Trovafloxacine, astemizole, FDA news / Trovafloxacina y astemizole, FDA noticias

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TROVAFLOXACINA Y ASTEMIZOL, NOTICIAS DE LA FDA
TROVAFLOXACIN AND ASTEMIZOL FDA NEWS
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****** DERMAGIC-EXPRESS No.59 *******
****** 23 JUNIO DE 1.999 ***********
23 JUNE 1.999
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EDITORIAL ESPAÑOL:
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Hola a todos, DERMAGIC, de nuevo con ustedes. La trovafloxacina (TROVAN), antibiótico (fluoroquinolona) relativamente nuevo en el mercado, liberado por la FDA en febrero del año pasado, con grandes expectativas, y lanzado por el famoso laboratorio PFIZER, esta siendo retirado de las farmacias y droguerías de nuestro país, y muchos otros más

El hecho es que han habido numerosos reportes de daño hepático, llevando incluso en algunos casos a trasplante de hígado y muerte.

La FDA estudia actualmente la conducta a seguir con este medicamento y advierte sus posibles efectos adversos (Junio de 1.999). Meses después fue RETIRADO COMPLETAMENTE del MERCADO MUNDIAL.

Este antibiótico resulto ser tan potente que con 4 (cuatro) días de tratamiento, producía NECROSIS HEPÁTICA MASIVA, e inclusive MUERTE. Yo tuve una muestra de ese producto en mi consultorio. NO lo Utilicé, y NO lo probé, por ser medicamento nuevo, y muchas veces como lo he dicho en otras ocasiones:

"NO TODO LO QUE BRILLA ES ORO".

Por otra parte el laboratorio JANSSEN el día 21 de Junio 1.999 decide sacar del mercado al ASTEMIZOL, (HISMANAL), en vista de nuevos reportes de efectos adversos y la salida al mercado de otras alternativas.

En estas 11 referencias quedan plasmados los hechos y eventos sobre HISMANAL Y TROVAN.

Saludos a todos !!!

BIENVENIDO a DERMAGIC/EXPRESS DR. Carlos Pinzón (Miami)

Dr. José Lapenta R.,,

EDITORIAL ENGLISH:
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Hello to all, DERMAGIC, again with you. The trovafloxacina(TROVAN), antibiotic (fluoroquinolona) relatively new in the market, liberated by the FDA in February of last year, with big promotion and marketed by the famous laboratory PFIZER, it is being retired of the pharmacies of our country and many other

The facts are that, there have been numerous reports of hepatic damage (MASSIVE LIVER NECROSIS), even taleading to, in some cases to liver transplant, and DEATH.

The FDA studies at this moment the behavior to take with this drug, and notifies its possible adverse effects (June of 1.999). Months later it was COMPLETELY WITHDRAWN from the WORLD MARKET.

This antibiotic turned out to be so potent that after just 4 (four) days of treatment, it caused massive liver necrosis and even DEATH. I had a sample of that product in my office. I did not try it, or test it, because it was a new medication. As I have said many times before:

"ALL THAT GLITTERS IS NOT GOLD."

On the other hand the laboratory JANSSEN the day 21 of June 1.999 decides to take out from of the market the
ASTEMIZOL, (HISMANAL) in view of new reports of adverse effects and the arrival to the market of other alternatives.

In these 11 references the facts and events about TROVAN and HISMANAL are shown.

WELCOME TO DERMAGIC/EXPRESS DR. Carlos Pinzón (Miami)

Greetings to ALL, !!

