ciprofloxacin 100 MG Oral Tablet

INDICATIONS AND USAGE 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 ) o Acute Exacerbation of Chronic Bronchitis Urinary Tract Infections ( 1.11 ) o Urinary Tract Infections (UTI) o Acute Uncomplicated Cystitis o 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. ( 1.13 ) 1.1 Skin and Skin Structure Infections Ciprofloxacin is indicated in adult patients for treatment of skin and skin structure infections caused by Escherichia coli , Klebsiella pneumoniae , Enterobacter cloacae , Proteus mirabilis , Proteus vulgaris , Providencia stuartii , Morganella morganii , Citrobacter freundii , Pseudomonas aeruginosa , methicillin-susceptible Staphylococcus aureus , methicillin-susceptible Staphylococcus epidermidis , or Streptococcus pyogenes . 1.2 Bone and Joint Infections Ciprofloxacin is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. 1.3 Complicated Intra-Abdominal Infections Ciprofloxacin is indicated in adult patients for treatment of complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. 1.4 Infectious Diarrhea Ciprofloxacin is indicated in adult patients for treatment of infectious diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni , Shigella boydii † , Shigella dysenteriae , Shigella flexneri or Shigella sonnei † when antibacterial therapy is indicated. † Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients. 1.5 Typhoid Fever (Enteric Fever) Ciprofloxacin is indicated in adult patients for treatment of typhoid fever (enteric fever) caused by Salmonella typhi . The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated. 1.6 Uncomplicated Cervical and Urethral Gonorrhea Ciprofloxacin is indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae [see Warnings and Precautions (5.17) ]. 1.7 Inhalational Anthrax (Post-Exposure) Ciprofloxacin is 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 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001 [see Clinical Studies (14.2) ]. 1.8 Plague Ciprofloxacin is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17 years of age. Efficacy studies of ciprofloxacin could not be conducted in humans with plague for feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [ see Clinical Studies (14.3) ] . 1.9 Chronic Bacterial Prostatitis Ciprofloxacin is indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis . 1.10 Lower Respiratory Tract Infections Ciprofloxacin is indicated in adult patients for treatment of lower respiratory tract infections caused by Escherichia coli , Klebsiella pneumoniae , Enterobacter cloacae , Proteus mirabilis , Pseudomonas aeruginosa , Haemophilus influenzae , Haemophilus parainfluenzae , or Streptococcus pneumoniae . Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae . Ciprofloxacin is 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 (5.1–5.16) ] and for some patients AECB is self-limiting, reserve ciprofloxacin for treatment of AECB in patients who have no alternative treatment options. 1.11 Urinary Tract Infections Urinary Tract Infections in Adults Ciprofloxacin is indicated in adult patients for treatment of urinary tract infections caused by Escherichia coli , Klebsiella pneumoniae , Enterobacter cloacae , Serratia marcescens , Proteus mirabilis , Providencia rettgeri , Morganella morganii , Citrobacter koseri , Citrobacter freundii , Pseudomonas aeruginosa , methicillin-susceptible Staphylococcus epidermidis , Staphylococcus saprophyticus , or Enterococcus faecalis . Acute Uncomplicated Cystitis Ciprofloxacin is indicated in adult female patients for treatment of acute uncomplicated cystitis caused by Escherichia coli or Staphylococcus saprophyticus . Because fluoroquinolones, including ciprofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions (5.1-5.16) ] and for some patients acute uncomplicated cystitis is self-limiting, reserve ciprofloxacin tablets for treatment of acute uncomplicated cystitis in patients who have no alternative treatment options. Complicated Urinary Tract Infection and Pyelonephritis in Pediatric Patients Ciprofloxacin is 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 is 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. Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions (5.13) , Adverse Reactions (6.1) , Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2) ]. 1.12 Acute Sinusitis Ciprofloxacin is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae , Streptococcus pneumoniae , or Moraxella catarrhalis . Because fluoroquinolones, including ciprofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions (5.1-5.16) ] and for some patients acute sinusitis is self-limiting, reserve ciprofloxacin for treatment of acute sinusitis in patients who have no alternative treatment options. 1.13 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 susceptible bacteria. When culture and susceptibility

