CIPROFLOXACIN- ciprofolxacin_tablet

Click here to enter Clinical Pharmacology Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12. 4 Absorption The absolute bioavailability of Ciprofloxacin when given as an oral tablet is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations (C max Table 9: Ciprofloxacin C max Dose (mg) C max (mcg/mL) AUC (mcghr/mL) 250 1. 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. 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 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 C max Table 10: Steady-state Pharmacokinetic Parameters Following Multiple Oral and Intravenous Doses (Adults) Parameters 500 mg 400 mg 750 mg 400 mg every 12 hours, orally every 12 hours, intravenously every 12 hours, orally every 8 hours, intravenously AUC 0-24h,ss 27. 9 ** C max,ss 2. 07 *: AUC 0en dash12h **: AUC 0en dash8h Food When ciprofloxacin tablets are 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. The overall absorption of ciprofloxacin tablets, however, is not substantially affected. Avoid concomitant administration of ciprofloxacin with dairy products (like milk or yogurt) or calcium-fortified juices alone since decreased absorption is possible; however, ciprofloxacin may be taken with a meal that contains these products. 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. Co-administration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug [see Contraindications ( 4. 16 7 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. Specific Populations Elderly Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older than 65 years) as compared to young adults. Although the C max [see Use in Specific Populations ( 8. 5 Renal Impairment In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required [see Use in Specific Populations ( 8. 3 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, have not been fully studied. Drug-Drug Interactions Antacids Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90% [see Dosage and Administration ( 2. 4 7 Histamine H2-receptor antagonists Histamine H 2 Metronidazole The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly. Tizanidine In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C max [see Contraindications ( 4. 2 Ropinirole In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once daily with 500 mg ciprofloxacin twice-daily, the mean C max [see Warnings and Precautions ( 5. 10 Clozapine Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. Sildenafil Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg ciprofloxacin to healthy subjects, the mean C max Duloxetine In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2. 5-fold increase in mean C max Lidocaine In a study conducted in 9 healthy volunteers, concomitant use of 1. 5 mg/kg IV lidocaine with ciprofloxacin 500 mg twice daily resulted in an increase of lidocaine C max Metoclopramide Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin. Omeprazole When ciprofloxacin was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and C max 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 -9 -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 [see Indications and Usage ( 1 Gram-positive bacteria Bacillus anthracis Enterococcus faecalis Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Gram-negative bacteria Campylobacter jejuni Citrobacter koseri Citrobacter freundii Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas aeruginosa Salmonella typhi Serratia marcescens Shigella boydii Shigella dysenteriae Shigella flexneri Shigella sonnei Yersinia pestis The following in vitro but their clinical significance is unknown Gram-positive bacteria Staphylococcus haemolyticus Staphylococcus hominis Gram-negative bacteria Acinetobacter lwoffi Aeromonas hydrophila Edwardsiella tarda Enterobacter aerogenes Klebsiella oxytoca Legionella pneumophila Pasteurella multocida Salmonella enteritidis Vibrio cholerae Vibrio parahaemolyticus Vibrio vulnificus Yersinia enterocolitica Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.

