Fluoroquinolones, including CIPRO IV®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart, or lung transplants [see WARNINGS AND PRECAUTIONS].
Fluoroquinolones, including CIPRO IV, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid CIPRO IV in patients with known history of myasthenia gravis [see WARNINGS AND PRECAUTIONS].
DESCRIPTION
CIPRO IV (ciprofloxacin) is a synthetic antimicrobial agent for intravenous (IV) administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:
Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO IV solutions are available as sterile 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. CIPRO IV contains lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is not made with natural rubber latex.. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, for example, di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.
The glucose content for the 200 mL flexible container is 10 g.
CIPRO IV is indicated for the treatment of infections
caused by susceptible isolates of the designated microorganisms in the
conditions and patient populations listed below when the intravenous
administration is needed [see DOSAGE AND ADMINISTRATION].
Urinary Tract Infections
CIPRO IV is indicated in adult patients for treatment of urinary
tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter
cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella
morganii, Citrobacter koseri, Citrobacter freundii, Pseudomonas aeruginosa,
methicillin-susceptible Staphylococcus epidermidis, Staphylococcus
saprophyticus, or Enterococcus faecalis.
Lower Respiratory Tract Infections
CIPRO IV is indicated in adult patients for treatment of
lower respiratory tract infections caused by Escherichia coli, Klebsiella
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa,
Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus
pneumoniae.* Also, CIPRO IV is indicated for the treatment of acute
exacerbations of chronic bronchitis caused by Moraxella catarrhalis [see
Limitation of Use].
Nosocomial Pneumonia
CIPRO IV is indicated in adult patients for treatment of
nosocomialpneumoniacaused by caused by Haemophilus influenzae or
Klebsiella pneumoniae.
Skin And Skin Structure Infections
CIPRO IV is indicated in adult patients for treatment of
skin and skin structure infections caused by Escherichia coli, Klebsiella
pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris,
Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas
aeruginosa, methicillinsusceptible Staphylococcus aureus, methicillin-susceptible
Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone And Joint Infections
CIPRO IV is indicated in adult patients for treatment of
bone and joint infections caused by Enterobacter cloacae, Serratia
marcescens, or Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections
CIPRO IV is indicated in adult patients for treatment of
complicated intra-abdominal infections (used in combination with metronidazole)
caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis,
Klebsiella pneumoniae, or Bacteroides fragilis.
Acute Sinusitis
CIPRO IV is indicated in adult patients for treatment of
acute sinusitis caused by Haemophilus influenzae, Streptococcus
pneumoniae, or Moraxella catarrhalis.
Chronic Bacterial Prostatitis
CIPRO IV is indicated in adult patients for treatment of
chronic bacterial prostatitis caused by Escherichia coli or Proteus
mirabilis.
Empirical Therapy For Febrile Neutropenic Patients
CIPRO IV is indicated in adult patients for the treatment
of febrileneutropenia in combination with piperacillin sodium [seeClinical
Studies].
Complicated Urinary Tract Infections And Pyelonephritis
CIPRO IV is indicated in adults and pediatric patients
from birth to 17 years of age for treatment of inhalational anthrax
(post-exposure) to reduce the incidence or progression of disease following
exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans
served as a surrogate endpoint reasonably likely to predict clinical benefit
and provided the initial basis for approval of this indication.1 Supportive
clinical information for ciprofloxacin for anthrax post-exposure prophylaxis
was obtained during the anthrax bioterror attacks of October 2001. [SeeClinical Studies]
Plague
CIPRO IV is indicated for treatment of plague, including
pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and
prophylaxis for plague in adults and pediatric patients from birth to 17 years
of age. Efficacy studies of ciprofloxacin could not be conducted in humans with
plague for feasibility reasons. Therefore this indication is based on an
efficacy study conducted in animals only [seeClinical Studies].
Limitation Of Use
Use in Pediatric Patients
Although effective in clinical trials, ciprofloxacin is
not a drug of first choice in the pediatric population due to an increased
incidence of adverse events compared to controls, including events related to
joints and/or surrounding tissues. CIPRO IV, like other fluoroquinolones, is
associated with arthropathy and histopathological changes in weight-bearing
joints of juvenile animals [see WARNINGS AND PRECAUTIONS, ADVERSE
REACTIONS, Use In Specific Populations, and Nonclinical
Toxicology].
Lower Respiratory Tract Infections
CIPRO IV is not a drug of first choice in the treatment
of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Usage
To reduce the development of drug-resistant bacteria and
maintain the effectiveness of CIPRO IV and other antibacterial drugs, CIPRO IV
should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying
antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
If anaerobic organisms are suspected of contributing to
the infection, appropriate therapy should be administered. Appropriate culture
and susceptibility tests should be performed before treatment in order to
isolate and identify organisms causing infection and to determine their
susceptibility to ciprofloxacin. Therapy with CIPRO IV may be initiated before
results of these tests are known; once results become available appropriate
therapy should be continued. As with other drugs, some isolates of Pseudomonas
aeruginosa may develop resistance fairly rapidly during treatment with
ciprofloxacin. Culture and susceptibility testing performed periodically during
therapy will provide information not only on the therapeutic effect of the
antimicrobial agent but also on the possible emergence of bacterial resistance.
Dosage
DOSAGE AND ADMINISTRATION
CIPRO IV should be administered intravenously at dosages
described in the appropriate Dosage Guidelines tables.
Dosage In Adults
The determination of dosage and duration for any
particular patient must take into consideration the severity and nature of the
infection, the susceptibility of the causative microorganism, the integrity of
the patient's host-defense mechanisms, and the status of renal and hepatic
function.
Table 1: Adult Dosage Guidelines
Infection1
Dose
Frequency
Usual Duration
Urinary Tract
200 mg to 400 mg
every 12 to every 8 hours
7–14 days
Lower Respiratory Tract
400 mg
every 12 to every 8 hours
7–14 days
Nosocomial Pneumonia
400 mg
every 8 hours
10–14 days
Skin and Skin Structure
400 mg
every 12 to every 8 hours
7–14 days
Bone and Joint
400 mg
every 12 to every 8 hours
4 to 8 weeks
Complicated Intra-Abdominal2
400 mg
every 12 hours
7-14 days
Acute Sinusitis
400 mg
every 12 hours
10 days
Chronic Bacterial prostatitis
400 mg
every 12 hours
28 days
Empirical Therapy In Febrile Neutropenic Patients
CIPRO IV 400 mg and Piperacillin 50 mg/kg
every 8 hours
7-14 days
every 4 hours
Inhalational anthrax (post-exposure)3
400 mg/td>
every 12 hours
60 days
Plague3
400 mg>
every 12 to 8 hours
14 days
1Due to the designated pathogens. 2Used in conjunction with metronidazole. 3Begin administration as soon as possible after suspected or
confirmed exposure.
Conversion of Intravenous to
Oral Dosing in Adults
Patients whose therapy is
started with CIPRO IV may be switched to CIPRO Tablets or Oral Suspension when
clinically indicated at the discretion of the physician (Table 2) [see CLINICAL
PHARMACOLOGY].
Table 2: Equivalent AUC
Dosing Regimens
CIPRO Oral Dosage
Equivalent CIPRO IV Dosage
250 mg Tablet every 12 hours
200 mg intravenous every 12 hours
500 mg Tablet every 12 h
400 mg intravenous every 12 hours
750 mg Tablet every 12 hours
400 mg intravenous every 8 hours
Dosage In Pediatric Patients
Dosing and initial route of
therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined
by the severity of the infection.
Table 3: Pediatric Dosage Guidelines
Infection
Dose (mg/kg)
Frequency
Total Duration
Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age)1
6 mg/kg to 10 mg/kg (maximum 400 mg per dose; not to be exceeded even in patients weighing more than 51 kg)
Every 8 hours
10-21 days1
Inhalational Anthrax (Post-Exposure)2
10 mg/kg (maximum 400 mg per dose)
Every 12 hours
60 days
Plague2,3
10 mg/kg (maximum 400 mg per dose)
Every 12 to 8 hours
10-21 days
1The total duration of therapy for cUTI and
pyelonephritis in the clinical trial was determined by the physician. The mean
duration of treatment was 11 days (range 10 to 21 days). 2Begin drug administration as soon as possible after suspected or
confirmed exposure. 3Begin drug administration as soon as possible after suspected or
confirmed exposure to Y. pestis.
Dosage Modifications In Patients
With Renal Impairment
Ciprofloxacin is eliminated
primarily by renal excretion; however, the drug is also metabolized and
partially cleared through the biliary system of the liver and through the
intestine. These alternative pathways of drug elimination appear to compensate
for the reduced renal excretion in patients with renal impairment. Nonetheless,
some modification of dosage is recommended, particularly for patients with
severe renal dysfunction. Dosage guidelines for use in patients with renal
impairment are shown in Table 4.
Table 4: Recommended
Starting and Maintenance Doses for Adult Patients with Impaired Renal Function
Creatinine Clearance (mL/min)
Dose
> 30
See Usual Dosage.
5-29
200-400 mg every 18-24 hours
When only the serum creatinine
concentration is known, the following formulas may be used to estimate
creatinine clearance:
Males:
(weight in kg) x (140 – age)
(72) x serum creatinine (mg/100 mL)
Females
(0.85) x (above value)
The serum creatinine should
represent a steady state of renal function.
In patients with severe
infections and severe renal impairment and hepatic insufficiency, careful
monitoring is suggested.
Pediatric patients with
moderate to severe renal insufficiency were excluded from the clinical trial of
cUTI and pyelonephritis. No information is available on dosing adjustments
necessary for pediatric patients with moderate to severe renal insufficiency
(that is, creatinine clearance of < 50 mL/min/1.73m²).
