, it resolves almost within minutes.

I've had a friend who was treated, and it took 120 minutes for the signs to disappear, although it took much longer for the lesion to resolve.

It responds extremely well to early treatment. Late, you cannot save people; you cannot save animals.

Next, please.

Workers in plants processing woolen hair. This is a slide that Phil Brackmann gave me from his work in New Jersey.

Next, please.

And most frequently on the hands, arms, not seen much elsewhere. People carrying stuff on their shoulders, you'll get lesions up there.

Also, it's in relation to insect bites. If, say, a horsefly has been feeding on an animal that's moribund, they can transfer it on their mouth parts or you get somebody who's been butchering an animal that died, and they then scratch their face, and you may sometimes get a lesion around the eye. It looks terrible, but with treatment, it resolves extremely nicely.

Thank you. Next.

Pulmonary form in human beings, normally occupational. It's not been seen in this country for many years. The onset is sort of like a bout of flu. Then so things calm down for a bit, and then somewhere around the second or third or fourth day usually, you'll develop cyanosis, dyspnea, rapid heart beat, and you get all the lesions which Dr. Friedlander and Dr. Walker will describe to you. So I won't get into that.

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