Cipro

Generic Name: Ciprofloxacin hydrochloride

Dosage Form: tablets, oral suspension
Cipro®

(Ciprofloxacin hydrochloride)

TABLETS

Cipro®

(Ciprofloxacin)

ORAL SUSPENSION

WARNING:

Fluoroquinolones, including Cipro®, 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).

Fluoroquinolones, including Cipro, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Cipro in patients with known history of myasthenia gravis (see WARNINGS).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cipro Tablets and Cipro Oral Suspension and other antibacterial drugs, Cipro Tablets and Cipro Oral Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Cipro Description

Cipro (Ciprofloxacin hydrochloride) Tablets and Cipro (Ciprofloxacin*) Oral Suspension are synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is C17H18FN3O3•HCl•H2O and its chemical structure is as follows:

Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:

Cipro film-coated tablets are available in 250 mg and 500 mg (Ciprofloxacin equivalent) strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients are cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate, hypromellose, titanium dioxide, and polyethylene glycol.

Ciprofloxacin Oral Suspension is available in 5% (5 g Ciprofloxacin in 100 mL) and 10% (10 g Ciprofloxacin in 100 mL) strengths. Ciprofloxacin Oral Suspension is a white to slightly yellowish suspension with strawberry flavor which may contain yellow-orange droplets. It is composed of Ciprofloxacin microcapsules and diluent which are mixed prior to dispensing (See Instructions for Use/Handling). The components of the suspension have the following compositions:

Microcapsules – Ciprofloxacin, povidone, methacrylic acid copolymer, hypromellose, magnesium stearate, and Polysorbate 20.

Diluent – medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor.

Five (5) mL of 5% suspension contains approximately 1.4 g of sucrose and 5 mL of 10% suspension contains approximately 1.3 g of sucrose.

CLINICAL PHARMACOLOGY

Absorption

Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range.

Dose (mg)	Maximum Serum Concentration (mcg/mL)	Area Under Curve (AUC) (mcg•hr/mL)
250	1.2	4.8
500	2.4	11.6
750	4.3	20.2
1000	5.4	30.8

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg.

A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg Ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed with a 400 mg IV dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg Ciprofloxacin given every 12 hours.

Steady-state Pharmacokinetic Parameters Following Multiple Oral and IV Doses

aAUC 0-12h
bAUC 24h=AUC0-12h x 2
cAUC 24h=AUC0-8h x 3
Parameters	500 mg	400 mg	750 mg	400 mg
AUC (mcg•hr/mL)	q12h, P.O. 13.7a	q12h, IV 12.7a	q12h, P.O. 31.6b	q8h, IV 32.9c
Cmax (mcg/mL)	2.97	4.56	3.59	4.07

Distribution

The binding of Ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs.

After oral 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

Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged Ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration 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 coadministered drug (see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).

Excretion

The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of Ciprofloxacin usually exceed 200 mcg/mL during the first two hours and are approximately 30 mcg/mL at 8 to 12 hours after dosing. The urinary excretion of Ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of Ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with Ciprofloxacin results in about a 50% reduction in the Ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of Ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

With oral administration, a 500 mg dose, given as 10 mL of the 5% Cipro Suspension (containing 250 mg Ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% Cipro Suspension (containing 250 mg Ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% Cipro Suspension (containing 500 mg Ciprofloxacin/5mL).

Drug-Drug Interactions

When Cipro Tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour whereas there is no delay observed when Cipro Suspension is given with food. The overall absorption of Cipro Tablet or Cipro Suspension, however, is not substantially affected. The pharmacokinetics of Ciprofloxacin given as the suspension are also not affected by food. Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of Ciprofloxacin by as much as 90%. (See PRECAUTIONS.)

The serum concentrations of Ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.

Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS.) Concomitant administration of Ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of paraxanthine after caffeine administration. (See WARNINGS: PRECAUTIONS.)

Special Populations

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 (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, 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 PRECAUTIONS: Geriatric Use.)

Renal Impairment

In patients with reduced renal function, the half-life of Ciprofloxacin is slightly prolonged. Dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.)

Hepatic Impairment

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, however, have not been fully elucidated.

Pediatrics

Following a single oral dose of 10 mg/kg Ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean Cmax was 2.4 mcg/mL (range: 1.5 – 3.4 mcg/mL) and the mean AUC was 9.2 mcg*h/mL (range: 5.8 – 14.9 mcg*h/mL). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given intravenous Ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 mcg/mL (range: 4.6 – 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 – 11.8 mcg/mL) in 10 children between 1 and 5 years of age. The AUC values were 17.4 mcg*h/mL (range: 11.8 – 32 mcg*h/mL) and 16.5 mcg*h/mL (range: 11 – 23.8 mcg*h/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 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.

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 as described in the INDICATIONS AND USAGE section of the package insert for Cipro (Ciprofloxacin hydrochloride) Tablets and Cipro (Ciprofloxacin*) 5% and 10% Oral Suspension.

