WARNINGS
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN
IN PEDIATRIC PATIENTS, ADOLESCENTS (LESS THAN 18 YEARS
OF AGE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT
BEEN ESTABLISHED. (See
PRECAUTIONS
, Pediatric Use, Pregnancy, Teratogenic
Effects, Pregnancy Category C and Nursing Mothers)
Ciprofloxacin causes lameness in immature dogs. Histopathological
examination of the weight-bearing joints of these dogs
revealed permanent lesions of the cartilage. Related quinolone-class
drugs also produce erosions of cartilage of weight-bearing
joints and other signs of arthropathy in immature animals
of various species. (See ANIMAL PHARMACOLOGY.)
Convulsions, increased intracranial pressure, and toxic
psychosis have been reported in patients receiving quinolones,
including ciprofloxacin. Ciprofloxacin may also cause
central nervous system (CNS) events including: dizziness,
confusion, tremors, hallucinations, depression, and, rarely,
suicidal thoughts or acts. These reactions may occur following
the first dose. If those reactions occur in patients receiving
ciprofloxacin, the drug should be discontinued and appropriate
measures instituted. As with all quinolones, ciprofloxacin
should be used with caution in patients with known or
suspected CNS disorders 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 or lower
the seizure threshold (e.g., certain drug therapy, renal
dysfunction). (See
PRECAUTIONS
, General;
PRECAUTIONS
,
Information for the Patient; DRUG INTERACTIONS
and ADVERSE REACTIONS.)
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED
IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN
AND THEOPHYLLINE. These reactions have included
cardiac arrest, seizure, status epilepticus, and respiratory
failure. Although similar serious adverse effects have
been reported in patients receiving theophylline alone,
the possibility that these reactions may be potentiated
by ciprofloxacin cannot be eliminated. If concomitant
use cannot be avoided, serum levels of theophylline should
be monitored and dosage adjustments made as appropriate.
Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported
in patients receiving quinolone therapy. Some reactions
were accompanied by cardiovascular collapse, loss of consciousness,
tingling, pharyngeal or facial edema, dyspnea, urticaria,
and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactic reactions require immediate
emergency treatment with epinephrine. For I.V. Only: Besides
epinephrine, other resuscitation measures, including oxygen,
intravenous fluids, intravenous antihistamines, corticosteroids,
pressor amines, and airway management, as clinically indicated.
For Oral Only: Oxygen, intravenous steroids, and airway
management, including intubatin, should be administered
as indicated.
Severe hypersensitivity reactions characterized by rash,
fever, eosinophilia, jaundice, and hepatic necrosis with
fatal outcome have also been rarely reported in patients
receiving ciprofloxacin along with other drugs. The possibility
that these reactions were related to ciprofloxacin cannot
be excluded. Ciprofloxacin should be discontinued at the
first appearance of a skin rash or any other sign of hypersensitivity.
Pseudomembranous colitis has been reported with nearly
all antibacterial agents, including ciprofloxacin, 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 antibacterial agents.
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 one primary cause of “antibiotic-associated
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.
Achilles and other tendon ruptures that required surgical
repair or resulted in prolonged disability have been reported
with ciprofloxacin and other quinolones. Ciprofloxacin
should be discontinued if the patient experiences pain,
inflammation, or rupture of a tendon.
Oral Only: Ciprofloxacin has not been
shown to be effective in the treatment of syphilis. Antimicrobial
agents used in high dose for short periods of time to
treat gonorrhea may mask or delay the symptoms of incubating
syphilis. All patients with gonorrhea should have a serologic
test for syphilis at the time of diagnosis. Patients treated
with ciprofloxacin should have a follow-up serologic test
for syphilis after three months.
PRECAUTIONS
General
I.V.
INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW
INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site
reactions have been reported with the intravenous administration
of ciprofloxacin. These reactions are more frequent if
infusion time is 30 minutes or less or if small veins
of the hand are used. (See ADVERSE REACTIONS.)
Oral and I.V.
Quinolones, including ciprofloxacin, may also cause central
nervous system (CNS) events, including nervousness, agitation,
insomnia, anxiety, nightmares or paranoia. (See
WARNINGS
,
PRECAUTIONS
, Information for the Patient and DRUG INTERACTIONS.)
