WARNINGS
THE SAFETY AND EFFICACY OF LEVOFLOXACIN IN CHILDREN, ADOLESCENTS
(UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN AND NURSING WOMEN HAVE NOT
BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric
Use, Pregnancy, and Nursing Mothers.)
In immature rats and dogs, the oral and intravenous administration
of levofloxacin increased the incidence and severity of osteochondrosis.
Other fluoroquinolones also produce similar erosions in the weight bearing
joints and other signs of arthropathy in immature animals of various species.
(See ANIMAL PHARMACOLOGY.)
Convulsions and toxic psychoses have been reported in patients receiving
quinolonas, including levofloxacin. Quinolones may also cause increased
intracranial pressure and central nervous system stimulation which may
lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations,
paranoia, depression, nightmares, insomnia, and rarely suicidal thoughts
or acts. These reactions may occur following the first dose. If these
reactions occur in patients receiving levofloxacin, the drug should be
discontinued and appropriate measures instituted. As with other quinolones,
levofloxacin should be used with caution in patients with a known or suspected
CNS disorder that may predispose to seizures or lower the seizure threshold
(e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence
of other risk factors that my predispose to seizures or lower the seizure
threshold (e.g., certain drug therapy, renal dysfunction.) (See PRECAUTIONS,
General, Information for Patients, DRUG INTERACTIONS
and ADVERSE REACTIONS.)
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions
have been reported in patients receiving therapy with quinolones. These
reactions often occur following the first dose. Some reactions have been
accompanied by cardiovascular collapse, hypotension/shock, seizure, loss
of consciousness, tingling, angioedema (including tongue, laryngeal, throat,
or facial edema/swelling), airway obstruction (including bronchospasm,
shortness of breath, and acute respiratory distress), dyspnea, urticaria,
itching, and other serious skin reactions. Levofloxacin should be discontinued
immediately at the first appearance of a skin rash or any other sign of
hypersensitivity. Serious acute hypersensitivity reactions may require
treatment with epinephrine and other resuscitative measures, including
oxygen, intravenous fluids, antihistamines, corticosteroids, pressoramines,
and airway management, as clinically indicated. (See PRECAUTIONS
and ADVERSE REACTIONS.)
Serious and sometimes fatal events, some due to hypersensitivity, and
some due to uncertain etiology, have been reported rarely in patients
receiving therapy with quinolones. These events may be severe and generally
occur following the administration of multiple doses. Clinical manifestations
may include one or more of the following: fever, rash or severe dermatologic
reactions (e.g., toxic epidermal necrotysis, Stevens-Johnson Syndrome);
vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis;
interstitial nephritis; acute renal insufficiency or failure; hepatitis;
jaundice; acute hepatic necrosis or failure; anemia, including hemolytic
and aplastic; thrombocytopenia, including thrombotic thrombocytopenic
purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic
abnormalities. The drug should be discontinued immediately at the first
appearance of a skin rash or any other sign of hypersensitivity and supportive
measures instituted. (See PRECAUTIONS, Information
for Patients and ADVERSE REACTIONS.)
Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including levofloxacin, 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 altars the normal flora of the colon
and may permit overgrowth of clostridia. Studies indicate that a toxin
produced by Clostridium difficile is one primary cause of "antibiotic-association
colitis".
After the diagnosis of pseudomembranous colitis has been established,
therapeutic measures should be initiated. Mild cases of pseudomembranous
colitis usually respond to drug discontinuation alone. In moderate to
severe cases, consideration should be given to management with fluids
and electrolytes, protein supplementation, and treatment with an antibacterial
drug clinically effective against C. difficile colitis. (See ADVERSE REACTIONS.)
Ruptures of the shoulder, hand, and Achilles tendons that required surgical
repair or resulted in prolonged disability have been reported in patients
receiving quinolones. Levofloxacin 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 tendinitis or tendon
rupture has been confidently excluded. Tendon rupture can occur during
or after therapy with quinolones, including levofloxacin.
PRECAUTIONS
General
Although levofloxacin is more soluble than other quinolones, adequate
hydration of patients receiving levofloxacin should be maintained to prevent
the formation of a highly concentrated urine.
Administer levofloxacin with caution in the presence of renal insufficiency.
Careful clinical observations and appropriate laboratory studies should
be performed prior to and during therapy since elimination of levofloxacin
may be reduced. In patients with impaired renal function (creatinine clearance
<80 ml/min), adjustment of the dosage regimen is necessary to avoid
the accumulation of levofloxacin due to decreased clearance. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
Moderate to severe phototoxicity reactions have been observed in patients
exposed to direct sunlight while receiving drugs in this class. Excessive
exposure to sunlight should be avoided. However, in clinical trials with
levofloxacin, phototoxicity has been observed in less than 0.1% of patients.
Therapy should be discontinued if phototoxicity (e.g., a skin eruption)
occurs.
As with other quinolones, levofloxacin should be used with caution in
any patient with a known or suspected CNS disorder that may predispose
to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis,
epilepsy) or in the presence of other risk factors that may predispose
to seizures of lower seizure threshold (e.g., certain drug therapy, renal
dysfunction). (See WARNINGS and DRUG
INTERACTIONS.)