DOSAGE AND ADMINISTRATION Ciprofloxacin tablets should be administered orally as described in the appropriate Dosage Guidelines tables. Adu l t D o s a g e G u i d e l i n es I n f e c ti o n D o se F re qu e n cy Du ra ti o n Skin and Skin Structure 500 mg to 750 mg every 12 hours 7 to 14 days Bone and Joint 500 mg to 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 (post­exposure) 500 mg every 12 hours 60 days Plague 500 mg to 750 mg every 12 hours 14 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract 500 mg to 750 mg every 12 hours 7 to 14 days Urinary Tract 250 mg to 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 30 mL/min to 50 mL/min 250 mg to 500 mg q 12 h ( 2.3 ) Adults with creatinine clearance 5 mL/min to 29 mL/min 250 mg to 500 mg q 18 h ( 2.3 ) Patients on hemodialysis or peritoneal dialysis 250 mg to 500 mg q 24 h (after dialysis) ( 2.3 ) Pediatric Oral Dosage Guidelines Infection Dose Frequency Duration Complicated UTI 10 mg/kg to 20 mg/kg and Pyelonephritis (maximum 750 mg Every 12 10 to 21 days (1 to 17 years of age) per dose) hours 15 mg/kg Inhalational Anthrax (maximum Every 12 60 days (Post-Exposure) 500 mg per dose) hours 15 mg/kg Plague (maximum 500 mg Every 8 to 14 days per dose) 12 hours 2.1 Dosage in Adults The determination of dosage and duration for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient’s host-defense mechanisms, and the status of renal and hepatic function. Ciprofloxacin tablets may be administered to adult patients when clinically indicated at the discretion of the physician. Table 1: Adult Dosage Guidelines Infection Dose Frequency Usual Durations 1 Skin and Skin Structure 500 mg to 750 mg every 12 hours 7 to 14 days Bone and Joint 500 mg to 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 (post­exposure) 3 500 mg every 12 hours 60 days Plague 3 500 mg to 750 mg every 12 hours 14 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract Infections 500 mg to 750 mg every 12 hours 7 to 14 days Urinary Tract Infections 250 mg to 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. Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure). 2. Used in conjunction with metronidazole. 3. Begin drug administration as soon as possible after suspected or confirmed exposure. Conversion of Intravenous to Oral Dosing in Adults Patients whose therapy is started with ciprofloxacin intravenous 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 Tablets Oral Dosage Equivalent Ciprofloxacin Intravenous 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 2.2 Dosage in Pediatric Patients Dosing and initial route of therapy (that is, intravenous 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 10 mg/kg to 20 mg/kg Complicated Urinary Tract or (maximum 750 mg per dose; not to be Pyelonephritis exceeded even in patients weighing more Every 12 hours 10 to 21 days 1 (patients from 1 to 17 years of age) than 51 kg) Inhalational Anthrax 15 mg/kg (Post-­Exposure) 2 (maximum 500 mg per dose) Every 12 hours 60 days Plague 2,3 15 mg/kg Every 8 to 12 (maximum 500 mg per dose) hours 14 days 1. The total duration of therapy for cUTI and pyelonephritis in the clinical trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days). 2. Begin drug administration as soon as possible after suspected or confirmed exposure. 3. Begin drug administration as soon as possible after suspected or confirmed exposure to Y. pestis . 2.3 Dosage Modifications in Patients with Renal Impairment Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. Dosage guidelines for use in patients with renal impairment are shown in Table 4. Table 4: Recommended Starting and Maintenance Doses for Adult Patients with Impaired Renal Function Creatinine Clearance (mL/min) Dose > 50 See Usual Dosage. 30 to 50 250 mg to 500 mg every 12 hours 5 to 29 250 mg to 500 mg every 18 hours Patients on hemodialysis or Peritoneal dialysis 250 mg to 500 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 - Creatinine clearance (mL/min) = Weight (kg) x (140–age) 72 x serum creatinine (mg/dL) Women - 0.85 x the value calculated for men. 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 ). 2.4 Important Administration Instructions 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; Videx ® (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 may be taken with a meal that contains these products. 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. Do

