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****** DATA-MEDICOS **********
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TROVAFLOXACINA Y ASTEMIZOL, NOTICIAS DE LA FDA
TROVAFLOXACIN AND ASTEMIZOL FDA NEWS
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****** DERMAGIC-EXPRESS No.62 ******* 
****** 23 JUNIO DE 1.999 *********** 
23 JUNE 1.999
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EDITORIAL ESPAÑOL
=================
Hola a todos, DERMAGIC, de nuevo con ustedes. La trovafloxacina(TROVAN),
antibiotico (fluoroquinolona) relativamente nuevo en el mercado, liberado
por la FDA en febrero del año pasado, con grandes espectativas y lanzado
por el famoso laboratorio PFIZER, esta siendo retirado de las farmacias y
drogerias de nuestro país y muchos otros más, pues han habido numerosos
reportes de daño hepatico, llevando incluso en algunos casos a transplante
de higado. La FDA estudia actualmente la conducta a seguir con este
medicamento y advierte sus posibles efectos adversos (Junio de 1.999). Por
otra parte el laboratorio JANSSEN el dia 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. Jose Lapenta R.,,,

EDITORIAL ENGLISH
=================
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 but, because they have had numerous reports of hepatic damage,
even taking in some cases to liver transplant. The FDA studies at this
moment the behavior to take with this drug, and notifies its possible
adverse effects (June of 1.999) 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 captured. 

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

Greetings to ALL, !!

Dr. Jose Lapenta R.,,,
=====================================================================
DERMAGIC/EXPRESS(62)
=====================================================================
TROVAFLOXACINA Y ASTEMIZOL, NOTICIAS DE LA FDA
TROVAFLOXACIN AND ASTEMIZOL FDA NEWS

======================================================================
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
======================================================================
======================================================================
1.) Levofloxacin and trovafloxacin: the next generation of fluoroquinolones?
======================================================================
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.

======================================================================
2.) Hepatobiliary elimination of trovafloxacin and metabolites following
single oral doses in healthy volunteers. 
======================================================================
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. 

======================================================================
3.) Pharmacokinetics and metabolism of single oral doses of trovafloxacin. 
======================================================================
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. 

======================================================================
4.) Pharmacokinetics of [18F]trovafloxacin in healthy human subjects
studied with positron emission tomography. 
======================================================================
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. 

======================================================================
5.) Pfizer Relabels Antibiotic Trovan For Serious Infections
======================================================================

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. 


======================================================================
6.) Pfizer Asks Canadian Doctors To Limit Trovan Use To Life-Threatening
Infections
======================================================================
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. 


======================================================================
7.) Public Health Advisory, Food and Drug Administration, Trovan, 09 June 1999
======================================================================
(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.

======================================================================
8.) Questions and Answers on Trovafloxacin Public Health Advisory
======================================================================

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.


======================================================================
9.) Trovan (alatrofloxacin mesylate), Pfizer notifies
======================================================================
[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. 

======================================================================
10.) FDA ISSUES PUBLIC HEALTH ADVISORY ON LIVER TOXICITY ASSOCIATED WITH
THE ANTIBIOTIC TROVAN
======================================================================
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.htm
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-MEDICOS/DERMAGIC-EXPRESS No 62) 23/06/99 DR. JOSE LAPENTA R. 
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