Preparation Of CIPRO IV For Administration
Flexible Containers
CIPRO IV is available as a 0.2%
premixed solution in 5% dextrose in flexible containers of 200 mL. The
solutions in flexible containers do not need to be diluted and may be infused
as described above.
Important Administration
Instructions
Intravenous Infusion
CIPRO IV should be administered
to by intravenous infusion over a period of 60 minutes. Slow infusion of a
dilute solution into a larger vein will minimize patient discomfort and reduce
the risk of venous irritation.
Development of Drug Resistant Bacteria [see WARNINGS
AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Adult Patients
During clinical investigations with oral and parenteral
CIPRO IV, 49,038 patients received courses of the drug.
The most frequently reported adverse reactions, from clinical
trials of all formulations, all dosages, all drug-therapy durations, and for
all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%),
liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
In clinical trials the following adverse reactions were
reported in greater than 1% of patients treated with intravenous CIPRO IV:
nausea, diarrhea, central nervous system disturbance, local intravenous site
reactions, liver function tests abnormal, eosinophilia, headache, restlessness,
and rash. Local intravenous site reactions are more frequent if the infusion
time is 30 minutes or less. These may appear as local skin reactions that
resolve rapidly upon completion of the infusion. Subsequent intravenous
administration is not contraindicated unless the reactions recur or worsen.
Table 5: Medically Important Adverse Reactions That
Occurred in less than 1% Ciprofloxacin Patients
Decreased Visual Acuity
Blurred Vision
Disturbed Vision (diplopia, chromatopsia, and photopsia)
Anosmia
Hearing Loss
Tinnitus
Nystagmus
Bad Taste
In several instances, nausea,
vomiting, tremor, irritability, or palpitation were judged by investigators to
be related to elevated serum levels of theophylline possibly as a result of
drug interaction with ciprofloxacin.
In randomized, double-blind
controlled clinical trials comparing CIPRO (Intravenous and Intravenous/Oral.
sequential) with intravenous beta-lactam control antibiotics, the CNS adverse
reaction profile of CIPRO was comparable to that of the control drugs.
Pediatric Patients
Short (6 weeks) and long term
(1 year) musculoskeletal and neurological safety of oral/intravenous
ciprofloxacin was compared to a cephalosporin for treatment of cUTI or
pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4
years) in an international multicenter trial. The duration of therapy was 10 to
21 days (mean duration of treatment was 11 days with a range of 1 to 88 days).
A total of 335 ciprofloxacin-and 349 comparator-treated patients were enrolled.
An Independent Pediatric Safety
Committee (IPSC) reviewed all cases of musculoskeletal adverse reactions
including abnormal gait or abnormal joint exam (baseline or
treatment-emergent). Within 6 weeks of treatment initiation, the rates of
musculoskeletal adverse reactions were 9.3% (31/335) in the
ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients.
All musculoskeletal adverse reactions occurring by 6 weeks resolved (clinical
resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the
adverse reactions. Ciprofloxacin-treated patients were more likely to report
more than one adverse reaction and on more than one occasion compared to
control patients. The rate of musculoskeletal adverse reactions was
consistently higher in the ciprofloxacin group compared to the control group
across all age subgroups. At the end of 1 year, the rate of these adverse
reactions reported at any time during that period was 13.7% (46/335) in the
ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated
patients (Table 6).
Table 6: Musculoskeletal Adverse Reactions1
as Assessed by the IPSC
CIPRO
Comparator
All Patients (within 6 weeks)
31/335 (9.3%)
21/349 (6%)
95% Confidence Interval2
(-0.8%, +7.2%)
Age Group
12 months to 24 months
1/36 (2.8%)
0/41
2 years to < 6 years
5/124 (4%)
3/118 (2.5%)
6 years to < 12 years
18/143 (12.6%)
12/153 (7.8%)
12 years to 17 years
7/32 (21.9%)
6/37 (16.2 %)
All Patients (within 1 year)
46/335 (13.7%)
33/349 (9.5%)
95% Confidence Interval2
(-0.6%, + 9.1%)
1Included: arthralgia, abnormal gait, abnormal
joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain,
myalgia, arm pain, and decreased range of motion in a joint (knee, elbow,
ankle, hip, wrist, and shoulder) 2The study was designed to demonstrate that the arthropathy rate for
the CIPRO group did not exceed that of the control group by more than + 6%. At
both the 6 week and 1 year evaluations, the 95% confidence interval indicated
that it could not be concluded that the ciprofloxacin group had findings
comparable to the control group.
The incidence rates of
neurological adverse reactions within 6 weeks of treatment initiation were 3%
(9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group
and included dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall
incidence rates of adverse reactions within 6 weeks of treatment initiation
were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the
comparator group. The most frequent adverse reactions were gastrointestinal:
15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator
patients. Serious adverse reactions were seen in 7.5% (25/335) of ciprofloxacintreated
patients compared to 5.7% (20/349) of control patients. Discontinuation of drug
due to an adverse reaction was observed in 3% (10/335) of ciprofloxacin-treated
patients versus 1.4% (5/349) of comparator patients. Other adverse events that
occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting
4.8%, abdominal pain 3.3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8%
and rash 1.8%.
Short-term safety data for
ciprofloxacin was also collected in a randomized, double-blind clinical trial
for the treatment of acute pulmonary exacerbations in cystic fibrosis patients
(ages 5–17 years). Sixty seven patients received CIPRO IV 10 mg/kg/dose every 8
hours for one week followed by CIPRO tablets 20 mg/kg/dose every 12 hours to
complete 10–21 days treatment and 62 patients received the combination of
ceftazidime intravenous 50 mg/kg/dose every 8 hours and tobramycin intravenous
3 mg/kg/dose every 8 hours for a total of 10–21 days. Periodic musculoskeletal
assessments were conducted by treatment-blinded examiners. Patients were
followed for an average of 23 days after completing treatment (range 0– 93
days). Musculoskeletal adverse reactions 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. Other adverse reactions were
similar in nature and frequency between treatment arms. The efficacy of
CIPRO for the treatment of acute pulmonary exacerbations in pediatric cystic
fibrosis patients has not been established.
In addition to the adverse reactions reported in
pediatric patients in clinical trials, it should be expected that adverse
reactions reported in adults during clinical trials or postmarketing experience
may also occur in pediatric patients.
Postmarketing Experience
The following adverse reactions have been reported from
worldwide marketing experience with fluoroquinolones, including CIPRO IV.
Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure (Table 7).
Table 7: Postmarketing Reports of Adverse Drug
Reactions
System Organ Class
Adverse Reactions
Cardiovascular
QT prolongation
Torsade de Pointes
Vasculitis and ventricular arrhythmia
Central Nervous System
Hypertonia
Myasthenia
Exacerbation of myasthenia gravis
Peripheral neuropathy
Polyneuropathy
Twitching
Eye Disorders
Nystagmus
Gastrointestinal
Pseudomembranous colitis
Hemic/Lymphatic
Pancytopenia (life threatening or fatal outcome)
Methemoglobinemia
Hepatobiliary
Hepatic failure (including fatal cases)
Infections and Infestations
Candidiasis (oral, gastrointestinal, vaginal)
Investigations
Prothrombin time prolongation or decrease
Cholesterol elevation (serum)
Potassium elevation (serum)
Renal-Elevations of serum creatinine, BUN, and uric acid
Other elevations of serum creatine phosphokinase, serum
theophylline (in patients receiving theophylline concomitantly), blood glucose,
and triglycerides
Other changes occurring were:
decreased leukocyte count, elevated atypicallymphocyte count, immature WBCs,
elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (gGT),
decreased BUN, decreased uric acid, decreased total serum protein, decreased
serum albumin, decreased serum potassium, elevated serum potassium, elevated
serum cholesterol. Other changes occurring during administration of
ciprofloxacin were: elevation of serum amylase, decrease of blood glucose,
pancytopenia, leukocytosis, elevated sedimentation rate, change in serum
phenytoin, decreased prothrombin time, hemolytic anemia, and bleeding
diathesis.
Drug Interactions
Ciprofloxacin is an inhibitor of human cytochrome P450
1A2 (CYP1A2) mediated metabolism. Coadministration of CIPRO IV with other drugs
primarily metabolized by CYP1A2 results in increased plasma concentrations of
these drugs and could lead to clinically significant adverse events of the coadministered
drug.
Table 8: Drugs That are Affected by and Affecting
CIPRO IV
Drugs That are Affected by CIPRO IV
Drug(s)
Recommendation
Comments
Tizanidine
Contraindicated
Concomitant administration of tizanidine and CIPRO IV is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see CONTRAINDICATIONS]
Theophylline
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)
Concurrent administration of CIPRO IV with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See WARNINGS AND PRECAUTIONS.]
Drugs Known to Prolong QT Interval
Avoid Use
CIPRO IV may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see WARNINGS AND PRECAUTIONS andUse in Specific Populations].
Oral antidiabetic drugs
Use with caution Glucose-lowering effect potentiated
Hypoglycemia sometimes severe has been reported when CIPRO IV and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See ADVERSE REACTIONS]
Phenytoin
Use with caution Altered serum levels of phenytoin (increased and decreased)
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO IV discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO IV with phenytoin.
Cyclosporine
Use with caution (transient elevations in serum creatinine)
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs
Use with caution (Increase in anticoagulant effect)
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO IV to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO IV with an oral anticoagulant (for example, warfarin).
Methotrexate
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO IV therapy is indicated.
Ropinirole
Use with caution
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO IV [see WARNINGS AND PRECAUTIONS].
Clozapine
Use with caution
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO IV are advised.
NSAIDs
Use with caution
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Avoid Use Five-fold increase in duloxetine exposure
If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life
CIPRO IV inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Probenecid
Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels)
Fluoroquinolones, including CIPRO IV, are associated with
an increased risk of tendinitis and tendonrupture in all ages. This adverse
reaction most frequently involves the Achilles tendon, and rupture of the
Achilles tendon may require surgical repair. Tendinitis and tendon rupture in
the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other
tendon sites have also been reported. The risk of developing
fluoroquinolone-associated tendinitis and tendon rupture is further increased
in older patients usually over 60 years of age, in patients taking
corticosteroid drugs, and in patients with kidney, heart or lung transplants.