Click here to enter Indications Ciprofloxacin is a fluoroquinolone antibacterial indicated in adults (18 years of age and older) with the following infections caused by designated, susceptible bacteria and in pediatric patients where indicated: Skin and Skin Structure Infections ( 1. 1 Bone and Joint Infections ( 1. 2 Complicated Intra-Abdominal Infections ( 1. 3 Infectious Diarrhea ( 1. 4 Typhoid Fever (Enteric Fever) ( 1. 5 Uncomplicated Cervical and Urethral Gonorrhea ( 1. 6 Inhalational Anthrax post-exposure in adult and pediatric patients ( 1. 7 Plague in adult and pediatric patients ( 1. 8 Chronic Bacterial Prostatitis ( 1. 9 Lower Respiratory Tract Infections ( 1. 10 Acute Exacerbation of Chronic Bronchitis Urinary Tract Infections ( 1. 11 Urinary Tract Infections (UTI) Acute Uncomplicated Cystitis Complicated UTI and Pyelonephritis in Pediatric Patients Acute Sinusitis ( 1. 12 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin and other antibacterial drugs, ciprofloxacin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 13 Ciprofloxacin tablets are indicated in adult patients for treatment of skin and skin structure infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes. Ciprofloxacin tablets are indicated in adult patients for treatment of bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa. Ciprofloxacin tablets are indicated in adult patients for treatment of complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Bacteroides fragilis Ciprofloxacin tablets are indicated in adult patients for treatment of infectious diarrhea caused by Escherichia coli Campylobacter jejuni, Shigella boydii dagger , Shigella dysenteriae, Shigella flexneri Shigella sonnei dagger dagger Ciprofloxacin tablets are indicated in adult patients for treatment of typhoid fever (enteric fever) Salmonella typhi. Ciprofloxacin tablets are indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae [see Warnings and Precautions ( 5. 17 Ciprofloxacin tablets are indicated in adults and pediatric patients from birth to 17 years of age for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication. 1 [see Clinical Studies ( 14. 2 Ciprofloxacin tablets are indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) [see Clinical Studies ( 14. 3 Ciprofloxacin tablets are indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli Proteus mirabilis. Ciprofloxacin tablets are indicated in adult patients for treatment of lower respiratory tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. Ciprofloxacin tablets are not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. Ciprofloxacin tablets are indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by Moraxella catarrhalis. Because fluoroquinolones, including ciprofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5. 16 Urinary Tract Infections in Adults Ciprofloxacin tablets are indicated in adult patients for treatment of urinary tract infections caused by Escherichia coli Klebsiella pneumoniae Enterobacter cloacae Serratia marcescens Proteus mirabilis Providencia rettgeri Morganella morganii Citrobacter koseri Citrobacter freundii Pseudomonas aeruginosa Staphylococcus epidermidis Staphylococcus saprophyticus Enterococcus faecalis Acute Uncomplicated Cystitis Ciprofloxacin tablets are indicated in adult female patients for treatment of acute uncomplicated cystitis caused by Escherichia coli Staphylococcus saprophyticus. 16 Complicated Urinary Tract Infection and Pyelonephritis in Pediatric Patients Ciprofloxacin tablets are indicated in pediatric patients aged one to 17 years of age for treatment of complicated urinary tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Use in Specific Populations ( 8. 4 Although effective in clinical trials, ciprofloxacin tablets are not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues. [see Warnings and Precautions ( 5. 2 Ciprofloxacin tablets are indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis. To reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin tablets and other antibacterial drugs, ciprofloxacin 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. 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 tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some isolates of Pseudomonas aeruginosa.