As with other quinolones, disturbances of blood glucose, including symptomatic
hyper- and hypoglycemia, have been reported usually in diabetic patients
receiving concomitant treatment with an oral hypoglycemic agent (e.g.,
glyburide/glibenciamide) or with insulin. In these patients, careful monitoring
of blood glucose is recommended. If a hypoglycemic reaction occurs in
a patient being treated with lavofloxacin, levofloxacin should be discontinued
immediately and appropriate therapy should be initiated immediately. (See
DRUG INTERACTIONS and ADVERSE REACTIONS.)
As with any potent antimicrobial drug, periodic assessment of organ system
functions, including renal, hepatic, and hematopoietic, is advisable during
therapy. (See WARNINGS and ADVERSE REACTIONS.)
Information for the Patient
Patients should be advised:
- to drink fluids liberally;
- that antacids containing magnesium, or aluminum, as well as sucraifate,
metal cations such as iron, and multi-vitamin preparations with zinc
should be taken at least two hours before or two hours after levofloxacin
administration. (See DRUG INTERACTIONS);
- that levofloxacin can be taken without regard to meals;
- that levofloxacin may cause neurologic adverse effects (e.g.,
dizziness, lightheadedness) and that patients should know how they react
to levofloxacinbefore they operate an automobile or machinery or engage
in other activities requiring mental alertness and coordination. (See
WARNINGS and ADVERSE REACTIONS)
- to discontinue treatment and inform their physician if they experience
pain, inflammation, or rupture of a tendon, and to rest and refrain
from exercise until the diagnosis of tendinitis or tendon rupture has
been confidently excluded;
- that levofloxacin may be associated with hypersensitivity reactions,
even following the first dose, and to discontinue the drug at the first
sign of a skin rash, hives, or other skin reactions, a rapid heartbeat,
difficulty in swallowing or breathing, any swelling suggesting angioedema
(e.g., swelling of the lips, tongue, face, tightness of the throat,
hoarseness), or other symptoms of an allergic reaction. (See WARNINGS
and ADVERSE REACTIONS);
- to avoid excessive sunlight or artificial ultraviolet light while
receiving levofloxacin and to discontinue therapy if phototoxicity (i.e.,
skin eruption) occurs;that if they are diabetic and are being treated
with insulin or an oral hypoglycemic agent and a hypoglycemic reaction
occurs, they should discontinue levofloxacin and consult a physician.
(See PRECAUTIONS, General and DRUG
INTERACTIONS.)
Carcinogenesis, Mutagenesis, and Impairment
of Fertility
In a long term carcinogenicity study in rats, levofloxacin exhibited no
carcinogenic or tumorigenic potential following daily dietary administration
for 2 years; the highest dose was 2 or 10 times the recommended human
dose based on surface area or body weight, respectively.
Levofloxacin was not mutagenic in the following assays: Ames bacterial
mutation assay (S. typhimurium and E. coli), CHO/HGPRT forward mutation
assay, mouse micronucleus test, mouse dominant lethal test, rat unscheduled
DNA synthesis assay, and the mouse sister chromatid exchange assay. It
was positive in the in vitro chromosomal aberration (CHL cell line) and
sister chromatid exchange (CHL/IU cell line) assays.
Levofloxacin caused no impairment of fertility or reproductive performance
in rats at oral doses as high as 360 mg/kg/day (2124 mg/m2),
corresponding to 3.0 or 18 times the recommended maximum human doses based
on surface area or body weight, respectively, and intravenous doses as
high as 100 mg/kg/day (590 mg/m2), corresponding to 1.0 or
5 times the recommended maximum human dose based on surface area or body
weight, respectively.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Levofloxacin was not teratogenic in rats at oral doses as high as 810
mg/kg/day (4779 mg/m2), which corresponds to 14 or 82 times
the recommended maximum human dose base on surface area or body weight,
respectively, or at intravenous doses as high as 160 mg/kg/day (944 mg/m2)
corresponding to 2.7 or 16 times the recommended maximum human dose based
on surface area or body weight, respectively. Doses equivalent to 26 or
81 times the recommended maximum human dose of levofloxacin (based on
surface area or body weight, respectively) caused decreased fetal body
weight and increased fetal mortality in rats when administered orally
at 810 mg/kg/day (8910 mg/m2). No teratogenicity was observed
when rabbits were dosed orally as high as 50 mg/kg/day (550 mg/m2)
which corresponds to 1.6 or 5.0 times the recommended maximum human dose
based on surface area or body weight, respectively, or when dosed intravenously
as high as 25 mg/kg/day (275 mg/m2), corresponding to 0.8 or
2.5 times the maximum recommended human dose based on surface area or
body weight, respectively.
Levofloxacin should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. (See WARNINGS.)
Nursing Mothers
Levofloxacin has not been measured in human milk. Based upon data from
ofloxacin, it can be presumed that levofloxacin will be excreted in human
milk. Because of the potential for serious adverse reactions from levofloxacin
in nursing infants, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Safety and effectiveness in children and adolescents below the age
of 18 years have not been established. Quinolones, including levofloxacin,
cause arthropathy and osteochondrosis in juvenile animals of several
species. (See WARNINGS.)
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