PFPC Daily - November 30, 2004

FDA Grants Approval for Factive(R) (gemifloxacin) in spite of
fluoroquinolones being associated with irreversible Peripheral
Neuropathy

Health News - November 28, 2004

Oscient Pharmaceuticals has announced the launching of Factive(R)
(gemifloxacin) which was approved by the FDA in 2003, stating that
their product is safe and well tolerated, claiming a low adverse drug
reaction rate consisting mainly of diarrhea (3.6%), rash (2.8%) and
nausea (2.7%). Factive(R) is a member of a class of extremely potent
chemotherapeutic agents commonly referred to as fluoroquinolones
(quinolones).

In sharp contrast to the statements made by Oscient Pharmaceuticals,
regarding the safety profile of Factive(R), the FDA has recently
added the following warnings to gemifloxacin as well as all drugs
within this class of chemotherapeutic agents, (fluoroquinolones)
concerning:

- Irreversible Peripheral neuropathy
- Tendon Effects such as spontaneous tendon rupture both during and
after therapy
- Caffeine accumulation resulting in CNS stimulation
- Pseudomembranous colitis (life-threatening diarrhea)
- QTc interval prolongation (ventricular arrhythmias including
torsades de pointes)
- Commitment use of Non-steroidal anti-inflammatory agents (provoking
convulsions)

"QT Effects: Fluoroquinolones may prolong the QT interval in some
patients. Gemifloxacin should be avoided in patients with a history
of prolongation of the QTc interval, patients with uncorrected
electrolyte disorders (hypokalemia or hypomagnesemia), and patients
receiving Class IA (e.g., quinidine, procainamide) or Class III
(e.g., amiodarone, sotalol) antiarrhythmic agents…Pharmacokinetic
studies between gemifloxacin and drugs that prolong the QTc interval
such as erythromycin, antipsychotics, and tricyclic antidepressants
have not been performed…"

"Peripheral Neuropathy: Rare cases of sensory or sensorimotor
axonal polyneuropathy affecting small and/or large axons resulting in
paresthesias, hypoesthesias, dysesthesias and weakness have been
reported in patients receiving quinolones." (Note: This is a much
abbreviated form of the warnings added to the other fluoroquinolones
and the statements to the effect that such a condition may be
irreversible are missing from the warnings found within the package
inserts for Factive(R))

"Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon
or other tendons that required surgical repair or resulted in
prolonged disability have been reported in patients receiving
quinolones. Post-marketing surveillance reports indicate that this
risk may be increased in patients receiving concomitant
corticosteroids, especially the elderly. Gemifloxacin should be
discontinued if the patient experiences pain, inflammation, or
rupture of a tendon. Patients should rest and refrain from exercise
until the diagnosis of tendonitis or tendon rupture has been
excluded. Tendon rupture can occur during or after therapy with
quinolones."

"CNS Effects: In clinical studies with gemifloxacin, central
nervous system (CNS) effects have been reported infrequently. As with
other fluoroquinolones, gemifloxacin should be used with caution in
patients with CNS diseases such as epilepsy or patients predisposed
to convulsions. Although not seen in gemifloxacin clinical trials,
convulsions, increased intracranial pressure, and toxic psychosis
have been reported in patients receiving other fluoroquinolones. CNS
stimulation which may lead to tremors, restlessness, anxiety,
lightheadedness, confusion, hallucinations, paranoia, depression,
insomnia, and rarely suicidal thoughts or acts may also be caused by
other fluoroquinolones…"

"Antibiotic Associated Colitis: Pseudomembranous colitis has been
reported with nearly all antibacterial agents, including
gemifloxacin, and may range in severity from mild to
life-threatening. Therefore, it is important to consider this
diagnosis in patients who present with diarrhea subsequent to the
administration of any antibacterial agent. Treatment with
antibacterial agents alters the normal flora of the colon and may
permit overgrowth of clostridia. Studies indicate that a toxin
produced by Clostridium difficile is the primary cause of
antibiotic-associated colitis."

Other adverse drug reactions associated with Factive(R) included:
abdominal pain, anorexia, arthralgia, constipation, dermatitis,
dizziness, dry mouth, dyspepsia, fatigue, flatulence, fungal
infection, gastritis, genital moniliasis, hyperglycemia, insomnia,
leukopenia, moniliasis, pruritus, somnolence, taste perversion,
thrombocythemia, urticaria, vaginitis, and vomiting.