Crystals of ciprofloxacin have been observed rarely in
the urine of human subjects but more frequently in the
urine of laboratory animals, which is usually alkaline.
(See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin
has been reported only rarely in humans because human
urine is usually acidic. Alkalinity of the urine should
be avoided in patients receiving ciprofloxacin. Patients
should be well hydrated to prevent the formation of highly
concentrated urine.
Alteration of the dosage regimen is necessary for patients
with impairment of renal function. (See DOSAGE AND ADMINISTRATION.)
Moderate to severe phototoxicity manifested as an exaggerated
sunburn reaction has been observed in some patients who
were exposed to direct sunlight while receiving some members
of the quinolone class of drugs. Excessive sunlight should
be avoided.
As with any potent drug, periodic assessment of organ
system functions, including renal, hepatic, and hematopoietic,
is advisable during prolonged therapy.
Information for the Patient
Oral
Patients Should be Advised:
That ciprofloxacin may be taken with or without meals.
The preferred time of dosing is two hours after a meal.
Patients should also be advised to drink fluids liberally
and not take antacids containing magnesium, aluminum or
calcium, products containing iron, or multivitamins containing
zinc. Ciprofloxacin should not be taken concurrently with
milk or yogurt alone, since absorption of ciprofloxacin
may be significantly reduced. Dietary calcium as party
of a meal, however, does not significantly affect ciprofloxacin
absorption.
That ciprofloxacin may be associated with hypersensitivity
reactions, even following a single dose, and to discontinue
the drug at the first sign of a skin rash or other allergic
reaction.
To avoid excessive sunlight or artificial ultraviolet
light while receiving ciprofloxacin and to discontinue
therapy if phototoxicity occurs.
To discontinue treatment; rest and refrain from exercise;
and inform their physician if they experience pain, inflammation
or rupture of a tendon
Ciprofloxacin may cause dizziness and lightheadedness;
therefore, patients should know how they react to this
drug before they operate an automobile or machinery or
engage in activities requiring mental alertness or coordination.
That ciprofloxacin may increase the effects of theophylline
and caffeine. There is a possibility of caffeine accumulating
when products containing caffeine are consumed while taking
quinolones.
That convulsions have been reported in patients taking
quinolones, including ciprofloxacin, and to notify their
physician before taking the drug if there is a history
of this condition.
I.V.
Patients should be advised that ciprofloxacin may be
associated with hypersensitivity reactions, even following
a single dose, and to discontinue the drug at the first
sign of a skin rash or other allergic reaction.
Ciprofloxacin may cause dizziness and lightheadedness;
therefore, patients should know how they react to this
drug before they operate an automobile or machinery or
engage in activities requiring mental alertness or coordination.
Patients should be advised that ciprofloxacin may increase
the effects of theophylline and caffeine. There is a possibility
of caffeine accumulation when products containing caffeine
are consumed while taking ciprofloxacin.
Patients should be advised to discontinue treatment;
rest and refrain from exercise; and inform their physician
if they experience pain, inflammation, or rupture of a
tendon.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Oral and I.V.
Eight in vitro mutagenicity tests have been conducted
with ciprofloxacin. Test results are listed below:
- Salmonella/Microsome Test (Negative).
- E. coli DNA Repair Assay (Negative).
- Mouse Lymphoma Cell Forward Mutation Assay (Positive).
- Chinese Hamster V79 Cell HGPRT Test (Negative).
- Syrian Hamster Embryo Cell Transformation Assay (Negative).
- Saccharomyces cerevisiae Point Mutation Assay (Negative).
- Saccharomyces cerevisiae Mitotic Crossover and Gene
Conversion Assay (Negative).
- Rat Hepatocyte DNA Repair Assay (Positive).
Thus, 2 of the 8 tests were positive, but results of the
following 3 in vivo test systems gave negative results:
- Rat Hepatocyte DNA Repair Assay.
- Micronucleus Test (Mice).
- Dominant Lethal Test (Mice).
Long-term carcinogenicity studies in mice and rats have
been completed. After daily oral doses of 750 mg/kg
(mice) and 250 mg/kg (rats) were administered for up
to 2 years, there was no evidence that ciprofloxacin
had any carcinogenic or tumorigenic effects in these
species.
