SIDE EFFECTS
The incidence of drug-related adverse reactions in patients
during Phase 2 and 3 clinical trials conducted in North America was 6.2%.
Among patients receiving multiple-dose therapy, 3.7% discontinued therapy
with levofloxacin due to adverse experiences.
In clinical trials, the following events were considered likely to be
drug-related in patients receiving multiple doses of levofloxacin: diarrhea
1.2%, nausea 1.2%, vaginitis 0.8%, flatulence 0.5%, pruritus 0.5%, rash
0.3%, abdominal pain 0.3%, genital moniliasis 0.3%, dizziness 0.3%, dyspepsia
0.3%, insomnia 0.3%, taste perversion 0.2%, vomiting 0.2%, anorexia 0.1%,
anxiety 0.1%, constipation 0.1%, edema 0.1%, fatigue 0.1%, headache 0.1%,
increased sweating 0.1%, leukorrhea 0.1%, malaise 0.1%, nervousness 0.1%,
sleep disorders 0.1%, tremor 0.1%, urticaria 0.1%. In clinical trials,
the most frequently reported adverse events occurring >3% of the study
population regardless of drug relationship were: nausea 6.6%, diarrhea
5.4%, headache 5.4%, constipation 3.1%.
In clinical trials, the following events occurred in 1 to 3% of patients,
regardless of drug relationship: insomnia 2.9%, dizziness 2.5%, vomiting
2.1%, abdominal pain 2.0%, dyspepsia 2.0%, rash 1.7%, vaginitis 1.8%,
flatulence 1.6%, pruritus 1.6%, pain 1.4%, chest pain 1.1%, back pain
1.0%.
The following adverse events occurred in clinical trials at a rate of
0.5 to less than 1%, regardless of drug relationship: agitation, anorexia,
anxiety, arthralgia, dry mouth, dyspnea, edema, fatigue, fever, genital
pruritus, increased sweating, nervousness, pharyngitis, rhinitis, skin
disorder, somnolence, taste perversion.
Additional adverse events occurring in clinical trials at a rate of 0.3
to less than 0.5% regardless of drug relationship include: cardia failure,
hypertension, leukorrhea, myocardial infarction, myalgia, purpura, tinnitus,
tremor, urticaria.
Events occurring at a frequency lower than 0.3% regardless of drug relationship
but considered medically important include: abnormal coordination, abnormal
dreaming, abnormal hepatic function, abnormal platelets, abnormal renal
function, abnormal vision, acute renal failure, aggravated diabetes mellitus,
aggressive reaction, anemia, angina pectoris, ARDS, arrhythmia, arthritis,
asthma, bradycardia, cardiac arrest, cerebrovascular disorder, circulatory
failure, coma, confusion, convulsions (seizures), coronary thrombosis,
delirium, depression, diplopia, embolism-blood clot, emotionally lability,
erythema nodosum, G.I. hemorrhage, granulocytopenia, hallucination, heartblock,
hepatic coma, hypoglycemia, hypotension, impaired concentration, increased
LDH, jaundice, leukocytosis, leukopenia, lymphadenopathy, manic reaction,
mental deficiency, muscle weakness, pancreatitis, paralysis, paranoia,
postural hypotension, pseudomembranous colitis, rhabdomyolysis, sleep
disorders, speech disorder, stupor, syncope, tachycardia, tendinitis,
thrombocytopenia, vertigo, weight decrease, WBC abnormal not otherwise
specified.
In clinical trials using multiple-dose therapy, ophthalmologic abnormalities,
including cataracts and multiple punctate lenticular opacities, have been
noted in patients undergoing treatment with other quinolones. The relationship
of the drugs to these events is not presently established.
Crystalluria and cylindruria have been reported with
other quinolones.
The following laboratory abnormalities appeared in 1.9% of patients receiving
multiple doses of levofloxacin . It is not known whether these abnormalities
were caused by the drug or the underlying condition being treated.