Factors, in addition to age and corticosteroid use, that may independently
increase the risk of tendon rupture include strenuous physical activity, renal
failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis
and tendon rupture have also occurred in patients taking fluoroquinolones who
do not have the above risk factors. Inflammation and tendon rupture can occur,
sometimes bilaterally, even within the first 48 hours, during or after
completion of therapy; cases occurring up to several months after completion of
therapy have been reported. CIPRO IV should be used with caution in patients
with a history of tendon disorders. CIPRO IV should be discontinued if the
patient experiences pain, swelling, inflammation or rupture of a tendon. [See ADVERSE
REACTIONS]
Exacerbation Of Myasthenia Gravis
Fluoroquinolones, including CIPRO IV, have neuromuscular
blocking activity and may exacerbate muscle weakness in persons with myasthenia
gravis. Postmarketing serious adverse events, including deaths and requirement
for ventilatory support, have been associated with fluoroquinolone use in
persons with myasthenia gravis. Avoid CIPRO in patients with known history of
myasthenia gravis. [SeeADVERSE REACTIONS]
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions, some following the first dose, have been reported in patients
receiving quinolone therapy, including CIPRO IV. 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 and other
resuscitation measures, including oxygen, intravenous fluids, intravenous
antihistamines, corticosteroids, pressor amines, and airway management,
including intubation, as indicated. [SeeADVERSE REACTIONS].
Other Serious And Sometimes Fatal Reactions
Other serious and sometimes fatal events, some due to
hypersensitivity, and some due to uncertain etiology, have been reported in
patients receiving therapy with quinolones, including CIPRO IV. These events
may be severe and generally occur following the administration of multiple
doses. Clinical manifestations may include one or more of the following:
Discontinue CIPRO IV immediately at the first appearance
of a skin rash, jaundice, or any other sign of hypersensitivity and supportive
measures instituted [see ADVERSE REACTIONS].
Hepatotoxicity
Cases of severe hepatotoxicity, including hepatic
necrosis, life-threatening hepatic failure, and fatal events, have been
reported with CIPRO IV. Acute liver injury is rapid in onset (range 1–39 days),
and is often associated with hypersensitivity. The pattern of injury can be
hepatocellular, cholestatic or mixed. Most patients with fatal outcomes were
older than 55 years old. In the event of any signs and symptoms of hepatitis
(such as anorexia, jaundice, dark urine, pruritus, or tender abdomen),
discontinue treatment immediately.
There can be a temporary increase in transaminases,
alkaline phosphatase, or cholestatic jaundice, especially in patients with
previous liver damage, who are treated with CIPRO IV. [See ADVERSE REACTIONS]
Serious Adverse Reactions With Concomitant Theophylline
Serious and fatal reactions have been reported in
patients receiving concurrent administration of Intravenous CIPRO and
theophylline. These reactions have included cardiac arrest, seizure, status
epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor,
irritability, or palpitation have also occurred.
Although similar serious adverse reactions have been
reported in patients receiving theophylline alone, the possibility that these
reactions may be potentiated by CIPRO cannot be eliminated. If concomitant use
cannot be avoided, monitor serum levels of theophylline and adjust dosage as
appropriate. [SeeDRUG INTERACTIONS]
Central Nervous System Effects
Convulsions, increased intracranial pressure (including
pseudotumor cerebri), and toxic psychosis have been reported in patients
receiving fluoroquinolones, including CIPRO IV. CIPRO IV may also cause central
nervous system (CNS) events including: nervousness, agitation, insomnia,
anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations,
depression, and, psychotic reactions have progressed to suicidal
ideations/thoughts and self-injurious behavior such as attempted or completed
suicide. These reactions may occur following the first dose. Advise patients
receiving CIPRO IV to inform their healthcare provider immediately if these
reactions occur, discontinue the drug, and institute appropriate care. CIPRO IV,
like other fluoroquinolones, is known to trigger seizures or lower the seizure
threshold. As with all fluoroquinolones, use CIPRO with caution in epileptic
patients and patients with known or suspected CNS disorders that may predispose
to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow,
altered brain structure, or stroke), or in the presence of other risk factors
that may predispose to seizures or lower the seizure threshold (for example,
certain drug therapy, renal dysfunction). Use CIPRO IV when the benefits of
treatment exceed the risks, since these patients are endangered because of
possible undesirable CNS side effects. Cases of status epilepticus have been
reported. If seizures occur, discontinue CIPRO. [See ADVERSE REACTIONS and
DRUG INTERACTIONS]
Clostridium Difficile-Associated Diarrhea
Clostridium Difficile (C. difficile)-associated
diarrhea (CDAD) has been reported with use of nearly all antibacterial agents,
including CIPRO IV, and may range in severity from mild diarrhea to fatal
colitis. Treatment with antibacterial agents alters the normal flora of the
colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which
contribute to the development of CDAD. Hypertoxin producing isolates of C.
difficile cause increased morbidity and mortality, as these infections can
be refractory to antimicrobial therapy and may require colectomy. CDAD must be
considered in all patients who present with diarrhea following antibacterial
use. Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial
use not directed against C. difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation,
antibacterial treatment of C. difficile, and institute surgical
evaluation as clinically indicated. [See ADVERSE REACTIONS]
Peripheral Neuropathy
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
fluoroquinolones, including CIPRO IV. Symptoms may occur soon after initiation
of CIPRO IV and may be irreversible. Discontinue CIPRO IV immediately if the
patient experiences symptoms of peripheral neuropathy including pain, burning,
tingling, numbness, and/or weakness, or other alterations in sensations
including light touch, pain, temperature, position sense and vibratory
sensation, and/or motor strength in order to minimize the development of an
irreversible condition. [See ADVERSE REACTIONS]
Prolongation Of The QT Interval
Some fluoroquinolones, including CIPRO IV, have been
associated with prolongation of the QT interval on the electrocardiogram and
cases of arrhythmia. Cases of torsade de pointes have been reported during
postmarketing surveillance in patients receiving fluoroquinolones, including
CIPRO IV. Avoid CIPRO IV in patients with known prolongation of the QT
interval, risk factors for QT prolongation or torsade de pointes (for example,
congenitallong QT syndrome , uncorrected electrolyte imbalance, such as
hypokalemia or hypomagnesemia and cardiac disease, such as heart failure,
myocardial infarction, or bradycardia), and patients receiving Class IA
antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic
agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and
antipsychotics. Elderly patients may also be more susceptible to
drug-associated effects on the QT interval. [SeeADVERSE REACTIONS and Use
in Specific Populations]
Musculoskeletal Disorders In Pediatric Patients And Arthropathic
Effects In Animals
CIPRO IV is indicated in pediatric patients (less than 18
years of age) only for cUTI, prevention of inhalational anthrax (post
exposure), and plague [seeINDICATIONS AND USAGE]. An increased
incidence of adverse reactions compared to controls, including reactions
related to joints and/or surrounding tissues, has been observed [see ADVERSE
REACTIONS].
In pre-clinical studies, oral administration of CIPRO IV
caused 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 Use in Specific Populations and Nonclinical
Toxicology]
Crystalluria
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 Nonclinical Toxicology]. Crystalluria
related to ciprofloxacin has been reported only rarely in humans because human
urine is usually acidic. Avoid alkalinity of the urine in patients receiving
CIPRO IV. Hydrate patients well to prevent the formation of highly concentrated
urine [see DOSAGE AND ADMINISTRATION].
Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity
reactions, the latter of which may manifest as exaggerated sunburn reactions
(for example, burning, erythema, exudation, vesicles, blistering, edema)
involving areas exposed to light (typically the face, “V” area of the neck,
extensor surfaces of the forearms, dorsa of the hands), can be associated with
the use of quinolones, including CIPRO IV, after sun or UV light exposure.
Therefore, avoid excessive exposure to these sources of light. Discontinue
CIPRO IV if phototoxicity occurs. [See ADVERSE REACTIONS]
Development Of Drug Resistant Bacteria
Prescribing CIPRO IV in the absence of a proven or
strongly suspected bacterial infection or a prophylactic indication is unlikely
to provide benefit to the patient and increases the risk of the development of
drug-resistant bacteria.
Potential Risks With Concomitant Use Of Drugs Metabolized
By Cytochrome P450 1A2 Enzymes
Ciprofloxacin is an inhibitor of the hepatic CYP1A2
enzyme pathway. Co-administration of CIPRO IV and other drugs primarily
metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine,
tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma
concentrations of the coadministered drug and could lead to clinically
significant pharmacodynamic adverse reactions of the coadministered drug. [See DRUG
INTERACTIONS and CLINICAL PHARMACOLOGY]
Periodic Assessment Of Organ System Functions
As with any potent drug, periodic assessment of organ
system functions, including renal, hepatic, and hematopoietic function, is
advisable during prolonged therapy.
Patient Counseling Information
Advise the patient to read the FDA-Approved patient
labeling (Medication Guide)
Antibacterial Resistance
Inform patients that antibacterial drugs including CIPRO
IV should only be used to treat bacterial infections. They do not treat viral
infections (for example, the common cold). When CIPRO IV prescribed to treat a
bacterial infection, patients should be told that although it is common to feel
better early in the course of therapy, the medication should be taken exactly
as directed. Skipping doses or not completing the full course of therapy may
(1) decrease the effectiveness of the immediate treatment and (2) increase the
likelihood that bacteria will develop resistance and will not be treatable by
CIPRO IV or other antibacterial drugs in the future.