Dr. José Lapenta R.,,,

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DERMAGIC/EXPRESS(59)
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TROVAFLOXACINA Y ASTEMIZOL, FDA NOTICIAS /
TROVAFLOXACIN AND ASTEMIZOL FDA NEWS
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1.) Levofloxacin and trovafloxacin: the next generation of fluoroquinolones?
2.) Hepatobiliary elimination of trovafloxacin and metabolites following single oral doses in healthy volunteers.
3.) Pharmacokinetics and metabolism of single oral doses of trovafloxacin.
4.) Pharmacokinetics of [18F]trovafloxacin in healthy human subjects studied with positron emission tomography.
5.) Pfizer Relabels Antibiotic Trovan For Serious Infections
6.) Pfizer Asks Canadian Doctors To Limit Trovan Use To Life-Threatening Infections
7.) Public Health Advisory, Food and Drug Administration, Trovan, 09 June 1999
8.) Questions and Answers on Trovafloxacin Public Health Advisory
9.) Trovan (alatrofloxacin mesylate), Pfizer notifies
10.) FDA ISSUES PUBLIC HEALTH ADVISORY ON LIVER TOXICITY ASSOCIATED WITH
THE ANTIBIOTIC TROVAN
11.) JANSSEN PHARMACEUTICA ANNOUNCES THE WITHDRAWAL OF HISMANAL FROM THE
MARKET
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1.) Levofloxacin and trovafloxacin: the next generation of fluoroquinolones?
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AU: Ernst-ME; Ernst-EJ; Klepser-ME
AD: College of Pharmacy, University of Iowa (UI), Iowa City 52242-1112, USA.
SO: Am-J-Health-Syst-Pharm. 1997 Nov 15; 54(22): 2569-84
ISSN: 1079-2082
PY: 1997
LA: ENGLISH
CP: UNITED-STATES

AB: The pharmacology, spectrum of activity, pharmacokinetics, clinical efficacy, and adverse effects of levofloxacin, recently approved by FDA, and trovafloxacin, currently undergoing clinical trials, are reviewed. Compared with quinolones in current use, levofloxacin is more potent against gram-negative bacteria and exhibits better antipseudomonal activity as well as greater oral bioavailability.

Trovafloxacin is more potent than existing quinolones against gram-positive bacteria. Both agents exert their antibacterial effects by inhibiting bacterial DNA synthesis. Compared with other quinolones, levofloxacin and trovafloxacin both demonstrate superior activity against the Bacteroides fragilis group, Chlamydia spp., Mycoplasma pneumoniae, and Mycobacterium spp.

The half-life (t1/2) of levofloxacin is nearly eight hours. Levofloxacin can therefore be administered once daily for mild to moderate infections and twice daily for more serious infections. The recommended daily dose is 500 mg. Trovafloxacin has a t1/2 of 12 hours, which allows for single daily doses, and is extensively metabolized.

Levofloxacin has demonstrated clinical efficacy in the treatment of community-acquired respiratory-tract infections, genitourinary infections, skin and skin-structure infections, acute bacterial sinusitis, and infections of the head and neck. Trovafloxacin may have a role in treating skin and skin-structure or soft-tissue infections respiratory-tract infections, sexually transmitted diseases, and meningitis. Both agents are well tolerated, with central-nervous-system and gastrointestinal adverse effects reported most frequently.

Concomitant administration of antacids or compounds containing meal cations decreases absorption of these quinolones. Levofloxacin and trovafloxacin have favorable antimicrobial and pharmacokinetic profiles, offering the advantages of once-daily doses as well as superior potency and spectrum of activity compared with currently available quinolones.

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2.) Hepatobiliary elimination of trovafloxacin and metabolites following single oral doses in healthy volunteers.
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Author
Melnik G; Schwesinger WH; Teng R; Dogolo LC; Vincent J
Address
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, South Texas Veterans Health Care System, 78284, USA.
Source
Eur J Clin Microbiol Infect Dis, 17(6):424-6 1998 Jun

Abstract

Trovafloxacin, a fluoronaphthyridone derivative related to fluoroquinolones, has significant activity against gram-negative and gram-positive pathogens, including penicillin-resistant Streptococcus pneumoniae, anaerobes and atypical organisms, good tissue penetration and a long elimination half-life.

Following oral administration, less than 10% of the dose is renally eliminated as unchanged drug. Hepatobiliary elimination of trovafloxacin was examined by comparing the time course and bile and serum concentrations of trovafloxacin and its metabolites following oral administration to three patients with in-dwelling nasobiliary catheters or T-tubes.

Following a single 200 mg oral dose, the mean maximum plasma trovafloxacin concentration was 2.0+/-0.4 mg/l, the area under the concentration-time curve 22.0+/-5.5 mg x h/l and the elimination half-life 8.5 h.