Blood chemistry: decreased glucose, decreased
lymphocytes
Post-Marketing Adverse Reactions: Additional serious adverse events reported
from the marketing experience with levofloxacin outside of the United
States regardless of drug relationship include: allergic pneumonitis,
anaphylactic shock, anaphylactoid reaction, dysphoria, abnormal EEG, encephalopathy,
erythema multiforme, hemolytic anemia, multi-system organ failure, palpitation,
paresthesia, Stevens-Johnson Syndrome, tendon rupture, vasodilation.
DRUG INTERACTIONS
Antacids, Sucralfate, Metal Cations, Multi-Vitamins:
While the chelation by divalent cations is less marked than other
quinolones, concurrent administration of levofloxacin with antacids containing
magnesium, or aluminum, as well as sucralfate, metal cations such as iron,
and multi-vitamin preparations with zinc may interfere with the gastrointestinal
absorption of levofloxacin resulting in systematic levels considerably
lower than desired. These agents should be taken at least two hours before
or two hours after levofloxacin administration.
Theophylline: No significant effect of levofloxacin
on the plasma concentrations, AUC, and other disposition parameters for
theophylline was detected in a clinical study involving 14 healthy volunteers.
Similarly, no apparent affect of theophylline on levofloxacin absorption
and disposition was observed. However, concomitant administration of other
quinolones with theophylline has resulted in prolonged elimination half-life,
elevated serum theophylline levels, and a subsequent increase in the risk
of theophylline related adverse reactions in the patient population. therefore,
the theophylline levels should be closely monitored and appropriate dosage
adjustments made when levofloxacin is co-administered. Adverse reactions,
including seizures, may occur with or without an elevation in serum theophylline
levels. (See WARNINGS and PRECAUTIONS,
General.)
Warfarin: No significant effect of levofloxacin
on the peak plasma concentrations, AUC, and other disposition parameters
for R- and S- warfarin was detected in a clinical study involving healthy
volunteers. No significant change in prothrombin time was noted in the
presence of levofloxacin. Similarly, no apparent effect of warfarin on
levofloxacin absorption and disposition was observed. However, since some
quinolones have been reported to enhance the effects of oral anticoagulant
warfarin or its derivatives in the patient population, prothrombin time
or other suitable coagulation test should be closely monitored if a quinolone
antimicrobial is administered concomitantly with warfarin or its derivatives.
Cyclosporine: No significant effect
of levofloxacin on the peak plasma concentrations, AUC, and other
disposition parameters for cyclosporine was detected in a clinical
study involving healthy volunteers. However, elevated serum levels
of cyclosporine have been reported in the patient population when
co-administered with some other quinolones. Levofloxacin Cmax
and kawere slightly lower while Tmax and t½
were slightly longer in the presence of cyclosporine than those
observed in other studies without concomitant medication. The differences,
however, are not considered to be clinically significant. Therefore,
no dosage adjustment is required for levofloxacin or cyclosporine
when administered concomitantly.
Digoxin: No significant effect of levofloxacin
on the peak plasma concentrations, AUC, and other disposition parameters
for digoxin was detected in a clinical study involving healthy volunteers.
Levofloxacin absorption and disposition kinetics were similar in
the presence or absence of digoxin. Therefore, no dosage adjustment
for levofloxacin or digoxin is required when administered concomitantly.
Probanacid and Cimetidine: No significant
effect of probenecid or cimetidine on the rate and extent of levofloxacin
absorption wasobserved in a clinical study involving healthy volunteers.
The AUC and t½ of levofloxacin were 27-38% and
30% higher, respectively, while CL/F and CLR were 21-35%
lower during concomitant treatment with probenecid or cimetidine
compared to levofloxacin alone. Although these differences were
statistically significant, the changes were not high enough to warrant
dosage adjustment for levofloxacin when probenecid or cimetidine
is co-administered.
Non-steroidal anti-inflammatory drugs:
The concomitant administration of a non-steroidal anti-inflammatory
drug with a quinolone, including levofloxacin, may increase the
rick of CNS stimulation and convulsive seizures. (See WARNINGS
and PRECAUTIONS, General.)
Antidiabetic agents: Disturbances of blood
glucose, including hyperglycemia and hypoglycemia, have been reported
in patients treated concomitantly with quinolones and an antidiabetic
agent. Therefore, careful monitoring of blood glucose is recommended
when these agents are co-administered.
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