Administration
Inform patients to drink fluids liberally while taking
CIPRO to avoid formation of highly concentrated urine and crystal formation in
the urine.
Serious and Potentially Serious Adverse Reactions
Inform patients of the following serious adverse
reactions that have been associated with CIPRO or other fluoroquinolone use:
Tendon Disorders Instruct patients to contact
their healthcare provider if they experience pain, swelling, or inflammation of
a tendon, or weakness or inability to use one of their joints; rest and refrain
from exercise; and discontinue CIPRO treatment. The risk of severe tendon
disorder with fluoroquinolones is higher in older patients usually over 60
years of age, in patients taking corticosteroid drugs, and in patients with
kidney, heart or lung transplants.
Exacerbation of Myasthenia Gravis: Instruct
patients to inform their physician of any history of myasthenia gravis.
Instruct patients to notify their physician if they experience any symptoms of
muscle weakness, including respiratory difficulties.
Hypersensitivity Reactions: Inform patients that
ciprofloxacin can cause hypersensitivity reactions, even following a single
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 (for example, swelling of the lips, tongue,
face, tightness of the throat, hoarseness), or other symptoms of an allergic
reaction.
Hepatotoxicity: Inform patients that severe
hepatotoxicity (including acute hepatitis and fatal events) has been reported
in patients taking CIPRO IV. Instruct patients to inform their physician if
they experience any signs or symptoms of liver injury including: loss of
appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant
tenderness, itching, yellowing of the skin and eyes, light colored bowel
movements or dark colored urine.
Convulsions: Inform patients that convulsions have been
reported in patients receiving fluoroquinolones, including ciprofloxacin.
Instruct patients to notify their physician before taking this drug if they
have a history of convulsions.
Neurologic Adverse Effects (for example,
dizziness, lightheadedness, increased intracranial pressure): Inform patients
that they should know how they react to CIPRO IV before they operate an
automobile or machinery or engage in other activities requiring mental
alertness and coordination. Instruct patients to notify their physician if
persistent headache with or without blurred vision occurs.
Diarrhea: Diarrhea is a common problem caused by
antibiotics which usually ends when the antibiotic is discontinued. Sometimes
after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or
more months after having taken the last dose of the antibiotic. If this occurs,
Instruct patients to contact their physician as soon as possible.
Peripheral Neuropathies: Inform patients that
peripheral neuropathies have been associated with ciprofloxacin use, symptoms
may occur soon after initiation of therapy and may be irreversible If symptoms
of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness
develop, immediately discontinue CIPRO IV and contact their physician.
Prolongation of the QT Interval: Instruct patients
to inform their physician of any personal or family history of QT prolongation
or proarrhythmic conditions such as hypokalemia, bradycardia, or recent
myocardial ischemia if they are taking any Class IA (quinidine, procainamide),
or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to
notify their physician if they have any symptoms of prolongation of the QT
interval, including prolonged heart palpitations or a loss of consciousness.
Musculoskeletal Disorders in Pediatric Patients: Instruct
parents to inform their child's physician if the child has a history of
joint-related problems before taking this drug. Inform parents of pediatric
patients to notify their child's physician of any joint-related problems that
occur during or following ciprofloxacin therapy [see WARNINGS AND
PRECAUTIONS and Use In Specific Populations].
Tizanidine: Instruct patients not to use
ciprofloxacin if they are already taking tizanidine. Ciprofloxacin increases
the effects of tizanidine (Zanaflex®).
Theophylline: Inform patients that ciprofloxacin
CIPRO IV may increase the effects of theophylline. Life-threatening CNS effects
and arrhythmias can occur. Advise the patients to immediately seek medical help
if they experience seizures, palpitations, or difficulty breathing.
Caffeine: Inform patients that ciprofloxacin may
increase the effects of caffeine. There is a possibility of caffeine
accumulation when products containing caffeine are consumed while taking
quinolones.
Photosensitivity/Phototoxicity: Inform patients
that photosensitivity/phototoxicity has been reported in patients receiving
fluoroquinolones. Inform patients to minimize or avoid exposure to natural or
artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones.
If patients need to be outdoors while using quinolones, instruct them to wear
loose-fitting clothes that protect skin from sun exposure and discuss other sun
protection measures with their physician. If a sunburn-like reaction or skin
eruption occurs, instruct patients to contact their physician.
Drug Interactions Oral Antidiabetic Agents
Inform patients that hypoglycemia has been reported when
ciprofloxacin and oral antidiabetic agents were co-administered; if low blood
sugar occurs with CIPRO IV, instruct them toconsult their physician and that
their antibacterial medicine may need to be changed.
Anthrax and Plague Studies
Inform patients given CIPRO IV for this condition that
efficacy studies could not be conducted in humans for ethical and feasibility
reasons. Therefore, approval for these conditions was based on efficacy studies
conducted in animals.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis,
Impairment Of Fertility
A total of 8 in vitro mutagenicity
tests have been conducted with ciprofloxacin, and the test results are listed
below:
Long-term carcinogenicity
studies in rats and mice resulted in no carcinogenic or tumorigenic effects due
to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to
rats and mice, respectively (approximately 1.7-times and 2.5-times the highest
recommended therapeutic dose based upon body surface area, respectively).
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 body surface area), as opposed
to 34 weeks when animals were treated with both UVA and vehicle. The times to
development of skin tumors ranged from 16 to32 weeks in mice treated
concomitantly with UVA and other quinolones.9
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 (approximately 0.7-times
the highest recommended therapeutic dose based upon body surface area) revealed
no evidence of impairment.
Use In Specific Populations
Pregnancy
Pregnancy Category C
There are no adequate and
well-controlled studies in pregnant women. CIPRO IV should not be used during
pregnancy unless the potential benefit justifies the potential risk to both
fetus and mother. An expert review of published data on experiences with
ciprofloxacin use during pregnancy by TERIS–the Teratogen Information
System–concluded that therapeutic doses during pregnancy are unlikely to pose a
substantial teratogenic risk (quantity and quality of data=fair), but the data
are insufficient to state that there is no risk.2
A controlled prospective
observational study followed 200 women exposed to fluoroquinolones (52.5%
exposed to ciprofloxacin and 68% first trimester exposures) during gestation.3
In utero exposure to fluoroquinolones during embryogenesis was not associated
with increased risk of major malformations. The reported rates of major
congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for
the control group (background incidence of major malformations is 1–5%). Rates
of spontaneous abortions, prematurity and low birth weight did not differ
between the groups and there were no clinically significant musculoskeletal
dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up
study reported on 549 pregnancies with fluoroquinolone exposure (93% first
trimester exposures).4 There were 70 ciprofloxacin exposures, all
within the first trimester. The malformation rates among live-born babies
exposed to ciprofloxacin and to fluoroquinolones overall were both within
background incidence ranges. No specific patterns of congenital abnormalities
were found. The study did not reveal any clear adverse reactions due to in
utero exposure to ciprofloxacin.
No differences in the rates of
prematurity, spontaneous abortions, or birth weight were seen in women exposed
to ciprofloxacin during pregnancy.2,3 However, these small
postmarketing epidemiology studies, of which most experience is from short
term, first trimester exposure, are insufficient to evaluate the risk for less
common defects or to permit reliable and definitive conclusions regarding the
safety of ciprofloxacin in pregnant women and their developing fetuses.
Reproduction studies have been
performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 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, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately
0.4-and 1.3-times the highest recommended therapeutic dose based upon body
surface area) produced gastrointestinal toxicity resulting in maternal weight
loss and an increased incidence of abortion, but no teratogenicity was observed
at either dose level. After intravenous administration of doses up to 20
mg/kg (approximately 0.3-times the highest recommended therapeutic dose based
upon body surface area), no maternal toxicity was produced and no embryotoxicity
or teratogenicity was observed.
Nursing Mothers
Ciprofloxacin is excreted in human milk. The amount of
ciprofloxacin absorbed by the nursing infant is unknown. Because of the
potential risk of serious adverse reactions (including articular damage) in
infants nursing from mothers taking CIPRO IV, 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
Although effective in clinical trials, CIPRO IV is not a
drug of first choice in the pediatric population due to an increased incidence
of adverse reactions compared to controls. Quinolones, including CIPRO IV,
cause arthropathy in juvenile animals [see WARNINGS AND PRECAUTIONS and Nonclinical
Toxicology].
Complicated Urinary Tract Infection and Pyelonephritis
CIPRO IV is indicated for the treatment of cUTI and
pyelonephritis due to Escherichia coli in pediatric patients 1 to 17 years of
age. Although effective in clinical trials, CIPRO IV is not a drug of first
choice in the pediatric population due to an increased incidence of adverse
reactions compared to the controls, including events related to joints and/or
surrounding tissues. [See ADVERSE REACTIONS and Clinical Studies]
Inhalational Anthrax (Post-Exposure)
CIPRO IV is indicated in pediatric patients from birth to
17 years of age for inhalational anthrax (postexposure). The risk-benefit
assessment indicates that administration of ciprofloxacin to pediatric patients
is appropriate [see DOSAGE AND ADMINISTRATION and Clinical Studies].
Plague
CIPRO IV is indicated in pediatric patients from birth to
17 years of age, for treatment of plague, including pneumonic and septicemic
plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy
studies of CIPRO IV could not be conducted in humans with pneumonic plague for
feasibility reasons. Therefore, approval of this indication was based on an
efficacy study conducted in animals. The risk-benefit assessment indicates that
administration of CIPRO to pediatric patients is appropriate. [See INDICATIONS
AND USAGE, DOSAGE AND ADMINISTRATION, and Clinical Studies]
Geriatric Use
Geriatric patients are at increased risk for developing
severe tendon disorders including tendon rupture when being treated with a
fluoroquinolone such as CIPRO IV. This risk is further increased in patients
receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can
involve the Achilles, hand, shoulder, or other tendon sites and can occur
during or after completion of therapy; cases occurring up to several months after
fluoroquinolone treatment have been reported. Caution should be used when
prescribing CIPRO IV to elderly patients especially those on corticosteroids.