Values in bile for the same subjects were 27.8+/-9.6 mg/l, 327.7+/-142.9 mg x h/l and 10.7 h. Corresponding values for the N-acetyl metabolite in bile were 3.8+/-3.4 mg/l, 35.3+/-29.8 mg x h/l and 8.3 h.

The mean bile : serum ratio of trovafloxacin was 14:9 and consistent with biliary elimination. Serum concentrations of trovafloxacin in this study were similar to those reported in healthy volunteers. Bile concentrations of trovafloxacin substantially exceeded those of the N-acetyl metabolite, suggesting efficient clearance of the metabolite or that hepatic metabolism of trovafloxacin is not extensive.

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3.) Pharmacokinetics and metabolism of single oral doses of trovafloxacin.
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Author
Vincent J; Teng R; Dalvie DK; Friedman HL
Address
Department of Clinical Research, Pfizer Central Research, Groton, Connecticut 06340, USA. Source Am J Surg, 176(6A Suppl):8S-13S 1998 Dec
Abstract

Trovafloxacin, a new fluoronaphthyridone derivative related to fluoroquinolone antimicrobial drugs, has demonstrated the following characteristics: significant gram-positive and gram-negative activity; significant activity against anaerobes and atypical respiratory pathogens; approximately 11-hour elimination half-life, permitting once-daily administration; and good tissue penetration.

Because <10% of an orally administered dose is recovered in urine as unchanged drug, the predominant route of trovafloxacin elimination appears to be nonrenal. The two studies described in this review examined the metabolism and excretion of trovafloxacin and compared the time course and concentrations of trovafloxacin and its metabolites in bile to those in serum. In the first study, four healthy male volunteers received a single, oral 200-mg dose of radiolabeled trovafloxacin. In the second study, three patients with indwelling nasobiliary tubes received a single 200-mg dose of trovafloxacin. Samples of blood, urine, bile, and feces were collected.

Trovafloxacin in urine and serum was analyzed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection and in bile by HPLC-mass spectroscopy (MS). Levels of the N-acetyl metabolite in bile were determined by HPLC/UV/MS. Metabolites in serum, urine, and feces were determined by reverse-phase HPLC/MS, and radioactivity in these samples was assayed by liquid scintillation counting. In the first study, 63.3% and 23.1% of total radioactivity were recovered in feces and urine, respectively, with most of the radioactivity in urine in the form of the ester glucuronide metabolite (12.8%) and unchanged trovafloxacin (5.9%).

Unchanged drug, the N-acetyl metabolite, and the N-sulfate of trovafloxacin accounted for 43.2%, 9.2%, and 3.9%, respectively, of the radioactivity in feces. In the second study, biliary trovafloxacin concentrations were highest between 1.5 and 10 hours postdose, and the maximum concentrations ranged from 18.9 to 37.9 microg/mL. The mean bile:serum ratio of trovafloxacin was 14.9, and the biliary concentration of parent drug was higher than that of its N-acetyl metabolite. In both studies, trovafloxacin was well tolerated, with no discontinuations due to adverse events. The pharmacokinetic profile of trovafloxacin in serum was consistent in healthy subjects and in individuals who had undergone recent hepatobiliary surgery.

Trovafloxacin is metabolized primarily by the liver, through phase II metabolism (glucuronidation 13.2%, N-acetylation 10.4%, and N-sulfoconjugation 4.1%); minimal oxidative metabolism was detected. Renal elimination accounted for <10% of the administered dose.

The high bile to serum ratio and higher trovafloxacin concentrations relative to metabolite concentrations are consistent with nonrenal elimination. These pharmacokinetic and pharmacodynamic results, together with a broad antimicrobial spectrum, long 11-hour elimination half-life, and low drug-interaction potential, suggest that trovafloxacin may be particularly appropriate for use in the surgical setting.

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4.) Pharmacokinetics of [18F]trovafloxacin in healthy human subjects studied with positron emission tomography.
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Author
Fischman AJ; Babich JW; Bonab AA; Alpert NM; Vincent J; Callahan RJ; Correia JA; Rubin RH
Address
Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School,
Boston, MA 02114, USA. [email protected]
Source
Antimicrob Agents Chemother, 42(8):2048-54 1998 Aug

Abstract

Tissue pharmacokinetics of trovafloxacin, a new broad-spectrum fluoroquinolone antimicrobial agent, were measured by positron emission tomography (PET) with [18F]trovafloxacin in 16 healthy volunteers (12 men and 4 women). Each subject received a single oral dose of trovafloxacin (200 mg) daily beginning 5 to 8 days before the PET measurements.

