E-drug: Petition to FDA on trovafloxacin
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June 3, 1999
Jane Henney, M.D.
Commissioner, Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
Dear Dr. Henney:
Based on a review of FDA documents, we hereby petition the Food and Drug
Administration (FDA) as authorized by 21 U.S.C. , section 355 (e) of the
Federal Food, Drug and Cosmetic Act to immediately ban the widely-used
antibiotic, TROVAN (trovafloxacin, Pfizer), before more patients die,
require a liver transplant or are otherwise injured from liver toxicity
caused by this drug. Like two other drugs also approved in 1997, the
painkiller Duract (bromfenac) and the diabetes drug Rezulin (troglitazone),
there was also clear evidence of liver damage caused by TROVAN (in animals
and in humans) before the drug was approved in December 1997. For example,
in one study prior to approval in which the drug was used to treat
prostatitis, almost 10% of the men (14 out of 140) given the drug developed
evidence of liver toxicity (see below). With eight other drugs in the
fluoroquinolone family already available in the U.S, as well as dozens of
other safer and equally or more effective drugs for infections, the removal
of TROVAN from the market will not deprive doctors or patients of a drug
which could possibly be considered indispensable. This is yet another
instance of a lower standard for approving drugs in recent years than in the
past, adding to the toll of Americans killed or seriously injured by drugs
which should never have been approved in the first place.
Since February 1998, 140 documented cases of serious liver
reactions--largely in the U.S.--have been reported with the use of
trovafloxacin. These included eight cases with five deaths and three liver
transplants. A spokeswoman for the FDA has said the reports of liver damage
were serious, and the Agency is meeting with Pfizer to evaluate the risk.
FDA Pharmacology Review (December 18, 1997)
The FDA knew about liver toxicity with trovafloxacin before approval from
animal studies that Public Citizen's Health Research Group obtained from the
FDA's pharmacology review of this drug, dated December 18, 1997:
In a six month rat toxicity study, the FDA pharmacologist reviewing the
animal studies found "A dose-related increase in the incidence of minimal
to mild `fatty change' was seen in the livers of male rats from all
trovafloxacin groups." This means that there was no safe dose established
for this drug in this species.
In a six month dog toxicity study, hepatocellular vacuolar degeneration
and necrosis (direct damage to liver cells) was seen in two of eight dogs at
higher doses. Elevated liver enzymes (an indication of liver damage) were
seen in both animals.
In a second six month dog toxicity study, the drug was stopped in three of
sixteen dogs because their liver enzymes increased three-fold and biopsies
revealed liver changes (necrotizing hepatocellular inflammation). The FDA
pharmacologist wrote: "Data from this study indicated that elevation in
liver enzymes, especially ALT, accurately predicted the presence of
necrotizing inflammation of perivenular hepatocyctes. The necrotic changes
were no longer evident approximately 2 months after discontinuation of the
drug."
Human Premarketing Studies: NDA Medical Review--December 1997
Background: The Medical Officer (MO) for the drug had been concerned over
findings in the two six month dog toxicity studies: increased liver function
tests (LFTs) at two months and histologic findings at six months coupled
with a small safety factor between human and canine exposure.
Liver adverse events in the clinical trials: In one clinical trial
involving 140 patients with prostatitis, lasting 28 days, five patients were
discontinued by the investigator for treatment-related increases in liver
function transaminases [TAS--a liver test] (values redacted from the FDA
document).
Ten additional patients had elevations of LFTs 3x normal (data redacted).
"Despite the fact that the investigators did not consider the LFT
abnormalities in the 10 patients as attributable to trovafloxacin, the MO
determined that the pattern of the abnormalities was consistent with that of
the previously listed 5 patients. . .both in terms of the timing of the
events as well as the duration. . . .Therefore, the MO determined that the
true incidence of LFT abnormalities ( 3x normal), attributable to the study
drug was 14/140 (10%). "
"A trend was observed for liver enzyme elevations after 3 to 4 weeks of
trovafloxacin therapy, suggesting that subjects receiving prolonged
treatment ( 21 days) may need to have periodic assessment of hepatic function."
Trovafloxacin 200 mg QD was statistically equivalent to ofloxacin 300 mg
BID (there was no advantage to trovafloxacin). Fourteen percent of TROVAN
patients were discontinued vs 6% of ofloxacin patients.
FDA Safety Update (April to June 1998--after the drug was on the market)
"The MO was of the opinion that trovafloxacin induced a chemical hepatitis
(i.e., asymptomatic) after >14 days of therapy. . ."
The April 1998 quarterly report listed 3 cases of increased TAS associated
with liver biopsy findings of eosinophilic infiltration of the liver in
patients after <14 days therapy.
Of the 11 serious safety reports for liver toxicity, as of June 1998, "the
most typical" (MO comment) was a healthy female who developed evidence of an
eosinophilic hepatitis with no other obvious etiology.
".... it became apparent that trovafloxacin had the most reported
liver-associated AEs [adverse events] within the first 6 months after
approval of any of the approved and on the market quinolone antimicrobial
agents. Only temofloxacin (withdrawn in 6/92) had a larger number of
reported events. [This]. . . serve(s) to illustrate the magnitude of the
trovafloxacin-related hepatotoxicity as compared to other approved
quinolones."
Symptoms of drug-induced liver disease are non-specific and may mimic many
other illnesses. They include rash, loss of appetite, tiredness, pain on
the right side just below the rib cage (where the liver is situated), dark
urine or a yellowing of the skin or whites of the eyes (jaundice). The
symptoms of liver toxicity may also include fever.
Trovafloxacin and alatrofloxacin (the intravenous form of the drug) are
among the 39 drugs approved in 1997 when the FDA was under tremendous
pressure, exerted by Congress, at the behest of the drug industry, to
approve new drugs. This notorious class of `97 includes the diabetes drug
troglitazone (REZULIN) that was withdrawn from the market in the United
Kingdom because of liver toxicity, mibefradil (POSICOR) a heart drug banned
worldwide because of fatal drug interactions, the painkiller bromfenac
(DURACT) also withdrawn because of liver toxicity, and the dangerous diet
drug sibutramine (MERIDIA) that was approved over the objections of the
FDA's own Medical Officer and outside advisory committee of experts.
In conclusion, TROVAN is another example of a drug with no unique benefits
and unquestionably unique, life-threatening risks. It should never have been
approved. Now, with more of the liver damage predicted by the pre-marketing
animal and human studies occurring in more than 100 reported cases (the
actual number is likely well over 1,000 by now) including five deaths and
three liver transplants, the drug must be immediately taken off the market.
We look forward to a prompt response to this petition.
Sincerely,
Sidney M. Wolfe, M.D.
Director
Public Citizen's Health Research Group
Larry D Sasich, Pharm.D., M.P.H., FASHP
Public Citizen's Health Research Group
Elizabeth K. Barbehenn, PhD Public Citizen's
Health Research Group
Sidney Wolfe, M.D.
Public Citizen's Health Research Group
1600 20th St. NW
Washington, D.C. 20009
Phone: 202 588-1000
Fax: 202 588-7796
e-mail swolfe@citizen.org Web Site: www.citizen.org
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