Ciprofloxacin Extended Release Tablets

Dosage Form: tablet, film coated, extended release

WARNING

Fluoroquinolones, including ciprofloxacin extended-release, 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 extended-release, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid ciprofloxacin extended-release in patients with known history of myasthenia gravis. (See WARNINGS.)

 

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

Ciprofloxacin Extended Release Tablets Description

Ciprofloxacin1 extended-release tablets contain ciprofloxacin, a synthetic broad-spectrum antimicrobial agent for oral administration. Ciprofloxacin extended-release tablets are coated, bilayer tablets consisting of an immediate-release layer and an erosion-matrix type controlled release layer. The tablets contain a combination of two types of ciprofloxacin drug substance, ciprofloxacin hydrochloride, USP and ciprofloxacin, USP. Ciprofloxacin hydrochloride is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride. It is provided as the monohydrate. The molecular formula is C17H18FN3O3•HCl•H2O and its molecular weight is 385.8. The drug substance is faintly yellowish to light yellow crystals. The chemical structure is as follows:

Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. As the anhydrous form, its molecular formula is C17H18FN3O3 and its molecular weight is 331.3. It is a white to pale yellow crystalline powder and its chemical structure is as follows:

Ciprofloxacin extended-release tablets are available in 500 mg or 1000 mg (ciprofloxacin equivalent) tablet strengths. Ciprofloxacin extended-release tablets are orange film-coated, modified capsule shaped tablets. Each ciprofloxacin extended-release 500 mg tablet contains 500 mg of ciprofloxacin as ciprofloxacin hydrochloride, USP (287.5 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin, USP (212.6 mg, calculated on the dried basis). Each ciprofloxacin extended-release 1000 mg tablet contains 1000 mg of ciprofloxacin as ciprofloxacin hydrochloride, USP (574.9 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin, USP (425.2 mg, calculated on the dried basis). The inactive ingredients are carnauba wax, colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate (anhydrous), FD&C Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, pregelatinized starch, sodium lauryl sulfate, stearic acid, succinic acid, talc, and titanium dioxide.

1

as ciprofloxacin and ciprofloxacin hydrochloride

Ciprofloxacin Extended Release Tablets - Clinical Pharmacology

Absorption

Ciprofloxacin extended-release tablets are formulated to release drug at a slower rate compared to immediate-release tablets. Approximately 35% of the dose is contained within an immediate-release component, while the remaining 65% is contained in a slow-release matrix.

Maximum plasma ciprofloxacin concentrations are attained between 1 and 4 hours after dosing with ciprofloxacin extended-release. In comparison to the 250 mg and 500 mg ciprofloxacin immediate-release BID treatment, the Cmax of ciprofloxacin extended-release 500 mg and 1000 mg once daily are higher than the corresponding BID doses, while the AUCs over 24 hours are equivalent.

The following table compares the pharmacokinetic parameters obtained at steady-state for these four treatment regimens (500 mg QD ciprofloxacin extended-release vs. 250 mg BID ciprofloxacin immediate-release tablets and 1000 mg QD ciprofloxacin extended-release vs. 500 mg BID ciprofloxacin immediate-release).

Ciprofloxacin Pharmacokinetics (Mean ±SD) Following Ciprofloxacin Immediate-Release and Ciprofloxacin Extended-Release Administration

* median (range)
	Cmax (mg/L)	AUC0-24h (mg·h/L)	T½ (hr)	Tmax (hr)*
Ciprofloxacin Extended-Release 500 mg QD	1.59 ± 0.43	7.97 ± 1.87	6.6 ± 1.4	1.5 (1 to 2.5)
Ciprofloxacin Immediate-Release 250 mg BID	1.14 ± 0.23	8.25 ± 2.15	4.8 ± 0.6	1 (0.5 to 2.5)
Ciprofloxacin Extended-Release 1000 mg QD	3.11 ± 1.08	16.83 ± 5.65	6.31 ± 0.72	2 (1 to 4)
Ciprofloxacin Immediate-Release 500 mg BID	2.06 ± 0.41	17.04 ± 4.79	5.66 ± 0.89	2 (0.5 to 3.5)

Results of the pharmacokinetic studies demonstrate that ciprofloxacin extended-release may be administered with or without food (e.g. high-fat and low-fat meals or under fasted conditions).