Approximately 2 h after the final oral dose, the subject was positioned in the gantry of the PET camera, and 1 h later 10 to 20 mCi of [18F]trovafloxacin was infused intravenously over 1 to 2 min. Serial PET images and blood samples were collected for 6 to 8 h, starting at the initiation of the infusion. Drug concentrations were expressed as the percentage of injected dose per gram, and absolute concentrations were estimated by assuming complete absorption of the final oral dose. In most tissues, there was rapid accumulation of the radiolabeled drug, with high levels achieved within 10 min after tracer infusion.

Peak concentrations of more than five times the MIC at which 90% of the isolates are inhibited (MIC90) for most members of Enterobacteriaceae and anaerobes (>10-fold for most organisms) were achieved in virtually all tissues, and the concentrations remained above this level for more than 6 to 8 h.

Particularly high peak concentrations (micrograms per gram; mean +/- standard error of the mean [SEM]) were achieved in the liver (35.06 +/- 5.89), pancreas (32.36 +/- 20. 18), kidney (27.20 +/- 10.68), lung (22.51 +/- 7.11), and spleen (21. 77 +/- 11.33). Plateau concentrations (measured at 2 to 8 h; micrograms per gram; mean +/- SEM) were 3.25 +/- 0.43 in the myocardium, 7.23 +/- 0.95 in the lung, 11.29 +/- 0.75 in the liver, 9.50 +/- 2.72 in the pancreas, 4.74 +/- 0.54 in the spleen, 1.32 +/- 0.09 in the bowel, 4.42 +/- 0.32 in the kidney, 1.51 +/- 0.15 in the bone, 2.46 +/- 0.17 in the muscle, 4.94 +/- 1.17 in the prostate, and 3.27 +/- 0.49 in the uterus.

In the brain, the concentrations (peak, approximately 2.63 +/- 1.49 microg/g; plateau, approximately 0.91 +/- 0.15 microg/g) exceeded the MIC90s for such common causes of central nervous system infections as Streptococcus pneumoniae (MIC90, <0.2 microg/ml), Neisseria meningitidis (MIC90, <0.008 microg/ml), and Haemophilus influenzae (MIC90, <0.03 microg/ml). These PET results suggest that trovafloxacin will be useful in the treatment of a broad range of infections at diverse anatomic sites.

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5.) Pfizer Relabels Antibiotic Trovan For Serious Infections
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NEW YORK, NY -- June 9, 1999 -- Pfizer Inc. said today it will be notifying prescribing physicians to limit the use of Trovan(R) (trovafloxacin) tablets and intravenous formulation to certain serious infections.

This action follows discussions with the United States Food and Drug Administration regarding the agency's interpretation of spontaneous adverse event reports of rare serious hepatic events associated with Trovan observed in post-marketing surveillance. More than 2.5 million prescriptions have been written for Trovan, which was introduced in February 1998.

Pfizer has received reports of 140 cases of hepatic adverse events world-wide from February 1998 through early May, all of which have been submitted to regulatory authorities.

"The spontaneous adverse event reporting system is helpful in identifying rare adverse events, but data derived from these reports cannot be used exclusively to draw conclusions about a product's risk-benefit profile," said Joe Feczko, M.D., Pfizer's senior vice president of world-wide medical operations and regulatory affairs. "We have a difference of opinion with the agency over the interpretation of these data and the regulatory action being taken.

"Pfizer believes that this risk assessment requires additional scientific evaluation and analysis in order to provide physicians with the proper clinical guidance to use Trovan safely and effectively. Trovan has unique therapeutic advantages that are not shared by other commonly used antibiotics and the degree of risk associated with Trovan use is not markedly different when compared with other widely used antibiotics such as penicillins."

Pfizer is continuing to collect medical information and conduct additional analyses to further understand the incidence of these events. The company will continue to work collaboratively with the FDA to ensure Trovan's appropriate use.

