Ciprofloxacin Injection

Ciprofloxacin Injection, USP

For Intravenous Infusion

SAGENT™

Rx only

WARNING:

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

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

DESCRIPTION

Ciprofloxacin Injection, USP is a synthetic broad-spectrum antimicrobial agent for intravenous (IV) administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic 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. Ciprofloxacin Injection, USP solution is available as 0.2% ready-for-use infusion solution in 5% Dextrose Injection. The formula 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 latex-free and is fabricated from a specially formulated polyvinyl chloride. 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, Cyclohexanone and Chlorobenzene, up to 115 and 0.09 parts per million, respectively. 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 100 mL bag is 5 g and 10 g for the 200 mL flexible container.

CLINICAL PHARMACOLOGY

Absorption

Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin 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.

Steady-state Ciprofloxacin Serum Concentrations (mcg/mL) After 60-minute IV Infusions q12h.
Time after starting the infusion
Dose	30 min	1 hr	3 hr	6 hr	8 hr	12 hr
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 to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th IV dose on a q 12 h 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 IV dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.

a AUC 0-12h
b AUC 24h=AUC 0-12h × 2
c AUC 24h=AUC 0-8h × 3
Steady-state Pharmacokinetic Parameter Following Multiple Oral and IV Doses
Parameters	500 mg q12h, P.O.	400 mg q12h, IV	750 mg q12h, P.O.	400 mg q8h, IV
AUC (mcg·hr/mL)	13.7 a	12.7 a	31.6 b	32.9 c
Cmax (mcg/mL)	2.97	4.56	3.59	4.07

Distribution

After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in serum.

Metabolism

After IV administration, three metabolites of ciprofloxacin have been identified in human urine which together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum proteins is 20 to 40%. 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 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 IV 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 IV 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 (< 1%) is recovered from the bile as unchanged drug. Approximately 15% of an IV dose is recovered from the feces within 5 days after dosing.

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 and 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. However, the kinetics of ciprofloxacin in patients with acute hepatic insufficiency 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: 11.8-32.0 mcg*h/mL) and 16.5 mcg*h/mL (range: 11.0-23.8 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%.

Drug-Drug Interactions

Concomitant administration with tizanidine is contraindicated (See CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS: PRECAUTIONS, Drug Interactions.)

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 mutation 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 Ciprofloxacin Injection, USP (ciprofloxacin for intravenous infusion).

Gram-positive bacteria

Enterococcus faecalis

Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative bacteria

Citrobacter diversus Citrobacter freundii Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Moraxella catarrhalis

Morganella morganii Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas aeruginosa Serratia marcescens

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 of 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 Aeromonas hydrophila Campylobacter jejuni Edwardsiella tarda Enterobacter aerogenes Klebsiella oxytoca Legionella pneumophila Pasteurella multocida Salmonella enteritidis

Salmonella typhi Shigella boydii Shigella dysenteriae Shigella flexneri Shigella sonnei Vibrio cholerae Vibrio parahaemolyticus Vibrio vulnificus 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 the 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 compunds. 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.
aThe current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding zone diameter results suggestive of a “Non-Susceptible” category should be submitted to a reference laboratory for further testing.
	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 influenzaea	≤1			≥21
Haemophilus parainfluenzaea	≤1			≥21
Streptococcus pneumoniae	≤1	2	≥4	≥21	16-20	≤15
Streptococcus pyogenes	≤1	2	≥4	≥21	16-20	≤15

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.1,2 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

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 ATCC 29213	0.12–0.5	-
Staphylococcus aureus ATCC 25923	-	22–30

INDICATIONS AND USAGE

Ciprofloxacin Injection, USP is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below when the intravenous administration offers a route of administration advantageous to the patient. Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Adult Patients

Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia), Klebsiella pneumoniae subspecies 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.

Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies 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.

Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.

Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies 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 conjunction with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.

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

Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.

Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See CLINICAL STUDIES.)

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.4 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 Ciprofloxacin Injection, USP 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 Ciprofloxacin Injection, USP and other antibacterial drugs, Ciprofloxacin Injection, USP 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 Ciprofloxacin Injection, USP, 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. Ciprofloxacin Injection, USP 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 Ciprofloxacin Injection, USP, 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 CIPROFLOXACIN 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 and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.

Other Serious and Somtimes 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 Patients and ADVERSE REACTIONS).

Theophylline

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse events 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 (e.g., severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions and ADVERSE REACTIONS.)

Clostridium Difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CIPROFLOXACIN, 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.

Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS.)

In pre-clinical studies, oral administration of ciprofloxacin 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 ANIMAL PHARMACOLOGY.)

Prolongation of the QT Interval

Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin. Ciprofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval (See PRECAUTIONS, Drug Interactions and Geriatric Use).

Cytochrome P450 (CYP450)

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug. (See PRECAUTIONS, Drug Interactions.)

PRECAUTIONS

General

INTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW INFUSION OVER A PERIOD OF 60 MINUTES. Local IV site reactions have been reported with the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)

Central Nervous System

Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See Information for Patients, and Drug Interactions.)

Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.

Renal Impairment

Alteration of the dosage regimen is necessary for patients with impairment of renal function. (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 after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS, Post-Marketing Adverse Events).

As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Prescribing Ciprofloxacin Injection, USP 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.

Information For Patients

Patients should be advised:

• 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 Ciprofloxacin Injection, USP 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.


• That fluoroquinolones like Ciprofloxacin Injection, USP may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems.


• That antibacterial drugs including Ciprofloxacin Injection, USP should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When Ciprofloxacin Injection, USP is 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 Ciprofloxacin Injection, USP or other antibacterial drugs in the future.


• That ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction.


• That photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should 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, they should 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, patients should contact their physician.


• That ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.


• That ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use ciprofloxacin if they are already taking tizanidine.


• That ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking ciprofloxacin.


• That peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or