EDITORIAL ESPANOL:

====================

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, (1998) con grandes expectativas y lanzado por el famoso laboratorio PFIZER, está siendo retirado de las farmacias y droguerías de nuestro país y muchos otros más, pues han habido numerosos reportes de daño hepático, llevando incluso en algunos casos a trasplante de hígado. 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. 

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

Saludos,,,

Dr. José Lapenta R.,,,

 EDITORIAL ENGLISH:

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Hello to all, DERMAGIC, again with you. The trovafloxacin (TROVAN), antibiotic (fluoroquinolona) relatively new in the market, liberated by the FDA in February of last year, (1998) 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,,,

Dr. José Lapenta R. 

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DERMAGIC/EXPRESS(62)

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TROVAFLOXACINA Y ASTEMIZOL, NOTICIAS DE LA FDA

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?

======================================================================

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. fischman@petw6.mgh.harvard.edu 

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

======================================================================

[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

======================================================================

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-MÉDICOS/DERMAGIC-EXPRESS No 62) 23/06/99 DR. JOSE LAPENTA R. 

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Produced by Dr. José Lapenta R. Dermatologist
Venezuela 1.998-2.024

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.0024

Tlf: 0414-2976087 - 04127766810