Patients should be informed of this potential adverse reaction and advised to
discontinue CIPRO and contact their healthcare provider if any symptoms of
tendinitis or tendon rupture occur. [See BOXED WARNING, WARNINGS AND
PRECAUTIONS, and ADVERSE REACTIONS]
In a retrospective analysis of 23 multiple-dose controlled
clinical trials of CIPRO encompassing over 3500 ciprofloxacin-treated patients,
25% of patients were greater than or equal to 65 years of age and 10% were
greater than or equal to 75 years of age. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and
other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older
individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to
be substantially excreted by the kidney, and the risk of adverse reactions may
be greater in patients with impaired renal function. No alteration of dosage is
necessary for patients greater than 65 years of age with normal renal function.
However, since some older individuals experience reduced renal function by
virtue of their advanced age, care should be taken in dose selection for
elderly patients, and renal function monitoring may be useful in these
patients. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]
In general, elderly patients may be more susceptible to
drug-associated effects on the QT interval. Therefore, precaution should be
taken when using CIPRO IV with concomitant drugs that can result in
prolongation of the QT interval (for example, class IA or class III
antiarrhythmics) or in patients with risk factors for torsade de pointes (for
example, known QT prolongation, uncorrected hypokalemia). [See WARNINGS AND
PRECAUTIONS]
Renal Impairment
Ciprofloxacin is eliminated primarily by renal excretion;
however, the drug is also metabolized and partially cleared through the biliary
system of the liver and through the intestine. These alternative pathways of
drug elimination appear to compensate for the reduced renal excretion in
patients with renal impairment. Nonetheless, some modification of dosage is
recommended, particularly for patients with severe renal dysfunction. [See DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY]
Hepatic Impairment
In preliminary studies in patients with stable chronic
liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have
been observed. The pharmacokinetics of ciprofloxacin in patients with acute
hepatic insufficiency, have not been studied.
REFERENCES
2. Friedman J, Polifka J. Teratogenic effects of drugs: a
resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University
Press, 2000:149-195.
3. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome
following gestational exposure to fluoroquinolones: a multicenter prospective
controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339.
4. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy
outcome after prenatal quinolone exposure. Evaluation of a case registry of the
European network of teratology information services (ENTIS). Eur J Obstet
Gynecol Reprod Biol. 1996;69:83-89.
Overdosage & Contraindications
OVERDOSE
In the event of acute overdosage, reversible renal
toxicity has been reported in some cases. Observe the patient carefully and
give supportive treatment, including monitoring of renal function, urinary pH
and acidify, if required, to prevent crystalluria. Adequate hydration must be
maintained. Only a small amount of ciprofloxacin (less than 10%) is removed
from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity
including tonic/clonic convulsions was observed at intravenous doses of
ciprofloxacin between 125mg/kg and 300 mg/kg.
CONTRAINDICATIONS
Hypersensitivity
Ciprofloxacin is contraindicated in persons with a
history of hypersensitivity to ciprofloxacin, any member of the quinolone class
of antibacterials, or any of the product components [see WARNINGS AND
PRECAUTIONS].
Tizanidine
Concomitant administration with tizanidine is
contraindicated [see DRUG INTERACTIONS].
Clinical Pharmacology
Mechanism Of Action
Ciprofloxacin is a member of the fluoroquinolone class of
antibacterial agents [see Microbiology].
Pharmacokinetics
Absorption
Following 60-minute intravenous infusions of 200 mg and
400 mg CIPRO IV to normal volunteers, the mean maximum serum concentrations
achieved were 2.1 and 4.6 mcg/mL, respectively; the concentrations at 12 hours
were 0.1 and 0.2 mcg/mL, respectively (Table 9).
Table 9: Steady-state Ciprofloxacin Serum
Concentrations (mcg/mL) After 60-minute INTRAVENOUS Infusions every 12 hours.
Time after starting the infusion
Dose
30 minutes
1 hour
3 hour
6 hour
8 hour
12 hour
200 mg
1.7
2.1
0.6
0.3
0.2
0.1
400 mg
3.7
4.6
1.3
0.7
0.5
0.2
The pharmacokinetics of
ciprofloxacin are linear over the dose range of 200 mg to 400 mg administered
intravenously. Comparison of the pharmacokinetic parameters following the 1st
and 5th intravenous dose on an every 12 hour regimen indicates no evidence of
drug accumulation.
The absolute bioavailability of
oral ciprofloxacin is within a range of 70–80% with no substantial loss by
first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given
over 60 minutes every 12 hours has been shown to produce an area under the
serum concentration time curve (AUC) equivalent to that produced by a 500-mg
oral dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin
given over 60 minutes every 8 hours has been shown to produce an AUC at
steady-state equivalent to that produced by a 750-mg oral dose given
every 12 hours. A 400-mg intravenous dose results in a C max similar to that
observed with a 750-mg oral dose. An infusion of 200 mg CIPRO given every 12
hours produces an AUC equivalent to that produced by a 250-mg oral dose given
every 12 hours (Table 10).
Table 10: Steady-state
Pharmacokinetic Parameters Following Multiple Oral and Intravenous Doses
Parameters
500 mg
400 mg
750 mg
400 mg
every 12 hours Orally.
every 12 hours, intravenously
every 12 hours, orally
every 8 hours,
AUC (mcg•hr/mL)
13.71
12.71
31.62
32.93
Cmax (mcg/mL)
2.97
4.56
3.59
4.07
1AUC 0-12h 2AUC 24h = AUC 0-12h x 2 3AUC 24h = AUC 0-8h x 3
Distribution
After intravenous administration,
ciprofloxacin is widely distributed throughout the body. Tissue concentrations
often exceed serum concentrations in both men and women, particularly in
genital tissue including the prostate. Ciprofloxacin is present in active form
in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum,
skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions.
Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and
bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF
concentrations are generally less than 10% of peak serum concentrations. Low
levels of the drug have been detected in the aqueous and vitreous humors of the
eye.
Metabolism
After intravenous
administration, three metabolites of ciprofloxacin have been identified in
human urine which together account for approximately 10% of the intravenous
dose. The metabolites have antimicrobial activity, but are less active than
unchanged. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2)
mediated metabolism. Co-administration of ciprofloxacin with other drugs
primarily metabolized by CYP1A2 results in increased plasma concentrations of
these drugs and could lead to clinically significant adverse events of the
co-administered drug [seeCONTRAINDICATIONS, WARNINGS AND
PRECAUTIONS, DRUG INTERACTIONS].
Excretion
The serum elimination half-life
is approximately 5–6 hours and the total clearance is around 35 L/hr. After
intravenous administration, approximately 50% to 70% of the dose is excreted in
the urine as unchanged drug. Following a 200-mg intravenous dose,
concentrations in the urine usually exceed 200 mcg/mL 0–2 hours after dosing
and are generally greater than 15 mcg/mL 8–12 hours after dosing. Following a
400 mg intravenous dose, urine concentrations generally exceed 400 mcg/mL 0–2
hours after dosing and are usually greater than 30 mcg/mL 8–12 hours after
dosing. The renal clearance is approximately 22 L/hr. The urinary excretion of
ciprofloxacin is virtually complete by 24 hours after dosing.
Although bile concentrations of
ciprofloxacin are several fold higher than serum concentrations after
intravenous dosing, only a small amount of the administered dose ( < less
than1%) is recovered from the bile as unchanged drug. Approximately 15%
of an intravenous dose is recovered from the feces within 5 days after dosing.
Specific Populations
Elderly
Pharmacokinetic studies of the oral (single dose) and
intravenous (single and multiple dose) forms of ciprofloxacin indicate that
plasma concentrations of ciprofloxacin are higher in elderly subjects (older
than 65 years) as compared to young adults. Although the Cmax is increased 16%
to40%, the increase in mean AUC is approximately 30%, and can be at least
partially attributed to decreased renal clearance in the elderly. Elimination
half-life is only slightly (~20%) prolonged in the elderly. These differences
are not considered clinically significant. [See Use In Specific Populations]
In preliminary studies in patients with stable chronic
liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have
been observed. The kinetics of ciprofloxacin in patients with acute hepatic
insufficiency, have not been fully studied.
Pediatrics
Following a single oral dose of 10 mg/kg CIPRO suspension
to 16 children ranging in age from 4 months to 7 years, the mean C max was 2.4
mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2 mcg*hr/mL (range:
5.8 mcg*hr/mL to 14.9 mcg*hr/mL). There was no apparent age-dependence, and no
notable increase in C max or AUC upon multiple dosing (10 mg/kg three times a
day). In children with severe sepsis who were given intravenous ciprofloxacin
(10 mg/kg as a 1-hour infusion), the mean C max was 6.1 mcg/mL (range: 4.6
mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL
(range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of
age. The AUC values were 17.4 mcg*hr/mL (range: 11.8 mcg*hr/mL to 32.0 mcg*hr/mL)
and 16.5 mcg*hr/mL (range: 11 mcg*hr/mL to 23.8 mcg*hr/mL) in the respective
age groups. These values are within the range reported for adults at
therapeutic doses. Based on population pharmacokinetic analysis of pediatric
patients with various infections, the predicted mean half-life in children is
approximately 4 hours–5 hours, and the bioavailability of the oral suspension
is approximately 60%.
Drug-Drug Interactions
Metronidazole
The serum concentrations of ciprofloxacin and
metronidazole were not altered when these two drugs were given concomitantly.
Tizanidine
In a pharmacokinetic study, systemic exposure of
tizanidine (4 mg single dose) was significantly increased (C max 7-fold, AUC
10-fold) when the drug was given concomitantly with CIPRO (500 mg twice a day
for 3 days). Concomitant administration of tizanidine and CIPRO IV is
contraindicated due to the potentiation of hypotensive and sedative effects of
tizanidine [see CONTRAINDICATIONS].