Results from photo co-carcinogenicity testing indicate
that ciprofloxacin does not reduce the time to appearance
of UV-induced skin tumors as compared to vehicle control.
Hairless (Skh-1) mice were exposed to UVA light for 3.5
hours five times every two weeks for up to 78 weeks while
concurrently being administered ciprofloxacin. The time
to development of the first skin tumors was 50 weeks in
mice treated concomitantly with UVA and ciprofloxacin
(mouse dose approximately equal to maximum recommended
human dose based upon mg/m2), as opposed to 34 weeks when
animals were treated with both UVA and vehicle. The times
to development of skin tumors ranged from 16-32 weeks
in mice treated concomitantly with UVA and other quinolones.3
In this model, mice treated with ciprofloxacin alone
did not develop skin or systemic tumors. There are no
data from similar models using pigmented mice and/or fully
haired mice. The clinical significance of these findings
to humans is unknown.
Fertility studies performed in rats at oral doses of
ciprofloxacin up to 100 mg/kg (0.8 times the highest recommended
human dose of 1200 mg based upon body surface area) revealed
no evidence of impairment.
Pregnancy, Teratogenic Effects, Pregnancy Category
C
Oral and I.V.
Reproduction studies have been performed in rats and
mice using oral doses of up to 100 mg/kg (0.6 and 0.3
times the maximum daily human dose based upon body surface
area, respectively) and I.V. doses of up to 30 mg/kg (0.24
and 0.12 times the maximum daily human dose based upon
body surface area, respectively) and have revealed no
evidence of harm to the fetus due to ciprofloxacin. In
rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced
gastrointestinal disturbances resulting in maternal weight
loss and an increased incidence of abortion, but no teratogenicity
was observed at either dose. After intravenous administration
of doses up to 20 mg/kg, no maternal toxicity was produced
in the rabbit, and no embryotoxicity or teratogenicity
was observed. There are, however, no adequate and well-controlled
studies in pregnant women. Ciprofloxacin should be used
during pregnancy only if the potential benefit justifies
the potential risk to the fetus. (See
WARNINGS
.)
Nursing Mothers
Oral and I.V.
Ciprofloxacin is excreted in human milk. Because of the
potential for serious adverse reactions in infants nursing
from mothers taking ciprofloxacin, 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
Oral and I.V.
Safety and effectiveness in pediatric patients and adolescents
less than 18 years of age have not been established. Ciprofloxacin
causes arthropathy in juvenile animals. (See
WARNINGS
.)
Short-term safety data from a single trial in pediatric
cystic fibrosis patients are available. In a radndomized,
double-blind clinical trial for the treatment of acute
pulmonary exacerbations in cystic fibrosis patients (ages
5-17 years), 67 patients received ciprofloxacin I.V. 10
mg/kg/dose q8h for one week followed by ciprofloxacin
HCl tablets 20 mg/kg/dose q12h to complete 10-21 days
treatment and 62 patients received the combination of
ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V.
3 mg/kg/dose q8h for a total of 10-21 days. Patients less
than 5 years of age were not studied. Safety monitoring
in the study included periodic range of motion examinations
and gait assessments by treatment-blihnded examiners.
Patients were followe d for an average of 23 days after
completing treatment (range 0-93 days). This study was
not designed to determine long term effects and the safety
of repeated exposure to ciprofloxacin.
In the study, injection site reactions were more common
in the ciprofloxacin group (24%) than in the comparison
group (8%). Other adverse events were similar in nature
and frequency between treatment arms. Musculoskeletal
adverse events were reported in 22% of the patients in
the ciprofloxacin group and 21% in the comparison group.
Decreased range of motion was reported in 12% of the subjects
in the ciprofloxacin group and 16% in the comparison group.
Arthralgia was reported in 10% of the patients in the
ciprofloxacin group and 11% in the comparison group. One
of sixty-seven patients developed arthritis of the knee
nine days after a ten day course of treatment with ciprofloxacin.
Clinical symptoms resolved, but an MRI showed knee effusion
without other abnormalities eight months after treatment.
However, the relationship of this event to the patient's
course of ciprofloxacin can not be definitively determined,
particularly since patients with cystic fibrosis may develop
arthralgias/arthritis as party of their underlying disease
process.
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