"While these analyses continue, Pfizer believes it prudent and responsible to voluntarily limit the use of Trovan to serious in-patient infections where Trovan has an important role," Dr. Feczko said. "We will be widely communicating this new information about Trovan to the medical community, wholesalers and pharmacists as quickly as possible."

Pfizer noted that these serious hepatic events were too rare to be observed among the approximately 7,000 Trovan patients in the clinical trials, which were among the largest ever conducted for an anti-infective medicine. Many of the severe hepatic cases reported appear to be due to a hypersensitive (allergic) type reaction. Additional medical factors, such as underlying illnesses and the use of other medications, may also have contributed to the reported liver problems.

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6.) Pfizer Asks Canadian Doctors To Limit Trovan Use To Life-Threatening Infections
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June 15, 1999

KIRKLAND, QC -- June 15 -- Pfizer Canada Inc. is asking prescribing physicians to limit the use of its antibiotic Trovan (trovafloxacin/alatrofloxacin) to certain serious life-threatening infections, which are treated in the hospital. Pfizer Canada Inc. will restrict the distribution of Trovan to hospital pharmacies. This voluntary action follows consultation with Health Canada regarding the interpretation of spontaneous reports of rare serious unpredictable hepatic events associated with Trovan through post-marketing surveillance.

Post-marketing safety monitoring is performed by Pfizer Inc for all of its products where information on reported adverse events is continuously provided to regulatory authorities worldwide.

An estimated 2.5 million prescriptions have been issued for Trovan worldwide since its introduction in February 1998. To date, Pfizer Inc. has reported to regulatory agencies around the world 152 documented cases of serious hepatic adverse events associated with the drug therapy. These include nine spontaneous cases involving hepatic failure where patients required liver transplant and/or died. Trovan was introduced in Canada in January 1999.

Pfizer Canada is currently working with Health Canada to update the product labeling in order to reflect the new information. Pfizer Inc. will continue to collect and evaluate data to further understand the incidence of these events. In the interim, Pfizer Canada believes it is prudent and responsible to voluntarily limit the use of Trovan to serious life-threatening infections treated in the hospital, where Trovan has an important role. These infections include hospitalized community-acquired pneumonia, nosocomial pneumonia (hospital-acquired pneumonia), complicated intra-abdominal infections, pelvic infections, complicated skin and skin structure infections.

It is recommended that patients currently taking Trovan should NOT discontinue therapy until they have discussed their treatment options with their physician. Pfizer Canada Inc. will be issuing a letter with this new information to prescribing physicians and pharmacists.

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7.) Public Health Advisory, Food and Drug Administration, Trovan, 09 June 1999
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(Trovafloxacin/Alatrofloxacin Mesylate) INTERIM RECOMMENDATIONS
Trovan (trovafloxacin / alatrofloxacin) was approved by FDA in 1997 for the treatment of a wide variety of infections.

Based on new safety data related to serious liver injury, described below, the Food and Drug Administration is today advising physicians that the drug Trovan should be reserved for use ONLY in the treatment of patients who meet ALL of the following treatment criteria:

Have at least one of the following infections that is judged by the treating physician to be serious and life- or limb-threatening:

nosocomial pneumonia,

community acquired pneumonia,

complicated intra-abdominal infections (including post-surgical infections),

gynecologic and pelvic infections, or

complicated skin and skin structure infections, including diabetic foot infections;

Receive their initial therapy in an in-patient health care facility (i.e., hospital or long-term nursing care facility); and The treating physician believes that, even given the new safety information, the benefit of the product for the patient outweighs the potential risk.

In most cases, it is expected that therapy in these patients would begin with the intravenous formulation of Trovan. Due to the bioavailability of oral Trovan, patients who have stabilized clinically on IV therapy may be switched to oral Trovan to complete their course of therapy, if deemed appropriate by the treating physician. In some patients with these kinds of serious and life- or limb-threatening infections, oral Trovan may be considered appropriate initial therapy. Use of oral Trovan to treat less serious infections is not warranted.

Therapy with Trovan beyond 14 days duration generally should not be used, because the risk of liver injury may increase substantially with exposure beyond 14 days. Trovan should be discontinued prior to 14 days of therapy if the patient experiences any clinical signs or symptoms of liver dysfunction, including fatigue, anorexia, yellowing of the skin and eyes, severe stomach pain with nausea and vomiting, or dark urine.