Ropinirole
In a study conducted in 12 patients with Parkinson's
disease who were administered 6 mg ropinirole once daily with 500 mg CIPRO
twice-daily, the mean C max and mean AUC of ropinirole were increased by 60%
and 84%, respectively. Monitoring for ropinirole-related adverse reactions and
appropriate dose adjustment of ropinirole is recommended during and shortly
after co-administration with CIPRO IV [see WARNINGS AND PRECAUTIONS].
Clozapine
Following concomitant administration of 250 mg CIPRO with
304 mg clozapine for 7 days, serum concentrations of clozapine and
N-desmethylclozapine were increased by 29% and 31%, respectively. Careful
monitoring of clozapine associated adverse reactions and appropriate adjustment
of clozapine dosage during and shortly after co-administration with CIPRO IV
are advised.
Sildenafil
Following concomitant administration of a single oral
dose of 50 mg sildenafil with 500 mg CIPRO to healthy subjects, the mean C max and
mean AUC of sildenafil were both increased approximately two-fold. Use
sildenafil with caution when co-administered with CIPRO due to the expected
two-fold increase in the exposure of sildenafil upon co-administration of CIPRO
IV.
Duloxetine
In clinical studies it was demonstrated that concomitant
use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as
fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold
increase in mean C max of duloxetine.
Lidocaine
In a study conducted in 9 healthy volunteers, concomitant
use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily resulted in
an increase of lidocaine C max and AUC by 12% and 26%, respectively. Although
lidocaine treatment was well tolerated at this elevated exposure, a possible
interaction with CIPRO IV and an increase in adverse reactions related to
lidocaine may occur upon concomitant administration.
Microbiology
Mechanism of Action
The bactericidal action of ciprofloxacin results from
inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV
(both Type II topoisomerases), which are required for bacterial DNA
replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including
ciprofloxacin, is different from that of penicillins, cephalosporins,
aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms
resistant to these classes of drugs may be susceptible to ciprofloxacin.
Resistance to fluoroquinolones occurs primarily by either mutations in the DNA
gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance
to ciprofloxacin develops slowly by multiple step mutations. Resistance to
ciprofloxacin due to spontaneous mutations occurs at a general frequency of
between < 10-9 to 1x10-6 .
Cross Resistance
There is no known cross-resistance between ciprofloxacin
and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most
isolates of the following bacteria, both in vitro and in clinical infections [see
INDICATIONS AND USAGE].
The following in vitro data are available, but their
clinical significance is unknown. At least 90 percent of the following bacteria
exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal
to the susceptible breakpoint for ciprofloxacin ( ≤ 1 mcg/mL). However, the
efficacy of ciprofloxacin in treating clinical infections due to these bacteria
has not been established in adequate and well-controlled clinical trials.
Gram-positive Bacteria
Staphylococcus haemolyticus (methicillin-susceptible
isolates only)
Staphylococcus hominis (methicillin-susceptible
isolates only)
When available, the clinical microbiology laboratory
should provide the results of in vitro susceptibility test results for
antimicrobial drug products used in resident hospitals to the physician as
periodic reports that describe the susceptibility profile of nosocomial and
community-acquired pathogens. These reports should aid the physician in
selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
susceptibility of bacteria to antimicrobial compounds. The MICs should be
determined using a standardized test method (broth and/or agar).5,6,7 The
MIC values should be interpreted according to criteria provided in Table 10.
Diffusion Techniques
Quantitative methods that require measurement of zone
diameters can also provide reproducible estimates of the susceptibility of
bacteria to antimicrobial compounds. The zone size provides an estimate of the
susceptibility of bacteria to antimicrobial compounds. The zone size should be
determined using a standardized test method.6,7,8 This procedure
uses paper disks impregnated with 5 mcg ciprofloxacin to test the
susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive
criteria are provided in Table 11.
Table 11: Susceptibility Test Interpretive Criteria
for Ciprofloxacin
Bacteria
MIC
(mcg/mL)
Zone Diameter (mm)
S
I
R
S
I
R
Enterobacteriaceae
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Enterococcus faecalis
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Staphylococcus aureus
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Staphylococcus epidermidis
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Staphylococcus saprophyticus
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Pseudomonas aeruginosa
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Haemophilus influenzae1
≤ 1
-
-
≥ 21
-
-
Haemophilus parainfluenzae1
≤ 1
-
-
≥ 21
-
-
Streptococcus pneumoniae
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Streptococcus pyogenes
≤ 1
2
≥ 4
≥ 21
16-20
≤ 15
Bacillus anthracis1
≤ 0.25
-
-
-
-
-
Yersinia pestis1
≤ 0.25
-
-
-
-
-
S=Susceptible, I=Intermediate, and R=Resistant. 1The
current absence of data on resistant isolates precludes defining any results
other than “Susceptible”. If isolates yield MIC results other than susceptible,
they should be submitted to a reference laboratory for further testing.
A report of “Susceptible”
indicates that the antimicrobial is likely to inhibit growth of the pathogen if
the antimicrobial compound reaches the concentrations at the site of infection
necessary to inhibit growth of the pathogen. A report of “Intermediate”
indicates that the result should be considered equivocal, and, if the
microorganism is not fully susceptible to alternative, clinically feasible
drugs, the test should be repeated. This category implies possible clinical
applicability in body sites where the drug is physiologically concentrated or
in situations where high dosage of drug can be used. This category also
provides a buffer zone that prevents small uncontrolled technical factors from
causing major discrepancies in interpretation. A report of “Resistant”
indicates that the antimicrobial is not likely to inhibit growth of the
pathogen if the antimicrobial compound reaches the concentrations usually
achievable at the infection site; other therapy should be selected.
Quality Control
Standardized susceptibility
test procedures require the use of laboratory controls to monitor the accuracy
and precision of supplies and reagents used in the assay, and the techniques of
the individuals performing the test.5,6,7,8 Standard ciprofloxacin
powder should provide the following range of MIC values noted in Table 12. For
the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in
Table 12 should be achieved.
Table 12: Acceptable Quality
Control Ranges for Ciprofloxacin
Bacteria
MIC range (mcg/mL)
Zone Diameter (mm)
Enterococcus faecalis ATCC 29212
0.25-2
-
Escherichia coli ATCC 25922
0.004-0.015
30-40
Haemophilus influenzae ATCC 49247
0.004-0.03
34-42
Pseudomonas aeruginosa ATCC 27853
0.25-1
25-33
Staphylococcus aureus ATCC 29213
0.12-0.5
-
Staphylococcus aureus ATCC 25923
-
22-30
Animal Toxicology And/Or Pharmacology
Ciprofloxacin and other
quinolones have been shown to cause arthropathy in immature animals of most
species tested [see WARNINGS AND PRECAUTIONS].
Damage of weight-bearing joints
was observed in juvenile dogs and rats. In young beagles, 100 mg/kg
ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes
of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In
a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg
and 90 mg/kg ciprofloxacin (approximately 1.3-times and 3.5-times the pediatric
dose based upon comparative plasma AUCs) given daily for 2 weeks caused
articular changes which were still observed by histopathology after a
treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the
pediatric dose based upon comparative plasma AUCs), no effects on joints were
observed. This dose was also not associated with arthrotoxicity after an
additional treatment-free period of 5 months. In another study, removal of
weight bearing from the joint reduced the lesions but did not totally prevent
them.
Crystalluria, sometimes associated with secondary
nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is
primarily related to the reduced solubility of ciprofloxacin under alkaline
conditions, which predominate in the urine of test animals; in man,
crystalluria is rare since human urine is typically acidic. In rhesus monkeys,
crystalluria without nephropathy was noted after single oral doses as low as 5
mg/kg (approximately 0.07-times the highest recommended therapeutic dose based
upon body surface area). After 6 months of intravenous dosing at 10 mg/kg/day,
no nephropathological changes were noted; however, nephropathy was observed
after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the
highest recommended therapeutic dose based upon body surface area).
In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid
intravenous injection (15 sec.) produces pronounced hypotensive effects. These
effects are considered to be related to histamine release, since they are
partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid
intravenous injection also produces hypotension but the effect in this species
is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal
anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones
has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity seen with some related drugs has not been
observed in ciprofloxacin-treated animals
Clinical Studies
Empirical Therapy In Adult Febrile Neutropenic Patients
The safety and efficacy of CIPRO IV, 400 mg intravenously
every 8 hours, in combination with piperacillin sodium, 50 mg/kg intravenously
every 4 hours, for the empirical therapy of febrile neutropenic patients were
studied in one large pivotal multicenter, randomized trial and were compared to
those of tobramycin, 2 mg/kg intravenously every 8 hours, in combination with
piperacillin sodium, 50 mg/kg intravenously every 4 hours.
Clinical response rates observed in this study were as
follows:
The clinical success and bacteriologic eradication rates
in the Per Protocol population were similar between ciprofloxacin and the comparator
group as shown in Table 13.
Table 13: Clinical Response Rates
Outcomes
CIPRO IV/Piperacillin
N = 233 Success (%)
Tobramycin/ Piperacillin
N = 237 Success (%)
Clinical Resolution of Initial Febrile Episode with No
63 (27%)
52 (21.9%)
Modifications of Empirical Regimen1
Clinical Resolution of Initial Febrile Episode Including Patients with Modifications of Empirical Regimen
187 (80.3%)
185 (78.1%)
Overall Survival
224 (96.1%)
185 (78.1%)
1 To be evaluated as a clinical resolution, patients had to
have: (1) resolution of fever; (2) microbiological eradication of infection (if
an infection was microbiologically documented); (3) resolution of
signs/symptoms of infection; and (4) no modification of empirical antibiotic
regimen
Complicated Urinary Tract
Infection And Pyelonephritis–Efficacy In Pediatric Patients
Ciprofloxacin, administered IV
and/or orally, was compared to a cephalosporin for treatment of complicated
urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to
17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US,
Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The
duration of therapy was 10 to 21 days (mean duration of treatment was 11 days
with a range of 1 to 88 days). The primary objective of the study was to assess
musculoskeletal and neurological safety.