Ciprofloxacin tablets should be administered orally as described in the appropriate Dosage Guidelines tables. Adult Dosage Guidelines Infection Dose Frequency Duration Skin and Skin Structure 500 -750 mg every 12 hours 7 to 14 days Bone and Joint 500-750 mg every 12 hours 4 to 8 weeks Complicated Intra-Abdominal 500 mg every 12 hours 7 to 14 days Infectious Diarrhea 500 mg every 12 hours 5 to 7 days Typhoid Fever 500 mg every 12 hours 10 days Uncomplicated Gonorrhea 250 mg single dose single dose Inhalational anthrax (post-exposure) 500 mg every 12 hours 60 days Plague 500en dash750 mg every 12 hours 14 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract 500 -750 mg every 12 hours 7 to 14 days Urinary Tract 250-500 mg every 12 hours 7 to 14 days Acute Uncomplicated Cystitis 250 mg every 12 hours 3 days Acute Sinusitis 500 mg every 12 hours 10 days Adults with creatinine clearance 30en dash50 mL/min 250en dash500 mg q 12 h ( 2. 3 Adults with creatinine clearance 5en dash29 mL/min 250en dash500 mg q 18 h ( 2. 3 Patients on hemodialysis or peritoneal dialysis 250en dash500 mg q 24 h (after dialysis) ( 2. 3 Pediatric Oral Dosage Guidelines Infection Dose Frequency Duration Complicated UTI and Pyelonephritis (1 to 17 years of age) 10en dash20 mg/kg (maximum 750 mg per dose) Every 12 hours 10en dash21 days Inhalational Anthrax (Post-Exposure) 15 mg/kg (maximum 500 mg per dose) Every 12 hours 60 days Plague 15mg/kg (maximum 500 mg per dose) Every 8 to 12 hours 14days The determination of dosage and duration for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s host-defense mechanisms, and the status of renal and hepatic function. Ciprofloxacin Tablets may be administered to adult patients when clinically indicted at the discretions of the physician. Table 1: Adult Dosage Guidelines Infection Dose Frequency Usual Durations 1 Skin and Skin Structure 500 -750 mg every 12 hours 7 to 14 days Bone and Joint 500-750 mg every 12 hours 4 to 8 weeks Complicated Intra-Abdominal 2 500 mg every 12 hours 7 to 14 days Infectious Diarrhea 500 mg every 12 hours 5 to 7 days Typhoid Fever 500 mg every 12 hours 10 days Uncomplicated Urethral and Cervical Gonococcal Infections 250 mg single dose single dose Inhalational anthrax (post-exposure) 3 500 mg every 12 hours 60 days Plague 3 500en dash750 mg every 12 hours 14 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract Infections 500 -750 mg every 12 hours 7 to 14 days Urinary Tract Infections 250-500 mg every 12 hours 7 to 14 days Acute Uncomplicated Cystitis 250 mg every 12 hours 3 days Acute Sinusitis 500 mg every 12 hours 10 days 1 2 3 Conversion of IV to Oral Dosing in Adults Patients whose therapy is started with Ciprofloxacin IV may be switched to ciprofloxacin tablets when clinically indicated at the discretion of the physician (Table 2) [see Clinical Pharmacology ( 12. 3 Table 2: Equivalent AUC Dosing Regimens Ciprofloxacin Oral Dosage Equivalent Ciprofloxacin IV Dosage 250 mg Tablet every 12 hours 200 mg intravenous every 12 hours 500 mg Tablet every 12 hours 400 mg intravenous every 12 hours 750 mg Tablet every 12 hours 400 mg intravenous every 8 hours Dosing and initial route of therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined by the severity of the infection. Ciprofloxacin tablets should be administered as described in Table 3. Table 3: Pediatric Dosage Guidelines Infection Dose Frequency Total Duration Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age) 10 mg/kg to 20 mg/kg (maximum 750 mg per dose; not to be exceeded even in patients weighing more than 51 kg) Every 12 hours 10en dash21 days 1 Inhalational Anthrax (Post-Exposure) 2 15 mg/kg (maximum 500 mg per dose) Every 12 hours 60 days Plague 2,3 15 mg/kg (maximum 500 mg per dose) Every 8 to 12 hours 14 days 1. Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. Dosage guidelines for use in patients with renal impairment are shown in Table 4. Table 4: Recommended Starting and Maintenance Doses for Adult Patients with Impaired Renal Function Creatinine Clearance (mL/min) Dose > 50 See Usual Dosage. 30en dash50 250en dash500 mg every 12 hours 5en dash29 250en dash500 mg every 18 hours Patients on hemodialysis or Peritoneal dialysis 250en dash500 mg every 24 hours (after dialysis) When only the serum creatinine concentration is known, the following formulas may be used to estimate creatinine clearance: Men = Weight (kg) x (140en dashage) 72 x serum creatinine (mg/dL) Women The serum creatinine should represent a steady state of renal function. In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored. Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of cUTI and pyelonephritis. No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 mL/min/1. 73m 2 With Multivalent Cations Administer ciprofloxacin tablets at least 2 hours before or 6 hours after magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate; Videxregistered (didanosine) chewable/buffered tablets or pediatric powder for oral solution; other highly buffered drugs; or other products containing calcium, iron or zinc. With Dairy Products Concomitant administration of ciprofloxacin tablets with dairy products (like milk or yogurt) or calcium-fortified juices alone should be avoided since decreased absorption is possible; however, ciprofloxacin tablets Hydration of Patients Receiving Ciprofloxacin Tablets Assure adequate hydration of patients receiving ciprofloxacin tablets to prevent the formation of highly concentrated urine. Crystalluria has been reported with quinolones. Instruct the patient of the appropriate ciprofloxacin tablets administration [see Patient Counseling Information ( 17 Missed Doses If a dose is missed, it should be taken anytime but not later than 6 hours prior to the next scheduled dose. If less than 6 hours remain before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS,TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS
Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5. 1 Tendinitis and tendon rupture [see Warnings and Precautions ( 5. 2 Peripheral neuropathy [see Warnings and Precautions ( 5. 3 Central nervous system effects [see Warnings and Precautions ( 5. 4 Discontinue ciprofloxacin immediately and avoid the use of fluoroquinolones, including ciprofloxacin, in patients who experience any of these serious adverse reactions [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 5 Because fluoroquinolones, including ciprofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5. 16 Acute exacerbation of chronic bronchitis [see Indications and Usage ( 1. 10 Acute uncomplicated cystitis [see Indications and Usage ( 1. 11 Acute sinusitis [see Indications and Usage ( 1. 12 WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning. Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together ( 5. 1 Tendinitis and tendon rupture ( 5. 2 Peripheral neuropathy ( 5. 3 Central nervous system effects ( 5. 4 Discontinue ciprofloxacin immediately and avoid the use of fluoroquinolones, including ciprofloxacin, in patients who experience any of these serious adverse reactions ( 5. 1 Fluoroquinolones, including ciprofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis. 5 Because fluoroquinolones, including ciprofloxacin, have been associated with serious adverse reactions ( 5. 16 Acute exacerbation of chronic bronchitis ( 1. 10 Acute uncomplicated cystitis ( 1. 11 Acute sinusitis ( 1.
ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions ( 5. 1 Tendinitis and Tendon Rupture [see Warnings and Precautions ( 5. 2 Peripheral Neuropathy [see Warnings and Precautions ( 5. 3 Central Nervous System Effects [see Warnings and Precautions ( 5. 4 [see Warnings and Precautions ( 5. 5 Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions ( 5. 6 Hypersensitivity Reactions [see Warnings and Precautions ( 5. 7 Hepatotoxicity [see Warnings and Precautions ( 5. 8 Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions ( 5. 9 Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions ( 5. 10 Clostridioides difficile [see Warnings and Precautions ( 5. 11 Prolongation of the QT Interval [see Warnings and Precautions ( 5. 12 Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5. 13 Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5. 14 Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5. 15 The most common adverse reactions >=1% were nausea, diarrhea, liver function tests abnormal, vomiting, and rash. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact [Solco Healthcare US, LLC at 1-866-257-2597] or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients During clinical investigations with oral and parenteral ciprofloxacin, 49,038 patients received courses of the drug. The most frequently reported adverse reactions, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2. 5%), diarrhea (1. 6%), liver function tests abnormal (1. 3%), vomiting (1%), and rash (1%). Table 5: Medically Important Adverse Reactions That Occurred in less than 1% of Ciprofloxacin Patients System Organ Class Adverse Reactions Body as a Whole Headache Abdominal Pain/Discomfort Pain Cardiovascular Syncope Angina Pectoris Myocardial Infarction Cardiopulmonary Arrest Tachycardia Hypotension Central Nervous System Restlessness Dizziness Insomnia Nightmares Hallucinations Paranoia Psychosis (toxic) Manic Reaction Irritability Tremor Ataxia Seizures (including Status Epilepticus) Malaise Anorexia Phobia Depersonalization Depression (potentially culminating in self- injurious behavior (such as suicidal ideations/thoughts and attempted or completed suicide) Paresthesia Abnormal Gait Migraine Gastrointestinal Intestinal Perforation Gastrointestinal Bleeding Cholestatic Jaundice Hepatitis Pancreatitis Hemic/Lymphatic Petechia Metabolic/Nutritional Hyperglycemia Hypoglycemia Musculoskeletal Arthralgia Joint Stiffness Muscle Weakness Renal/Urogenital Interstitial Nephritis Renal Failure Respiratory Dyspnea Laryngeal Edema Hemoptysis Bronchospasm Skin/Hypersensitivity Anaphylactic Reactions including life-threatening anaphylactic shock Erythema Multiforme/Stevens-Johnson Syndrome Exfoliative Dermatitis Toxic Epidermal Necrolysis Pruritus Urticaria Photosensitivity/Phototoxicity reaction Flushing Fever Angioedema Erythema Nodosum Sweating Special Senses Blurred Vision Disturbed Vision (chromatopsia and photopsia) Decreased Visual Acuity Diplopia Tinnitus Hearing Loss Bad Taste In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets [500 mg two times daily (BID)] to cefuroxime axetil (250 mgen dash500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a CNS adverse reaction profile comparable to the control drugs. Pediatric Patients Short (6 weeks) and long term (1 year) musculoskeletal and neurological safety of oral/intravenous ciprofloxacin, was compared to a cephalosporin for treatment of cUTI or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 +/- 4 years) in an international multicenter trial. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled. An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse reactions including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6 weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9. 3% (31/335) in the ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse reaction and on more than one occasion compared to control patients. The rate of musculoskeletal adverse reactions was consistently higher in the ciprofloxacin group compared to the control group across all age subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period was 13. 7% (46/335) in the ciprofloxacin-treated group versus 9. 5% (33/349) in the comparator-treated patients (Table 6). Table 6: Musculoskeletal Adverse Reactions 1 Ciprofloxacin Tablets Comparator All Patients (within 6 weeks) 31/335 (9. 3%) 21/349 (6%) 95% Confidence Interval 2 (-0. 2%) Age Group 12 months < 24 months 1/36 (2. 8%) 0/41 2 years < 6 years 5/124 (4%) 3/118 (2. 5%) 6 years < 12 years 18/143 (12. 6%) 12/153 (7. 8%) 12 years to 17 years 7/32 (21. 9%) 6/37 (16. 2 %) All Patients (within 1 year) 46/335 (13. 7%) 33/349 (9. 5%) 95% Confidence Interval 1 (-0. The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3% (9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence. In this trial, the overall incidence rates of adverse reactions within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most frequent adverse reactions were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse reactions were seen in 7. 5% (25/335) of ciprofloxacin-treated patients compared to 5. 7% (20/349) of control patients. Discontinuation of drug due to an adverse reaction was observed in 3% (10/335) of ciprofloxacin -treated patients versus 1. 4% (5/349) of comparator patients. Other adverse reactions that occurred in at least 1% of ciprofloxacin patients were diarrhea 4. 8%, vomiting 4. 8%, abdominal pain 3. 3%, dyspepsia 2. 7%, nausea 2. 7%, fever 2. 1%, asthma 1. 8% and rash 1. Short-term safety data for ciprofloxacin was also collected in a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5en dash17 years). Sixty - seven patients received CIPRO IV 10 mg/kg/dose every 8 hours for one week followed by ciprofloxacin tablets 20 mg/kg/dose every 12 hours to complete 10en dash21 days treatment and 62 patients received the combination of ceftazidime intravenous 50 mg/kg/dose every 8 hours and tobramycin intravenous 3 mg/kg/dose every 8 hours for a total of 10en dash21 days. Periodic musculoskeletal assessments were conducted by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0en dash93 days). Musculoskeletal adverse reactions were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse reactions were similar in nature and frequency between treatment arms. The efficacy of ciprofloxacin for the treatment of acute pulmonary exacerbations in pediatric cystic fibrosis patients has not been established. In addition to the adverse reactions reported in pediatric patients in clinical trials, it should be expected that adverse reactions reported in adults during clinical trials or postmarketing experience may also occur in pediatric patients. The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure (Table 7). Table 7: Postmarketing Reports of Adverse Drug Reactions System Organ Class Adverse Reactions Cardiovascular QT prolongation Torsade de Pointes Vasculitis and ventricular arrhythmia Central Nervous System Hypertonia Myasthenia Exacerbation of myasthenia gravis Peripheral neuropathy Polyneuropathy Twitching Eye Disorders Nystagmus Gastrointestinal Pseudomembranous colitis Hemic/Lymphatic Pancytopenia (life threatening or fatal outcome) Methemoglobinemia Hepatobiliary Hepatic failure (including fatal cases) Infections and Infestations Candidiasis (oral, gastrointestinal, vaginal) Investigations Prothrombin time prolongation or decrease Cholesterol elevation (serum) Potassium elevation (serum) Musculoskeletal Myalgia Myoclonus Tendinitis Tendon rupture Psychiatric Disorders Agitation Confusion Delirium Skin/Hypersensitivity Acute generalize exanthematous pustulosis (AGEP) Fixed eruption Serum sickness-like reaction Special Senses Anosmia Hyperesthesia Hypesthesia Taste loss Changes in laboratory parameters while on ciprofloxacin tablets are listed below: Hepatic en dashElevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin. Hematologicen dashEosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, pancytopenia. Renalen dashElevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have been reported. Other changes occurring were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, and leukocytosis.