NEW SAFETY DATA

No reports of hepatic failure, liver transplant, or death due to possible hepatic etiology were reported in the 7000 patients in the pre-marketing clinical trials database exposed to Trovan. It is estimated that approximately 2,500,000 patients have received Trovan since approval for marketing. Following marketing of Trovan in the United States in February 1998, FDA began receiving reports of patients who experienced serious hepatic reactions in association with the use of the product. In July of 1998, FDA had worked with Trovan’s manufacturer to add information about hepatic toxicity to the Precautions section of Trovan’s package insert.

Since that time, FDA has received reports of over 100 cases of clinically symptomatic liver toxicity in patients receiving Trovan. Some of these patients developed serious liver injury leading to liver transplant and/or death. At present, FDA is aware of 14 cases of acute liver failure that are strongly associated with Trovan exposure.

Four of these patients required liver transplant (one of whom subsequently died). Five additional patients died of liver-related illness. Three patients recovered without transplantation, and the final outcome is still pending on two patients. These numbers of patients with acute liver failure, although few, represent a rate that appears to be significantly higher than would be expected to occur idiopathically in the general population - despite the under-reporting of cases that generally occurs to our post-marketing surveillance system.

Trovan-associated liver failure appears to be unpredictable. It has been reported with both short-term (as little as 2 days exposure) and longer-term drug exposure; therefore the efficacy of liver function monitoring in acceptably managing this risk is uncertain.

Trovan use exceeding 2 weeks duration appears to be associated with a substantially increased risk of acute liver failure.

Liver failure has also been reported following Trovan re-exposure.

These uncommon but very serious adverse reactions are typical of drug toxicities which, because of their rarity, may not always be detectable in clinical trials databases. However, such toxicities may become apparent after marketing when the product is used in a significantly broader population. As such, these adverse reactions are the types of important, new safety information the post-marketing spontaneous reporting system is designed to detect, as it did in this case.

CONCLUSIONS

FDA does not wish to deprive patients and physicians of access to effective antimicrobials, if the risks associated with these drugs can be managed successfully by other means. Based on the new safety data presently available to the agency and based on the availability of alternative products to treat other less serious indications for which this product was originally approved, FDA is issuing the interim recommendations outlined above.

FDA and Pfizer have agreed to a program that will limit the distribution of Trovan to in-patient health care facilities (hospitals and long-term nursing care facilities). Pfizer will be communicating in the near future with appropriate pharmacies to provide directions concerning possible return of their present inventories of Trovan.

FDA believes that this risk management program will better ensure that Trovan is used in clinical situations in which its benefits can be expected to outweigh its presently known risks. In this manner, FDA believes that Trovan can continue to be made available to those patients who may need it for treatment of serious and life- or limb-threatening infections, while minimizing other patients’ risk of exposure to the product.

FDA advises patients presently taking Trovan NOT to discontinue their therapy until they have discussed their treatment options with their physician.

FDA and the manufacturer will continue to collect and evaluate data on Trovan’s safety and will continue to assess the drug’s benefit/risk profile. As further information or recommendations about Trovan become available, FDA will continue to inform the health care and patient communities.

FDA requests that any suspected adverse events thought associated with Trovan be reported to the agency through MedWatch, FDA’s adverse event reporting system. Reports may be submitted to FDA by telephone (800-332-1088), by fax (800-332-0178) or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Maryland 20857. Reports can also be filed via the Internet at www.fda.gov/medwatch. Reports may also be filed directly to the manufacturer.

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8.) Questions and Answers on Trovafloxacin Public Health Advisory
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What action is FDA announcing today?

