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CLINICAL PHARMACOLOGY Mechanism of Action Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology]. Pharmacokinetics Absorption When Proquin XR is administered with food, approximately 87% of ciprofloxacin is gradually released from the tablet over a 6-hour period. When administered following a meal maximum plasma ciprofloxacin concentrations are attained approximately 4.5-7 hours after dosing with Proquin XR (ciprofloxacin hcl) tablets. Proquin XR (ciprofloxacin hcl) should be administered with a main meal of the day, preferably the evening meal; if Proquin XR (ciprofloxacin hcl) is given while fasting, the bioavailability will be lowered substantially. Administration of Proquin XR (ciprofloxacin hcl) with a standardized meal (1000 calories, 50% fat) increased the Cmax and AUC0-24h by approximately 120% and 170%, respectively, compared to administration under fasting conditions; the mean Tmax was prolonged from 2.3 hours to 4.5 hours. Table 2 presents the pharmacokinetic parameters obtained at steady state for Proquin XR 500 mg once daily versus ciprofloxacin immediate-release tablets 250 mg twice daily. Table 2: Steady-State Pharmacokinetics for Ciprofloxacin in Plasma of Healthy Subjects (Day 3)a Pharmacokinetic Parameters Proquin XR 500 mg Tablets (qd) (n=27) CIPRO 250 mg Tablets (bid) (n=27) Mean (%CV) AUC0-24h (mcg.hr/mL) 7.67 (25) 7.83 (16) Cmax (mcg/mL) 0.82 (28) Cmax,1 0.57 (25)b Cmax,2 0.93 (27) Cmin (mcg/mL) 0.06 (42) 0.14 (29) Mean ±SD Tmax (hr) 6.1 ±Tmax1 2.5 Tmax1 2.5 ± 1.2 c Tmax2 2.5 ± 1.4 a both treatments were administered following a standardized meal (approximately 1000 calories, 50% fat). b Cmax1 = peak concentration after the evening dose of ciprofloxacin immediate-release tablets twice daily. Cmax2 = peak concentration after the morning dose of ciprofloxacin immediate-release tablets twice daily. c Tmax1 = time of peak concentration after the evening dose ciprofloxacin immediate-release tablets twice daily. Tmax2 = time of peak concentration after the morning dose ciprofloxacin immediate-release tablets twice daily. Distribution The in vitro binding of ciprofloxacin to plasma proteins over a concentration ranging from 0.9 to 30 micromolar is 9.9% to 36.6%, which is not likely to cause clinically significant protein binding interactions with other drugs. Metabolism Four metabolites of ciprofloxacin have been identified in human urine and feces. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The metabolites are desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4), which account for approximately 11% of the total dose. Elimination The plasma elimination half-life of ciprofloxacin in healthy volunteers following a Proquin XR (ciprofloxacin hcl) 500 mg dose was approximately 4.5 hours. Following a 500 mg oral dose of Proquin XR (ciprofloxacin hcl) , 26.9% was excreted in the urine over 24 hours as unchanged drug for both formulations. Following administration of a single 500 mg dose of Proquin XR (ciprofloxacin hcl) , approximately 41% of the oral dose was excreted into the urine over 96 hours as unchanged drug and metabolites. The urinary excretion of ciprofloxacin was virtually complete within 24 hours after dosing. Urinary excretion is a main route of elimination of ciprofloxacin and its urinary concentrations relative to the MICs of the bacterial species may be important to understanding the efficacy of ciprofloxacin for the treatment of urinary tract infections. The mean urinary ciprofloxacin concentration after dosing with Proquin XR 500 mg once daily and ciprofloxacin immediate-release tablets 250 mg twice daily are shown in Table 3. Table 3: Mean Urinary Concentrations of Ciprofloxacin Treatment Day Mean (%CV) urinary ciprofloxacin concentration over 24 hours (mcg/mL) Proquin XR 500 mg once daily 1 71 (41) 3 67 (28) Ciprofloxacin immediate-release tablets 250 mg twice daily 1 79 (32) 3 75 (24) The renal clearance of ciprofloxacin following administration of Proquin XR (ciprofloxacin hcl) , which is approximately 304 - 383 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. Approximately 43% of the oral dose of Proquin XR (ciprofloxacin hcl) is recovered from the feces as unchanged drug and metabolites within 7 days after dosing. This may arise from either biliary clearance or transintestinal elimination. Specific Populations Elderly: When a single 500 mg dose of Proquin XR (ciprofloxacin hcl) was administered to elderly subjects ( > 65 years) Cmax and AUC values were increased by approximately 24% and 20% respectively, compared to younger subjects from a reference study. This can be at least partially attributed to decreased renal clearance in the elderly. However, in elderly subjects, the percentage of the ciprofloxacin