Distribution

The volume of distribution calculated for intravenous ciprofloxacin is approximately 2.1 to 2.7 L/kg. Studies with the oral and intravenous forms of ciprofloxacin have demonstrated penetration of ciprofloxacin into a variety of tissues. 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. Following administration of a single dose of ciprofloxacin extended-release, ciprofloxacin concentrations in urine collected up to 4 hours after dosing averaged over 300 mg/L for both the 500 mg and 1000 mg tablets; in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for the 500 mg tablet, and 58 mg/L for the 1000 mg tablet.

Metabolism

Four metabolites of ciprofloxacin were identified in human urine. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The primary metabolites are oxociprofloxacin (M3) and sulfociprofloxacin (M2), each accounting for roughly 3% to 8% of the total dose. Other minor metabolites are desethylene ciprofloxacin (M1), and formylciprofloxacin (M4). The relative proportion of drug and metabolite in serum corresponds to the composition found in urine. Excretion of these metabolites was essentially complete by 24 hours after dosing. 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).

Elimination

The elimination kinetics of ciprofloxacin are similar for the immediate-release and the ciprofloxacin extended-release tablet. In studies comparing the ciprofloxacin extended-release and immediate-release ciprofloxacin, approximately 35% of an orally administered dose was excreted in the urine as unchanged drug for both formulations. 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. Coadministration of probenecid with immediate-release 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 with the immediate-release tablet, 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 of immediate-release ciprofloxacin is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

Special Populations

Pharmacokinetic studies of the immediate-release oral tablet (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. Cmax is increased 16% to 40%, and mean AUC is increased approximately 30%, which 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. No dose adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg ciprofloxacin extended-release. For complicated urinary tract infection and acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of ciprofloxacin extended-release should be reduced to ciprofloxacin extended-release 500 mg q24h in patients with creatinine clearance equal to or below 30 mL/min. (See DOSAGE AND ADMINISTRATION.)

Hepatic Impairment

In studies in patients with stable chronic 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. (See DOSAGE AND ADMINISTRATION.)

Drug-Drug Interactions

Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS.) Previous studies with immediate-release ciprofloxacin have shown that 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. Absorption of ciprofloxacin is significantly reduced by concomitant administration of multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, or products containing calcium, iron, or zinc. (See WARNINGS, PRECAUTIONS: Drug Interactions and Information for Patients, and DOSAGE AND ADMINISTRATION.)

Antacids

When ciprofloxacin extended-release given as a single 1000 mg dose was administered 2 hours before, or 4 hours after a magnesium/aluminum-containing antacid (900 mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 18 healthy volunteers, there was a 4% and 19% reduction, respectively, in the mean Cmax of ciprofloxacin. The reduction in the mean AUC was 24% and 26%, respectively. Ciprofloxacin extended-release should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc. Although ciprofloxacin extended-release may be taken with meals that include milk, concomitant administration with dairy products or with calcium-fortified juices alone should be avoided, since decreased absorption is possible. (See PRECAUTIONS: Information for Patients and Drug Interactions, and DOSAGE AND ADMINISTRATION.)

Omeprazole

When ciprofloxacin extended-release was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for 3 days) to 18 healthy volunteers, the mean AUC and Cmax of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined. (See 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 other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; 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 1 × 10-6.

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 extended-release tablets.

Gram-positive bacteria  

Enterococcus faecalis

Staphylococcus saprophyticus

Gram-negative bacteria

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

The following in vitro data are available, but their clinical significance is unknown. At least 90% 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-negative bacteria