Click here to enter Contraindications Known hypersensitivity to ciprofloxacin or other quinolones ( 4. 7 Concomitant administration with tizanidine (4. 2) Ciprofloxacin tablets are contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components [see Warnings and Precautions ( 5. 7 Concomitant administration with tizanidine is contraindicated [see Drug Interactions ( 7.

Click here to enter Use in Specific Populations Lactation: 8. 2 See full prescribing information 8. 5 Risk Summary Prolonged experience with ciprofloxacin in pregnant women over several decades, based on available published information from case reports, case control studies and observational studies on ciprofloxacin administered during pregnancy, have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data). (see Data) Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective observational studies over several decades have not established an association with ciprofloxacin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available studies have methodological limitations including small sample size and some of them are not specific for ciprofloxacin. A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52. 5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2. 2% for the fluoroquinolone group and 2. 6% for the control group (background incidence of major malformations is 1en dash5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children. Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin. No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. Animal Data Developmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. In rats and mice, oral doses up to 100 mg/kg administered during organogenesis (Gestation Days, GD, 6-17) were not associated with adverse developmental outcomes, including embryofetal toxicity or malformations. In rats and mice, a 100 mg/kg dose is approximately 0. 3 times the maximum daily human oral dose (1500 mg/day) based upon body surface area, respectively. In a series of rabbit developmental toxicology studies, does received oral or intravenous ciprofloxacin for one of the following 5 day periods: GD 6 to 10, GD 10 to 14, or GD 14 to 18, intended to cover the period of organogenesis. This was an attempt to mitigate the gastrointestinal intolerance observed in rabbits that receive antibacterials manifested by reduced maternal food consumption and weight loss, that can lead to embryofetal resorption or spontaneous abortion. An oral ciprofloxacin dose of 100 mg/kg (approximately 1. 3 times the highest recommended clinical oral dose based on body surface area) caused excessive maternal toxicity confounding evaluation of the fetuses. A 30 mg/kg oral dose (approximately 0. 4 times the highest recommended clinical oral dose) was associated with suppression of maternal and fetal body weight gain, but fetal malformations were not observed. Intravenous administration of doses up to 20 mg/kg (approximately 0. 3 times the highest recommended clinical oral dose based upon body surface area) to pregnant rabbits was not maternally toxic and neither embryofetal toxicity nor fetal malformations were observed. In peri-and post-natal studies, rats received ciprofloxacin doses up to 200 mg/kg/day (oral) or up to 30 mg/kg/day (subcutaneous) from GD 16 to 22 days postpartum. The 200 mg/kg dose is approximately 1. 3-times the maximum recommended clinical oral dose based on body surface area. Neither maternal toxicity nor adverse effects on growth and development of the pups were observed, including no sign of arthropathy on the rear leg joints of the pups. Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested when administered directly [see Warnings and Precautions ( 5. 2 Risk Summary Published literature reports that ciprofloxacin is present in human milk following intravenous and oral administration. There is no information regarding effects of ciprofloxacin tablets on milk production or the breastfed infant. Because of the potential risk of serious adverse reactions in breastfed infants, including arthropathy shown in juvenile animal studies [see Use in Specific Populations ( 8. 4 However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on ciprofloxacin tablets may be acceptable [see Dosage and Administration ( 2. 2 Clinical Considerations Ciprofloxacin may cause intestinal flora alteration of the breastfeeding infant. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash). Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. Quinolones, including ciprofloxacin, cause arthropathy (arthralgia, arthritis), in juvenile animals [see Warnings and Precautions ( 5. 2 Complicated Urinary Tract Infection and Pyelonephritis Ciprofloxacin tablets are indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli [see Adverse Reactions ( 6. 1 Inhalational Anthrax (Post-Exposure) Ciprofloxacin is indicated in pediatric patients from birth to 17 years of age, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see Dosage and Administration ( 2. 2 Plague Ciprofloxacin is indicated in pediatric patients from birth to 17 years of age, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis Y. pestis [see Indications and Usage ( 1. 3 Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ciprofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ciprofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue ciprofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning, Warnings and Precautions ( 5. 2 Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see Warnings and Precautions ( 5. 9 In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing over 3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients [see Dosage and Administration ( 2. 3 In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using ciprofloxacin with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5. 12 Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction [see Dosage and Administration ( 2. 3 In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been studied.