Gram-positive bacteria

Enterococcus faecalis

Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative bacteria

Campylobacter jejuni	Proteus mirabilis
Citrobacter diversus	Proteus vulgaris
Citrobacter freundii	Providencia rettgeri
Enterobacter cloacae	Providencia stuartii
Escherichia coli	Pseudomonas aeruginosa
Haemophilus influenzae	Salmonella typhi
Haemophilus parainfluenzae	Serratia marcescens
Klebsiella pneumoniae	Shigella boydii
Moraxella catarrhalis	Shigella dysenteriae
Morganella morganii	Shigella flexneri
Neisseria gonorrhoeae	Shigella sonnei

 Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker (see INDICATIONS AND USAGE and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION).

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

Staphylococcus hominis

Gram-negative bacteria

Acinetobacter lwoffi	Pasteurella multocida
Aeromonas hydrophila	Salmonella enteritidis
Edwardsiella tarda	Vibrio cholerae
Enterobacter aerogenes	Vibrio parahaemolyticus
Klebsiella oxytoca	Vibrio vulnificus
Legionella pneumophila	Yersinia enterocolitica

Susceptibility Test Methods

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).1 The MIC values should be interpreted according to criteria provided in Table 1.


• 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.2 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 1.

Table 1: Susceptibility Test Interpretive Criteria for Ciprofloxacin

S=Susceptible, I=Intermediate, and R=Resistant.
* The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing. † This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined growth supplement.
	MIC (mcg/mL)			Zone Diameter (mm)
Species	S	I	R	S	I	R
Enterobacteriaceae	≤1	2	≥4	≥21	16-20	≤15
Enterococcus faecalis	≤1	2	≥4	≥21	16–20	≤15
Staphylococcus species	≤1	2	≥4	≥21	16–20	≤15
Pseudomonas aeruginosa	≤1	2	≥4	≥21	16–20	≤15
Haemophilus influenzae*	≤1			≥21
Haemophilus parainfluenzae*	≤1			≥21
Streptococcus pneumoniae	≤1	2	≥4	≥21	16–20	≤15
Streptococcus pyogenes	≤1	2	≥4	≥21	16–20	≤15
Neisseria gonorrhoeae†	≤0.06	0.12–0.5	≥1	≥41	28–40	≤27

 

 

 A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

• Quality Control: Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard Ciprofloxacin powder should provide the MIC values according to criteria outlined in Table 2. For diffusion technique, the 5-mcg Ciprofloxacin disk should provide the zone diameters outlined in Table 2.

Table 2: Quality Control for Susceptibility Testing of Ciprofloxacin

* N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1% defined growth supplement in a 5% CO2 environment at 35–37°C for 20–24 hours.3 † C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller Hinton broth with 2.5–5% lysed horse blood in a microaerophilic environment at 36–37°C for 48 hours and for 42°C for 24 hours,2 respectively.
Strains	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 ATCC29213	0.12–0.5	-
Staphylococcus aureus ATCC25923	-	22–30
Neisseria gonorrhoeae ATCC 49226 *	0.001–0.008	48–58
C. jejuni ATCC 33560†	0.06–0.25 and 0.03–0.12	-

 

 

INDICATIONS AND USAGE

Cipro is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Adult Patients

Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.

Acute Uncomplicated Cystitis in Females caused by Escherichia coli or Staphylococcus saprophyticus.

Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.

Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae.* Also, Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.

*Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.

Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis.

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, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.

Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.

Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.

Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni, Shigella boydii †, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial therapy is indicated.

†Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients.

Typhoid Fever (Enteric Fever) caused by Salmonella typhi.

NOTE: The efficacy of Ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated.

Uncomplicated Cervical and Urethral Gonorrhea due to Neisseria gonorrhoeae.

Pediatric Patients (1 to 17 years of age)

Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.

NOTE: 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. (See WARNINGS, PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL PHARMACOLOGY.)

Adult and Pediatric Patients

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.5 Supportive clinical information for Ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION).

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 may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some strains 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cipro Tablets and Cipro Oral Suspension and other antibacterial drugs, Cipro Tablets and Cipro Oral Suspension 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.

CONTRAINDICATIONS

Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to Ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components (see DESCRIPTION).

Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug Interactions.)

WARNINGS  

Tendinopathy and Tendon Rupture

 Fluoroquinolones, including Cipro, are associated with an increased risk of tendinitis and tendon rupture 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. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Cipro should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including Cipro, 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. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Post-Marketing Adverse Event Reports.)

Pregnant Women

THE SAFETY AND EFFECTIVENESS OF CiproFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

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 rarely in patients receiving therapy with quinolones, including Ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome);


• Vasculitis; arthralgia; myalgia; serum sickness;


• Allergic pneumonitis;


• Interstitial nephritis; acute renal insufficiency or failure;


• Hepatitis; jaundice; acute hepatic necrosis or failure;


• Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information for Patientsand ADVERSE REACTIONS).

Theophylline

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVINGCONCURRENT ADMINISTRATION OF CiproFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by Ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Central Nervous System Effects

Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones, including Ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving Ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all fluoroquinolones, Ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, epilepsy), 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). (See PRECAUTIONS: General, Information for Patients, Drug Interactionsand ADVERSE REACTIONS.)

Clostridium Difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cipro, 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 strains 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Peripheral Neuropathy

Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including Ciprofloxacin. Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.