Citrobacter koseri

Citrobacter freundii

Edwardsiella tarda

Enterobacter aerogenes

Enterobacter cloacae

Klebsiella oxytoca

Morganella morganii 

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Serratia marcescens

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 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.
Species	MIC (mcg/mL)			Zone Diameter (mm)
	S	I	R	S	I	R
Enterobacteriaceae	≤ 1	2	≥ 4	≥ 21	16 to 20	≤ 15
Enterococcus faecalis	≤ 1	2	≥ 4	≥ 21	16 to 20	≤ 15
Pseudomonas aeruginosa	≤ 1	2	≥ 4	≥ 21	16 to 20	≤ 15
Staphylococcus saprophyticus	≤ 1	2	≥ 4	≥ 21	16 to 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 to 2	-
Escherichia coli ATCC 25922	0.004 to 0.015	30 to 40
Pseudomonas aeruginosa ATCC 27853	0.25 to 1	25 to 33
Staphylococcus aureus ATCC 29213	0.12 to 0.5	-
Staphylococcus aureus ATCC 25923	-	22 to 30

 

Indications and Usage for Ciprofloxacin Extended Release Tablets

Ciprofloxacin extended-release tablets are indicated only for the treatment of urinary tract infections, including acute uncomplicated pyelonephritis, caused by susceptible strains of the designated microorganisms as listed below. Ciprofloxacin extended-release tablets and ciprofloxacin immediate-release tablets are not interchangeable. Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Uncomplicated Urinary Tract Infections (Acute Cystitis): Caused by Escherichia coli, Proteus mirabilis, Enterococcus faecalis, or Staphylococcus saprophyticus2.

Complicated Urinary Tract Infections: Caused by Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa2.

Acute Uncomplicated Pyelonephritis: Caused by Escherichia coli.

THE SAFETY AND EFFICACY OF CIPROFLOXACIN EXTENDED-RELEASE TABLETS IN TREATING INFECTIONS OTHER THAN URINARY TRACT INFECTIONS HAS NOT BEEN DEMONSTRATED. 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 extended-release tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. 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 extended-release tablets and other antibacterial drugs, ciprofloxacin extended-release tablets 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.

2

Treatment of infections due to this organism in the organ system was studied in fewer than 10 patients.

Contraindications

Ciprofloxacin extended-release tablets are 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.

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

Warnings

Tendinopathy and Tendon Rupture

Fluoroquinolones, including ciprofloxacin extended-release, 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 extended-release 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 extended-release, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid ciprofloxacin extended-release 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 EXTENDED-RELEASE 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 fluids, intravenous steroids, and airway management, 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 (e.g., 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 INTRAVENOUS 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 (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 2 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.)

The 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 Torsades de pointes have been spontaneously reported during post-marketing 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 (e.g. 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

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.

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

Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., 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.)

Prescribing ciprofloxacin extended-release 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 extended-release 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 extended-release 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 extended-release should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ciprofloxacin extended-release 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 extended-release or other antibacterial drugs in the future. 


• that ciprofloxacin extended-release may be taken with or without meals and to drink fluids liberally. As with other quinolones, concurrent administration with magnesium/aluminum antacids, polymeric phosphate binders (e.g., sevelamer, lanthanum carbonate) or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron, or zinc should be avoided. Ciprofloxacin extended-release may be taken 2 hours before or 6 hours after taking these products. (See CLINICAL PHARMACOLOGY: Drug-Drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS: Drug Interactions.) Ciprofloxacin extended-release should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin extended-release may be taken with a meal that contains these products. (See CLINICAL PHARMACOLOGY: Drug-Drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS: Drug Interactions.) 


• if the patient should forget to take ciprofloxacin extended-release at the usual time, he/she may take the dose later in the day. Do not take more than one ciprofloxacin extended-release tablet per day even if a patient misses a dose. Swallow the ciprofloxacin extended-release tablet whole. DO NOT SPLIT, CRUSH, OR CHEW THE TABLET. 


• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue ciprofloxacin extended-release 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 peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should discontinue treatment and contact their physicians. 


• that ciprofloxacin extended-release may cause dizziness and light-headedness; 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 extended-release may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones. 


• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking ciprofloxacin extended-release if there is a history of this condition. 


• that 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 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Tizanidine

In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single- dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated. (See CONTRAINDICATIONS.)

Theophylline

As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Other Xanthine Derivatives

Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life. On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline) containing products, elevated serum concentrations of these xanthine derivatives were reported.

Chelation Complex Formation

Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially interfere w