Patients were evaluated for
clinical success and bacteriological eradication of the baseline organism(s)
with no new infection or superinfection at 5 to 9 days post-therapy (Test of
Cure or TOC). The Per Protocol population had a causative organism(s) with
protocol specified colony count(s) at baseline, no protocol violation, and no
premature discontinuation or loss to follow-up (among other criteria).
The clinical success and
bacteriologic eradication rates in the Per Protocol population were similar
between ciprofloxacin and the comparator group as shown in Table 14.
Table 14: Clinical Success
and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy)
CIPRO
Comparator
Randomized Patients
337
352
Per Protocol Patients
211
231
Clinical Response at 5 to 9 Days PostTreatment
95.7% (202/211)
92.6% (214/231)
95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment1
84.4% (178/211)
78.3% (181/231)
95% CI [-1.3%, 13.1%]
Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days PostTreatment
Escherichia coli
156/178 (88%)
161/179 (90%)
1 Patients with baseline pathogen(s)
eradicated and no new infections or superinfections/total number of patients.
There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients
with superinfections or new infections.
Inhalational Anthrax In Adults And Pediatrics
Additional information
The mean serum concentrations of ciprofloxacin associated
with a statistically significant improvement in survival in the rhesus monkey
model of inhalational anthrax are reached or exceeded in adult and pediatric
patients receiving oral and intravenous regimens. Ciprofloxacin
pharmacokinetics have been evaluated in various human populations. The mean
peak serum concentration achieved at steady-state in human adults receiving 500
mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400 mg
intravenously every 12 hours. The mean trough serum concentration at
steady-state for both of these regimens is 0.2 mcg/mL. In a study of 10
pediatric patients between 6 and 16 years of age, the mean peak plasma
concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09
mcg/mL to 0.26 mcg/mL, following two 30-minute intravenous infusions of 10
mg/kg administered 12 hours apart. After the second intravenous infusion
patients switched to 15 mg/kg orally every 12 hours achieve a mean peak
concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data,
including effects on cartilage, following the administration of ciprofloxacin
to pediatric patients are limited. Ciprofloxacin serum concentrations achieved
in humans serve as a surrogate endpoint reasonably likely to predict clinical
benefit and provide the basis for this indication.11
A placebo-controlled animal study in rhesus monkeys
exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105) spores
(range 5-30 LD 50) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study
was 0.08 mcg/mL. In the animals studied, mean serum concentrations of
ciprofloxacin achieved at expected T max (1 hour post-dose) following oral
dosing to steady-state ranged from 0.98 mcg/mL to 1.69 mcg/mL. Mean
steady-state trough concentrations at 12 hours post-dose ranged from 0.12
mcg/mL to 0.19 mcg/mL.10 Mortality due to anthrax for animals that
received a 30-day regimen of oral ciprofloxacin beginning 24 hours
post-exposure was significantly lower (1/9), compared to the placebo group
(9/10) [p= 0.001]. The one ciprofloxacin-treated animal that died of anthrax
did so following the 30-day drug administration period.11
More than 9300 persons were recommended to complete a
minimum of 60 days of antibacterial prophylaxis against possible inhalational
exposure to B. anthracis during 2001. Ciprofloxacin was recommended to most of
those individuals for all or part of the prophylaxis regimen. Some persons were
also given anthrax vaccine or were switched to alternative antibacterial drugs.
No one who received ciprofloxacin or other therapies as prophylactic treatment
subsequently developed inhalational anthrax. The number of persons who received
ciprofloxacin as all or part of their post-exposure prophylaxis regimen is
unknown.
Plague
A placebo-controlled animal study in African green
monkeys exposed to an inhaled mean dose of 110 LD50 (range 92 to 127 LD50) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC)
of ciprofloxacin for the Y. pestis strain used in this study was 0.015 mcg/mL.
Mean peak serum concentrations of ciprofloxacin achieved at the end of a single
60 minute infusion were 3.49 mcg/mL ± 0.55 mcg/mL, 3.91 mcg/mL ± 0.58 mcg/mL
and 4.03 mcg/mL ± 1.22 mcg/mL on Day 2, Day 6 and Day 10 of treatment in
African green monkeys, respectively All trough concentrations (Day 2, Day 6 and
Day 10) were < 0.5 mcg/mL. Animals were randomized to receive either a
10-day regimen of intravenous ciprofloxacin 15 mg/kg, or placebo beginning when
animals were found to be febrile (a body temperature greater than 1.5oC
over baseline for two hours), or at 76 hours post-challenge, whichever occurred
sooner. Mortality in the ciprofloxacin group was significantly lower (1/10)
compared to the placebo group (2/2) [difference: -90.0%, 95% exact confidence
interval: -99.8% to -5.8%]. The one ciprofloxacin-treated animal that died did
not receive the proposed dose of ciprofloxacin due to a failure of the
administration catheter. Circulating ciprofloxacin concentration was below 0.5
mcg/mL at all timepoints tested in this animal. It became culture negative on
Day 2 of treatment, but had a resurgence of low grade bacteremia on Day 6 after
treatment initiation. Terminal blood culture in this animal was negative.12
REFERENCES
5. Clinical and Laboratory Standards Institute (CLSI),
Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically; Approved Standard–9th Edition. CLSI Document M7-A9
[2012]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite
2500, Wayne, PA, 19087-1898.
6. Clinical and Laboratory Standards Institute (CLSI). Performance
Standards for Antimicrobial Susceptibility Testing; 24th Informational
Supplement. CLSI Document M100 S24 [2014]. Clinical and Laboratory Standards
Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
7. Clinical and Laboratory Standards Institute (CLSI). Methods
for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently
Isolated or Fastidious Bacteria; Approved Guideline–2nd Edition.
CLSI Document M45-A2 [2010]. Clinical and Laboratory Standards Institute, 950
West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
8. Clinical and Laboratory Standards Institute (CLSI), Performance
Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard–11th
Edition. CLSI Document M2-A11[2012]. Clinical and Laboratory Standards
Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
9. CReport presented at the FDA's Anti-Infective Drug and
Dermatological Drug Product's Advisory Committee meeting, March 31, 1993,
Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants
Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
10. Kelly DJ, et al. Serum concentrations of penicillin,
doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J
Infect Dis 1992; 166:1184-7.
11. Friedlander AM, et al. Postexposure prophylaxis
against experimental inhalational anthrax. J Infect Dis 1993; 167:1239-42.
12. Anti-infective Drugs Advisory Committee Meeting,
April 3, 2012 -The efficacy of Ciprofloxacin for treatment of Pneumonic Plague.
Medication Guide
PATIENT INFORMATION
CIPRO®
(Sip-row)
(ciprofloxacin hydrochloride) Tablets for Oral Use
CIPRO®
(Sip-row)
(ciprofloxacin hydrochloride) for Oral Suspension
CIPRO®XR
(Sip-row)
(ciprofloxacin hydrochloride) Tablets for Oral Use
CIPRO®IV
(Sip-row)
(ciprofloxacin) Injection for Intravenous Infusion
Read this Medication Guide before you start taking CIPRO
and each time you get a refill. There may be new information. This information
does not take the place of talking to your healthcare provider about your
medical condition or your treatment.
What is the most important information I should know
about CIPRO?
CIPRO, a fluoroquinolone antibacterial medicine, can
cause serious side effects. Some of these serious side effects could result in
death.
If you get any of the following serious side effects
while you take CIPRO, get medical help right away. Talk with your healthcare
provider about whether you should continue to take CIPRO.
1. Tendon rupture or swelling of the tendon
(tendinitis).
Tendon problems can happen in people of all ages who
take CIPRO. Tendons are tough cords of tissue that connect muscles to
bones. Symptoms of tendon problems may include:
pain
swelling
tears and inflammation of tendons including the back of
the ankle (Achilles), shoulder, hand, or other tendon sites.
The risk of getting tendon problems while you take
CIPRO is higher if you:
Call your healthcare provider right away at the first
sign of tendon pain, swelling or inflammation. Stop taking CIPRO until
tendinitis or tendon rupture has been ruled out by your healthcare provider.
Avoid exercise and using the affected area.
The most common area of pain and swelling is the Achilles tendon at the back of
your ankle. This can also happen with other tendons. Talk to your healthcare
provider about the risk of tendon rupture with continued use of CIPRO. You may
need a different antibiotic that is not a fluoroquinolone to treat your
infection.
Tendon rupture can happen while you are taking or
after you have finished taking CIPRO. Tendon ruptures have happened up to
several months after people have finished taking their fluoroquinolone.
Get medical help right away if you get any of the
following signs or symptoms of a tendon rupture:
hear or feel a snap or pop in a tendon area
bruising right after an injury in a tendon area
unable to move the affected area or bear weight
2. Worsening of myasthenia gravis (a problem that
causes muscle weakness). Fluoroquinolones like CIPRO may cause worsening of
myasthenia gravis symptoms, including muscle weakness and breathing problems.
Call your healthcare provider right away if you have any worsening muscle
weakness or breathing problems.
See “What are the possible side effects of CIPRO?”
What is CIPRO?
CIPRO is a fluoroquinolone antibacterial medicine used in
adults age 18 years and older to treat certain infections caused by certain
germs called bacteria. These bacterial infections include:
Studies of CIPRO for use in the treatment of plague and
anthrax were done in animals only, because plague and anthrax could not be
studied in people.