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug. Table 8: Drugs That are Affected by and Affecting Ciprofloxacin Drugs That are Affected by Ciprofloxacin Drug(s) Recommendation Comments Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4. 2 Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions ( 5. 10 Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5. 5 Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6. 1 Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co- administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions ( 5. 16 Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology ( 12. 3 Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity. Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. Zolpidem Avoid Use Co-administration with ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended. Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx registered (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2. 4 Decrease ciprofloxacin absorption, resulting in lower serum and urine levels Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur. Interacting Drug Interaction Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7 Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding(7) Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7) Phenytoin Monitor phenytoin level (7) Methotrexate Monitor for methotrexate toxicity (7) Cyclosporine May increase serum creatinine. Monitor serum creatinine (7) Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take ciprofloxacin tablets 2 hours before or 6 hours after administration of multivalent cation containing drugs (7).

OVERDOSAGE
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Empty the stomach by inducing vomiting or by gastric lavage. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.
NONCLINICAL TOXICOLOGY
Click here to enter Nonclinical Toxicology Eight in vitro Salmonella/Microsome Test (Negative) E. coli Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V 79 Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Saccharomyces cerevisiae Rat Hepatocyte DNA Repair Assay (Positive) Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively (approximately 1. 5- times the highest recommended therapeutic dose based upon body surface area, respectively). Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3. 5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 weeks to 32 weeks in mice treated concomitantly with UVA and other quinolones. 5 In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown. Fertility studies performed in male and female rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0. 6 -times the highest recommended therapeutic oral dose based upon body surface area) revealed no evidence of impairment. Male rats received oral ciprofloxacin for 10 weeks prior to mating and females were dosed for 3 weeks prior to mating through Gestation Day 7. Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions ( 5. 13 Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0. 07-times the highest recommended therapeutic dose based upon body surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0. 2-times the highest recommended therapeutic dose based upon body surface area). In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec. ) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces hypotension but the effect in this species is inconsistent and less pronounced. In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones. Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
CLINICAL STUDIES
Click here to enter Clinical Studies Ciprofloxacin administered intravenously and/or orally was compared to a cephalosporin for treatment of cUTI and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 +/- 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety. Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria). The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown below. Table 11: Clinical Success and Bacteriologic Eradication at Test of Cure (5 to 9 Days Post-Therapy) Ciprofloxacin Comparator Randomized Patients 337 352 Per Protocol Patients 211 231 Clinical Response at 5 to 9 Days Post-Treatment 95. 7% (202/211) 92. 6% (214/231) 95% CI [-1. 3%] Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment 1 84. 4% (178/211) 78. 3% (181/231) 95% CI [-1. 1%] Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days Post-Treatment Escherichia coli 156/178 (88%) 161/179 (90%) 1 The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2. 97 mcg/mL, and 4. 56 mcg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8. 3 mcg/mL and trough concentrations range from 0. 09 mcg/mL to 0. 26 mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3. 6 mcg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication. 1 A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD 50 5 50 B anthracis max 6 7 More than 9300 persons were recommended to complete a minimum of 60 days of antibacterial prophylaxis against possible inhalational exposure to B. anthracis A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 110 LD 50 50 Yersinia pestis Y.
REFERENCES
21 CFR 314.510 (Subpart Hen dashAccelerated Approval of New Drugs for Life-Threatening Illnesses). Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998; 42(6):1336-1339. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996; 69:83-89. Report presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167:1239-42. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 - The efficacy of Ciprofloxacin for treatment of Pneumonic Plague.

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