FDA is issuing a Public Health Advisory to inform physicians and the public regarding new safety information about Trovan (trovafloxacin/alatrofloxacin), an antibiotic used to treat many different types of infections. Trovafloxacin was approved for marketing in December, 1997, and became available on the market in February, 1998. Its approved indications include many (14) types of infections that constitute a wide range of degrees of seriousness. Based on new safety data related to serious liver injury, FDA is advising physicians that trovafloxacin should be reserved for treatment ONLY in patients who meet ALL of the following criteria:

Who have at least one of five types of serious and life or limb-threatening infections listed below that is judged by the treating physician to be serious and life or limb-threatening;

Nosocomial pneumonia (pneumonia acquired in the hospital):

Community acquired pneumonia

Complicated intra-abdominal infections, including post-surgical infections

Gynecololgical and pelvic infections

Complicated skin and skin structure infections, including diabetic foot infections

Who begin their therapy in inpatient health care facilities (i.e., hospitals and long term nursing care facilities).

The treating physician believes that, given the new safety information, the benefit of the product for the patient still outweighs the potential risk.

2. What are the problems occurring with the use of Trovan?

Following the marketing of Trovan in the United States in February 1998, FDA began receiving reports of patients who experienced serious liver reactions in association with use of the product. In July of 1998, FDA worked with the manufacturer to add further information about this toxicity of the drug to Trovan’s label, or package insert, in order to inform practitioners . Since that time, FDA has received over 100 reports of cases of patients who were ill with symptoms of liver toxicity, in addition to others in which patients were without symptoms. Some of these patients developed serious liver injury leading to liver transplant and/or death. At present, FDA is aware of 14 cases in patients whose livers actually failed to function that are strongly associated with Trovan exposure.

Four patients required liver transplantation (one of whom subsequently died). Five additional patients died of liver-related disease. Three patients recovered from their acute liver failure without requiring a liver transplant.

The final outcome of two other patients is pending.

Trovan-associated liver failure appears to be unpredictable. It has been reported with treatment duration as short as two days and also in longer term exposure. It has been reported to occur in individuals over a wide range of ages, in men and in women, and in patients who were being treated for a wide variety of types of infection, many of which would not be considered serious or life-threatening. Also, when use exceeds two weeks there appears to be a substantial increase in risk of this toxicity. Liver failure has also been reported following Trovan re-exposure after some period of being off the drug.

These uncommon, but very serious adverse reactions, are typical of drug toxicities which, because of their rarity, may not be detected in clinical trials of drugs before marketing. However, they may become apparent after marketing when wider use of products occur among significantly more people. In the studies of Trovan approximately 7,000 patients were exposed to the drug. No cases of acute liver failure were reported in these pre-market clinical trials.

3. What does "limit distribution" mean?

In this case, the manufacturer of Trovan has agreed to direct distribution of the product only to pharmacies in inpatient health care facilities (i.e., hospitals and long-term nursing care facilities). This, in combination with labeling changes, educational programs and other risk communication strategies, will better ensure that Trovan is only used in clinical situations in which its demonstrated benefits can be expected to outweigh its presently known risks. In this manner, FDA believes that the product can continue to be made available to those patients who need it to treat serious life or limb-threatening infections, while minimizing other patients’ risk of exposure to the product.

4. When will the labeling changes take effect?

FDA is working with the manufacturer of Trovan to make appropriate changes to the product’s label expeditiously. While the details of that change are being worked out, we are putting forward a Public Health Advisory to inform physicians and patients of this new information.

5. What should patients do if they are currently using Trovan?

Patients should contact their physician. Patients should NOT stop taking Trovan until their physician has recommended that they do so.

6. What are alternative therapies?

Alternative therapies are different depending on what infection the patient is currently being treated for. That is why it is extremely important that patients direct questions about alternative therapy to their physician, who can then make an appropriate recommendation tailored to their needs.

7. How many people are currently using Trovan?

It is estimated that approximately 300,000 prescriptions are written for Trovan per month in the United States.

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9.) Trovan (alatrofloxacin mesylate), Pfizer notifies
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[January 12, 1999 ( Letter) - Pfizer]

Pfizer notifies health care professionals that the prescribing information for Trovan I.V. (alatrofloxacin mesylate injection) has been amended to include information on the potential incompatibility of alatrofloxacin mesylate injection with two commonly used diluents, 0.9% sodium chloride injection, USP (usually referred to as normal saline solution) and Lactated Ringer's, USP.