CIPRO is also used in children younger than 18 years
of age to treat complicated urinary tract and kidney infections or who may
have breathed in anthrax germs, have plague or have been exposed to plague
germs.
Children younger than 18 years of age have a higher
chance of getting bone, joint, or tendon (musculoskeletal) problems such as
pain or swelling while taking CIPRO. CIPRO should not be used as the first
choice of antibacterial medicine in children under 18 years of age.
CIPRO XR is only used in adults 18 years of age
and older to treat urinary tract infections (complicated and uncomplicated),
including kidney infections (pyelonephritis).
It is not known if CIPRO XR is safe and effective in
children under 18 years of age.
Who should not take CIPRO?
Do not take CIPRO if you:
Have ever had a severe allergic reaction to an
antibacterial medicine known as a fluoroquinolone, or are allergic to
ciprofloxacin hydrochloride or any of the ingredients in CIPRO. See the end of
this Medication Guide for a complete list of ingredients in CIPRO.
Also take a medicine called tizanidine (Zanaflex®).
Ask your healthcare provider if you are not sure.
What should I tell my healthcare provider before
taking CIPRO?
Before you take CIPRO, tell your healthcare provider
if you:
have tendon problems
have a disease that causes muscle weakness (myasthenia
gravis)
have or anyone in your family has an irregular heartbeat,
especially a condition called “QT prolongation”
have or have had seizures
have kidney problems. You may need a lower dose of CIPRO
if your kidneys do not work well.
have joint problems including rheumatoid arthritis (RA)
have trouble swallowing pills
have any other medical conditions
are pregnant or plan to become pregnant. It is not known
if CIPRO will harm your unborn baby.
are breastfeeding or plan to breastfeed. CIPRO passes
into breast milk. You and your healthcare provider should decide whether you will
take CIPRO or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines
you take, including prescription and over-the-counter medicines, vitamins,
and herbal supplements.
CIPRO and other medicines can affect each other causing
side effects.
Especially tell your healthcare provider if you take:
a blood thinner (such as warfarin, Coumadin®,
Jantoven®)
methotrexate (Trexall®)
ropinirole (Requip®)
clozapine (Clozaril®, Fazaclo®ODT®)
a Non-Steroidal Anti-Inflammatory Drug (NSAID). Many
common medicines for pain relief are NSAIDs. Taking an NSAID while you take
CIPRO or other fluoroquinolones may increase your risk of central nervous
system effects and seizures.
certain medicines may keep CIPRO Tablets, CIPRO Oral
Suspension from working correctly. Take CIPRO Tablets and Oral Suspension
either 2 hours before or 6 hours after taking these medicines, vitamins, or
supplements:
an antacid, multivitamin, or other medicine or
supplements that has magnesium, calcium, aluminum, iron, or zinc
sucralfate (Carafate®)
didanosine (Videx®, Videx EC®)
Ask your healthcare provider for a list of these
medicines if you are not sure.
Know the medicines you take. Keep a list of them to show
your healthcare provider and pharmacist when you get a new medicine.
How should I take CIPRO?
Take CIPRO exactly as your healthcare provider tells you
to take it.
Your healthcare provider will tell you how much CIPRO to
take and when to take it.
Take CIPRO Tablets in the morning and evening at about
the same time each day. Swallow the tablet whole. Do not split, crush or chew
the tablet. Tell your healthcare provider if you cannot swallow the tablet
whole.
Take CIPRO Oral Suspension in the morning and evening at
about the same time each day. Shake the CIPRO Oral Suspension bottle well each
time before use for about 15 seconds to make sure the suspension is mixed well.
Close the bottle completely after use.
Take CIPRO XR one time each day at about the same time
each day. Swallow the tablet whole. Do not split, crush or chew the tablet.
Tell your healthcare provider if you cannot swallow the tablet whole.
CIPRO IV is given to you by intravenous (IV) infusion
into your vein, slowly, over 60 minutes, as prescribed by your healthcare
provider.
CIPRO can be taken with or without food.
CIPRO should not be taken with dairy products (like milk
or yogurt) or calcium-fortified juices alone, but may be taken with a meal that
contains these products.
Drink plenty of fluids while taking CIPRO.
Do not skip any doses of CIPRO, or stop taking it, even
if you begin to feel better, until you finish your prescribed treatment unless:
you have tendon problems. See “What is the most
important information I should know about CIPRO?”
you have a serious allergic reaction. See “What are
the possible side effects of CIPRO?”
your healthcare provider tells you to stop taking CIPRO
Taking all of your CIPRO doses will help make sure that all of the bacteria are
killed. Taking all of your CIPRO doses will help lower the chance that the bacteria
will become resistant to CIPRO. If you become resistant to CIPRO, CIPRO and
other antibacterial medicines may not work for you in the future.
If you take too much CIPRO, call your healthcare provider
or get medical help right away.
What should I avoid while taking CIPRO?
CIPRO can make you feel dizzy and lightheaded. Do not drive,
operate machinery, or do other activities that require mental alertness or
coordination until you know how CIPRO affects you.
Avoid sunlamps, tanning beds, and try to limit your time
in the sun. CIPRO can make your skin sensitive to the sun (photosensitivity)
and the light from sunlamps and tanning beds. You could get a severe sunburn,
blisters or swelling of your skin. If you get any of these symptoms while you
take CIPRO, call your healthcare provider right away. You should use a
sunscreen and wear a hat and clothes that cover your skin if you have to be in
sunlight.
What are the possible side effects of CIPRO?
CIPRO may cause serious side effects, including:
See, “What is the most important information I should
know about CIPRO?”
Serious allergic reactions. Serious allergic
reactions, including death, can happen in people taking fluoroquinolones,
including CIPRO, even after only 1 dose. Stop taking CIPRO and get emergency
medical help right away if you get any of the following symptoms of a severe
allergic reaction:
skin rash
Skin rash may happen in people taking CIPRO even after only 1 dose. Stop taking
CIPRO at the first sign of a skin rash and call your healthcare provider. Skin
rash may be a sign of a more serious reaction to CIPRO.
Liver damage (hepatotoxicity). Hepatotoxicity can
happen in people who take CIPRO. Call your healthcare provider right away if
you have unexplained symptoms such as:
nausea or vomiting
unusual tiredness
stomach pain
loss of appetite
fever
light colored bowel movements
weakness
dark colored urine
abdominal pain or tenderness
yellowing of your skin or the whites of your eyes
itching
Stop taking CIPRO and tell your healthcare provider right away if you have
yellowing of your skin or white part of your eyes, or if you have dark urine.
These can be signs of a serious reaction to CIPRO (a liver problem).
Central Nervous System (CNS) effects. Seizures
have been reported in people who take fluoroquinolone antibacterial medicines,
including CIPRO. Tell your healthcare provider if you have a history of
seizures. Ask your healthcare provider whether taking CIPRO will change your
risk of having a seizure.
CNS side effects may happen as soon as after taking the first dose of CIPRO.
Talk to your healthcare provider right away if you get any of these side
effects, or other changes in mood or behavior:
seizures
trouble sleeping
hear voices, see things, or sense things that are not
there (hallucinations)
nightmares
feel lightheaded or dizzy
feel more suspicious (paranoia)
feel restless
suicidal thoughts or acts
tremors
headaches that will not go away, with or without blurred
vision
feel anxious or nervous
confusion
depression
Intestine infection (Pseudomembranous colitis). Pseudomembranous
colitis can happen with many antibacterial medicines, including CIPRO. Call
your healthcare provider right away if you get watery diarrhea, diarrhea that
does not go away, or bloody stools. You may have stomach cramps and a fever.
Pseudomembranous colitis can happen 2 or more months after you have finished
your antibacterial medicine.
Changes in sensation and possible nerve damage
(Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet
can happen in people who take fluoroquinolones, including CIPRO. Talk with your
healthcare provider right away if you get any of the following symptoms of
peripheral neuropathy in your arms, hands, legs, or feet:
pain
burning
tingling
numbness
weakness
CIPRO may need to be stopped to prevent permanent nerve damage.
Serious heart rhythm changes (QT prolongation and
torsade de pointes). Tell your healthcare provider right away if you have a
change in your heart beat (a fast or irregular heartbeat), or if you faint.
CIPRO may cause a rare heart problem known as prolongation of the QT interval.
This condition can cause an abnormal heartbeat and can be very dangerous. The
chances of this event are higher in people:
who take certain medicines to control heart rhythm
(antiarrhythmics)
Joint Problems. Increased chance of problems with
joints and tissues around joints in children under 18 years old can happen.
Tell your child's healthcare provider if your child has any joint problems
during or after treatment with CIPRO.
Sensitivity to sunlight (photosensitivity). See
“What should I avoid while taking CIPRO?”
The most common side effects of CIPRO include:
nausea
diarrhea
changes in liver function tests
vomiting
rash
Tell your healthcare provider about any side effect that
bothers you, or that does not go away.
These are not all the possible side effects of CIPRO. For
more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1800-FDA-1088.
How should I store CIPRO?
CIPRO Tablets
Store at 20° to 25°C (68° to 77°F); excursions permitted
to 15° to 30°C (59° to 86°F).
CIPRO Oral Suspension
Store microcapsules and diluent below 25°C (77°F);
excursions are permitted from 15°C to 30°C (59°F to 86°F).
Do not freeze.
After your CIPRO treatment is finished, safely throw away
any unused oral suspension.
CIPRO XR
Store CIPRO XR between 59°F to 86°F (15°C to 30°C).
Keep CIPRO and all medicines out of the reach of
children.
General Information about the safe and effective use
of CIPRO.
Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide. Do not use CIPRO for a condition for
which it is not prescribed. Do not give CIPRO to other people, even if they
have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important
information about CIPRO. If you would like more information about CIPRO, talk
with your healthcare provider. You can ask your healthcare provider or
pharmacist for information about CIPRO that is written for healthcare
professionals.