WARNINGS AND PRECAUTIONS Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions (for example, anaphylactic reactions) may occur after the first or subsequent doses of ciprofloxacin tablets. Discontinue ciprofloxacin tablets at the first sign of skin rash, jaundice or any sign of hypersensitivity. ( 4.1 , 5.6, 5.7 ) Hepatotoxicity: Discontinue immediately if signs and symptoms of hepatitis occur. ( 5.8 ) Clostridioides difficile -associated diarrhea: Evaluate if colitis occurs. ( 5.11 ) QT Prolongation: Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval. ( 5.12 , 7 , 8.5 ) 5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ciprofloxacin tablets. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]. Discontinue ciprofloxacin tablets immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ciprofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones. 5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ] . This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting ciprofloxacin tablets, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors 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. Discontinue ciprofloxacin tablets immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ciprofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture [see Adverse Reactions (6.2) ]. 5.3 Peripheral Neuropathy Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin tablets and may be irreversible in some patients [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 , 6.2 )] . Discontinue ciprofloxacin tablets immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ciprofloxacin, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions ( 6.1 , 6.2 )]. 5.4 Central Nervous System Effects Psychiatric Adverse Reactions Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations, or paranoia; depression, or self-injurious behavior such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care. Central Nervous System Adverse Reactions Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pseudotumor cerebri), dizziness, and tremors. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. As with all fluoroquinolones, use ciprofloxacin with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). If seizures occur, discontinue ciprofloxacin and institute appropriate care [see Adverse Reactions (6.1) and Drug Interactions (7) ]. 5.5 Exacerbation of Myasthenia Gravis Fluoroquinolones, including ciprofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis [see Adverse Reactions (6.2) ] . 5.6 Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome); Vasculitis; arthralgia; myalgia; serum sickness; Allergic pneumonitis; Interstitial nephritis; acute renal insufficiency or failure; Hepatitis; jaundice; acute hepatic necrosis or failure; Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. Discontinue ciprofloxacin tablets immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Adverse Reactions (6.1 , 6.2) ] . 5.7 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have be

CONTRAINDICATIONS • Known hypersensitivity to ciprofloxacin or other quinolones ( Error! Hyperlink reference not valid. , 5.6 , 5.7) • Concomitant administration with tizanidine ( 4.2 ) 4.1 Hypersensitivity 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 )]. 4.2 Tizanidine Concomitant administration with tizanidine is contraindicated [see Drug Interactions ( 7 )].

Click here to enter Clinical Pharmacology 12.1 Mechanism of Action Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)]. 12.3 Pharmacokinetics 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 (Cmax) and area under the curve (AUC) are shown in the chart for the 250 mg to 1000 mg dose range (Table 9). Table 9: Ciprofloxacin Cmax and AUC Following Administration of Single Doses of Ciprofloxacin Tablets to Healthy Subjects Dose (mg) Cmax (mcg/mL) AUC (mcg•hr/mL) 250 1.2 4.8 500 2.4 11.6 750 4.3 20.2 1000 5.4 30.8 Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg. A 500 mg oral dose given every 12 hours has been shown to produce an AUC equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed with a 400 mg intravenous dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours (Table 10). 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 (μg•h/mL) 27.4* 25.4* 31.6* 32.9** C max,ss (μg/mL) 2.97 4.56 3.59 4.07 *: AUC 0–12h x 2 **: AUC 0–8h x 3 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 (4.2), Warnings and Precautions (5.10, 5.16), and Drug Interactions (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 Cmax is increased 16% to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant [see 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 (8.6) and Dosage and Administration (2.3)]. 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) and Drug Interactions (7)]. Histamine H2-receptor antagonists Histamine H2 -receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin. 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 (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg twice a day for 3 days). Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [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 Cmax and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administr