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10.) FDA ISSUES PUBLIC HEALTH ADVISORY ON LIVER TOXICITY ASSOCIATED WITH THE ANTIBIOTIC TROVAN
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The Food and Drug Administration today issued a public health advisory to physicians concerning the risks of liver toxicity associated with the use of Trovan (trovafloxacin, an oral antibiotic) and Trovan-IV (alatrofloxacin, the intravenous formulation of the drug). This action follows postmarketing reports of rare but severe liver injuries leading to transplants and deaths.

In issuing this advisory, FDA is informing physicians that Trovan should be reserved for use only in patients who meet all of the following criteria:

Patients who have at least one of several specified infections such as nosocomial (hospital-acquired) pneumonia or complicated intra-abdominal infections that, in the judgment of the treating physician, is serious and life- or limb-threatening;

Patients who begin their therapy in in-patient health care facilities

(hospitals or longterm nursing care facilities); And patients for whom the treating physician believes that even given the new safety information, the benefit of the product outweighs the potential risks.

FDA is further informing physicians that, in general, therapy with Trovan should not continue for longer than 14 days. Therapy should be discontinued sooner if the patient experiences any clinical signs of liver dysfunction, including fatigue, loss of appetite, yellowing of the skin and eyes, severe stomach pain with nausea and vomiting, or dark urine.

FDA is also advising physicians that for most patients who meet the treatment criteria, therapy would most likely begin with intravenous Trovan. After clinical stabilization patients may be switched to the oral dosage form. Although oral therapy might be appropriate in some cases as an initial therapy, the agency emphasizes that the oral form of Trovan is not warranted for infections other than those specified.

In addition, the manufacturer has agreed to limit distribution of the product to hospitals and long-term nursing care facilities. The manufacturer will be communicating in the near future with other appropriate pharmacies to provide directions concerning possible return of their present inventories of Trovan.

FDA is taking this action to reduce the potential risk from Trovan, while at the same time preserving for physicians and patients alike the clinical option of an effective broad-spectrum antibiotic for serious and life- threatening infections. The agency considers this advisory an interim measure until revised labeling for the product can be approved.

It is estimated that 2.5 million prescriptions have been written for Trovan, a quinolone antibiotic, since its February 1998 market launch in oral and intravenous formulations. Trovan was initially approved for treating a broad range of infections, from minor skin infections to severe infections in hospitalized patients.

No reports of liver failure, liver transplant, or death due to liver problems were reported in the 7,000 patients studied in premarketing clinical trials for Trovan. In July 1998, FDA worked with the manufacturer to strengthen the product's labeling concerning liver problems after receiving reports of elevated liver enzymes and symptomatic hepatitis in patients after short- and long-term therapy. Since then, FDA has continued to receive reports of liver toxicity, including reports of a more serious nature.

FDA is now aware of 14 cases of acute liver failure that it has concluded are strongly associated with the drug. Six of these patients died: five due to liver failure and one of four additional patients who received liver transplants. Three patients recovered without requiring liver transplants, and for the remaining two patients the final outcome is still pending.

More information about Trovan, including FDA's public health advisory, is available on the World Wide Web at www.fda.gov/cder/news/trovan/default.html and from Pfizer, the manufacturer of the drug, at 1-800-438-1985.

The FDA asks that any adverse events associated with Trovan be reported to the agency through MedWatch, FDA's adverse event reporting system. Reports may be submitted to FDA by telephone (800-332-1088), by fax (800-332-0178) or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Md. 20857. Reports can also be filed via the internet at www.fda.gov/medwatch. Reports may also be filed directly to the manufacturer.

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11.) JANSSEN PHARMACEUTICA ANNOUNCES THE WITHDRAWAL OF HISMANAL FROM THE MARKET
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June 21, 1999

Janssen Pharmaceutica, Inc., of Titusville, N.J., has announced that it is voluntarily withdrawing the prescription antihistamine, Hismanal (astemizole) 10 mg., from the market.

Since the drugís approval in 1988, new adverse reaction data has required a series of labeling changes and warnings. In light of the choices of other prescription antihistamines now available, and the overall risk benefit profile of this drug, FDA supports the decision of the company to withdraw the product.

Patients who have been taking Hismanal for their allergy symptoms should consult with their doctors to determine an appropriate alternative treatment.

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DATA-MÉDICOS/DERMAGIC-EXPRESS No 59) 23/06/99 DR. JOSÉ LAPENTA R.
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