Other adverse events reported from clinical trials included: abnormal
urine, anemia, asthenia, back pain, bilirubinemia, dyspnea, eczema,
eosinophilia, flushing, gastroenteritis, granulocytopenia, hot
flashes, increased GGT, leg cramps, myalgia, nervousness,
non-specified gastrointestinal disorder, pain, pharyngitis,
pneumonia, thrombocyotopenia, tremor, vertigo, and vision abnormality.

Peripheral neuropathy may result in a life long disability.
Spontaneous tendon rupture, first reported in 1982 (Bailey et al), as
well as Peripheral Neuropathy (reported in 1988) continues to be
unrecognized as being associated with fluoroquinolone therapy by the
treating physician who fails to recognize, treat and report such
events. Such crippling and at time fatal reactions are far more
serious then the reports of nausea, diarrhea, and rash being referred
to by Oscient Pharmaceuticals within their safety profile.

Fluoroquinolones should be used only to treat or prevent infections
that are proven or strongly suspected to be caused by susceptible
bacteria. In the absence of a proven or strongly suspected bacterial
infection or a prophylactic indication, the use of drugs within this
class is unlikely to provide benefit to the patient and increases the
risk of the development of serious and irreversible adverse drug
reactions as outlined above. Contrary to what physicians are being
told, Fluoroquinolones are NOT to be considered a first line agent
but a drug of last resort when all else fails. These warnings issued
by the FDA regarding irreversible disease states such as Peripheral
Neuropathy as well as potentially fatal reactions such as
Rhabdomyolysis, Pseudomembranous Colitis, Steven Johnson Syndrome,
and Torsades de Pointes should prevent a physicians from utilizing
such a drug when safer alternatives are available. This, however,
does not occur. The statements made by Oscient Pharmaceuticals,
concerning the safety issues surrounding this drug, fails to convey
such a warning and continues to promote the patently false assumption
that fluoroquinolones are a "safe and effective antibiotic", much to
both the patient and the treating physician's demise.

On December 15, 2001 the FDA sent a non-approval letter to Oscient
Pharmaceuticals regarding their initial application for Factive(R)
(gemifloxacin). No reasons were ever disclosed regarding why this
application was rejected. Two years after rejecting this application
the FDA approved this drug. Though never confirmed, as no reason for
this rejection was ever made public, it was strongly suspected that
this rejection was due to the severe rashes associated with
gemifloxacin. Which in some cases covered greater than 60% of the
body area involved. Within the package insert it is stated:

"…7% of the rashes were reported as severe, and severity
appeared to correlate with the extent of the rash. In 68% of the
subjects reporting a severe rash and approximately 25% of all those
reporting rash, >60% of the body surface area was involved…"

Dr. Steven Galson, acting director of the FDA's Center for Drug
Evaluation said Friday, November 19, 2004, "we categorically reject
accusations the agency has done a poor job of protecting the public
against dangerous drugs." Yet the FDA continues to approve new
drugs within this class of chemotherapeutic agents, witnessed by the
recent approval received by Oscient Pharmaceuticals for Factive(R).
The FDA also provides "rubber stamp" approval of new
indications for older drugs currently utilized in clinical practice
today. Based upon these recent warnings one would hardly consider
fluoroquinolones to be anything but a "dangerous drug", one
that the FDA allows to be marketed as a "safe and effective
antibiotic
with minimum side effects". It appears that the statements being
made
by Dr. Galson are based upon political expediency, not fact. One also
has to wonder why Factive(R) does not include the same detailed
warnings one finds within the package inserts for the other drugs
within this class, even though such adverse reactions are stated as
being a "class effect".

The Fluoroquinolone Toxicity Research Foundation has been providing
documentation regarding these severe adverse reactions to Dr. Galson
for years only to find that the FDA ignores such reports when
approving these drugs. Dr. Jay S. Cohen released a study in 2001,
which detailed the horrendous damage suffered for years on end by the
patients afflicted with this disease state, peripheral neuropathy.
The FDA was fully aware of Dr. Cohen's study two years prior to
approving Factive(R). Dr. Cohen's study was conducted upon
various members of one of the leading quinolone adverse drug reaction
forums found on the Internet. Such adverse reactions had been
reported on that forum since 1999 and continue unabated to date.
(Cohen J.S., Peripheral Neuropathy with Fluoroquinolone Antibiotics.
Annals of Pharmacotherapy, Dec. 001;35(12):1540-47.)