dose excreted in the urine was 11% lower as compared to younger subjects. The elimination half-life was not significantly prolonged in elderly subjects (4.9 hours) compared to healthy young subjects (4.5 hours). These differences are not considered clinically significant [see Use In Specific Populations]. Renal Impairment: After receiving a single dose of Proquin XR 500 mg, the ciprofloxacin AUC0-24h in subjects with mild renal impairment (CLcr = 51-80 mL/min; n=10) and moderate renal impairment (CLcr = 30-50 mL/min; n=10) were 42% and 54% greater, respectively, compared to subjects with normal renal function (CLcr > 80 mL/min; n=10). The elimination half-life of ciprofloxacin in patients with mild and moderate renal impairment was approximately 1.7 times longer as compared to the control group (7.8 - 7.5 hours versus 4.5 hours). In patients with end-stage renal disease (CLcr < 10 mL/min), the half-life of ciprofloxacin is approximately doubled compared to subjects with normal renal function. No dose adjustment of Proquin XR (ciprofloxacin hcl) is required for patients with uUTI and mild to moderate renal impairment. The efficacy of Proquin XR (ciprofloxacin hcl) has not been studied in patients with severe renal impairment [see Use In Specific Populations]. Hepatic Impairment: In studies in patients with stable chronic cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, has not been fully elucidated [see Use In Specific Populations]. Pediatrics: The pharmacokinetics of Proquin XR (ciprofloxacin hcl) have not been studied in pediatric populations [see Use In Specific Populations]. Drug Interactions Antacids: The interaction of Proquin XR (ciprofloxacin hcl) (administered as a single 1000 mg [2 x 500 mg] dose) and magnesium/aluminum-containing antacids (900 mg aluminum hydroxide and 600 mg magnesium hydroxide administered as a single oral dose) was evaluated in healthy volunteers. When Proquin XR (ciprofloxacin hcl) was given 2 hours after antacids and 6 hours before antacids, the Cmax values were similar to those when Proquin XR (ciprofloxacin hcl) was given alone and AUC values were reduced by approximately 10%. When Proquin XR (ciprofloxacin hcl) was given 4 hours before antacids, Cmax was reduced by approximately 11% and AUC was reduced by approximately 22%. Thus, to minimize the effect of antacids on the absorption of ciprofloxacin, Proquin XR (ciprofloxacin hcl) should be given either 2 hours after or at least 4 hours before antacids [see DRUG INTERACTIONS]. 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. Omeprazole: The rate and extent of absorption of ciprofloxacin was bioequivalent when Proquin XR (ciprofloxacin hcl) was given alone or when Proquin XR (ciprofloxacin hcl) was given 2 hours after omeprazole at the dose that maximally suppresses gastric acid secretion. When Proquin XR (ciprofloxacin hcl) was administered following a meal as a single 1000 mg dose (2 x 500 mg), 2 hours after the third dose of omeprazole (given 40 mg once daily for three days) to 27 healthy volunteers, the mean AUC and Cmax of ciprofloxacin were bioequivalent to the mean AUC and Cmax values when Proquin XR (ciprofloxacin hcl) was administered alone. Omeprazole should be taken as directed and Proquin XR (ciprofloxacin hcl) should be taken with a main meal of the day, preferably the evening meal. Warfarin: The co-administration of single doses of Proquin XR (ciprofloxacin hcl) and warfarin (Coumadin® 7.5 mg) did not result in significant changes in the pharmacokinetics of ciprofloxacin nor did it significantly affect the pharmacodynamics of S-warfarin and R-warfarin. Although the Cmax and AUC of the two warfarin enantiomers and the elimination half-life of S-warfarin, the pharmacologically active enantiomer, were not significantly altered by ciprofloxacin coadministration, the half-life of R-warfarin was statistically significantly prolonged (P=0.029). When Proquin XR and oral anticoagulants are administered concomitantly, prothrombin time or other suitable coagulation tests should be monitored [see DRUG INTERACTIONS]. Microbiology Mechanism of Action The bactericidal action of ciprofloxacin results from inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases) which are required for bacterial DNA replication, transcription, repair and recombination. Drug Resistance The mechanism of action of quinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Resistance to ciprofloxacin in vitro develops slowly (multiple step mutation). Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6. Activity in vitro and in vivo Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms. Ciprofloxacin is less active when tested at acidic pH. The inoculum size has little effect when tested in vitro . The minimal bactericidal concentration (MBC) generally does not exceed the MIC by more than a factor of 2. Ciprofloxacin has been shown to be active against most strains of the following organisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic gram-negative microorganisms Escherichia coli Klebsiella pneumoniae The following in vitro data are available, but their clinical significance is unknown: Ciprofloxacin exhibits in vitro MICs of 1 mcg/mL or less against most ( > 90%) strains of the following microorganisms; however, the safety and effectiveness of Proquin XR (ciprofloxacin hcl) in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Aerobic gram-negative microorganisms Proteus mirabilis Susceptibility Tests Interpretive criteria for urinary isolates have not been established for Proquin XR. Interpretive criteria established based on systemic drug levels may not be appropriate for uncomplicated urinary tract infections. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted according to the criteria outlined in Table 4. Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-mcg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-mcg ciprofloxacin disk should be interpreted according to the f criteria outlined in Table 4. Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin. Table 4: Susceptibility Interpretive Criteria for Ciprofloxacin Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm) S I R S I R Enterobacteriaceae ≤ 1 2 ≥ 4 ≥ 21 16-20 ≤ 15 S=Susceptible, I=Intermediate, and R=Resistant A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully-susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For dilution technique, standard ciprofloxacin powder should give the MIC values provided in Table 4. For diffusion technique, the 5 mcg ciprofloxacin disk should provide zone diameters provided in Table 5. Table 5: Quality Control for Susceptibility Testing Microorganism Microorganism QC Number MIC (mcg/mL) Disk Diffusion (zone diameter in mm) Escherichia coli ATCC 25922 0.004-0.015 30-40 Staphylococcus aureus ATCC 29213 0.12-0.5 Not applicable Staphylococcus aureus ATCC 25923 Not applicable 22 – 30 Animal Pharmacology Gastrointestinal or other toxic effects were not observed in male and female beagle dogs following oral administration of Proquin XR (ciprofloxacin hcl) tablets at doses up to 1,000 mg/day for 28 consecutive days (approximately 3 and 5 times the human therapeutic dose based upon AUC comparisons to male and female dogs, respectively). Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with the fluoroquinolone class of drugs. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals. In contrast, crystalluria is rare in man since human urine is typically acidic [see ADVERSE REACTIONS]. In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effects of quinolones [see DRUG INTERACTIONS]. Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals. There was no indication of ocular toxicity in the dog study cited above. Clinical Studies Uncomplicated Urinary Tract Infections Proquin XR (ciprofloxacin hcl) was evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in a randomized, double-blind, controlled trial conducted in the US. This study compared Proquin XR 500 mg once daily for 3 days with ciprofloxacin immediate-release tablets. Of the 1,037 patients enrolled, 524 were randomly assigned to the Proquin XR (ciprofloxacin hcl) treatment group and 513 were randomly assigned to the control group. A total of 272 (52%) patients in the Proquin XR (ciprofloxacin hcl) group and 251 (49%) in the control group were evaluable for efficacy and included in the Per-Protocol population. The primary efficacy variable was bacteriologic eradication of the baseline organism(s) with no new infection at the Test-of-Cure (TOC) visit (Day 4 to 11 post-therapy). The bacteriological eradication and clinical success rates were similar for both treatment groups. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (Proquin XR minus control group) are given in Table 6. Table 6: Bacteriological Eradication and Clinical Cure Rates at the Test-of-Cure (TOC) Visit Proquin XR 500 mg once daily for 3 days Ciprofloxacin immediate- release tablet 250 mg twice daily for 3 days qd x 3 Days bid x 3 Days Randomized Patients 524 513 Per Protocol Patients 272 (52%) 251 (49%) Bacteriologic Eradication with no new infection at TOC 212 / 272 (78%) 193 / 251 (77%) (-6.2%,8.2%) Clinical Response at TOC 233 / 272 (86%) 216 / 251 (86%) (-6.4%,5.6%) Bacteriologic Eradication by organism* E. coli 211 / 222 (95%) 184 / 202 (91%) K. pneumoniae 11 / 12 (92%) 10 / 13 (77%) *Number of patients with specified baseline organism eradicated /Number of per-protocol patients with specified baseline organism. The bacteriological eradication rates for baseline organisms at the TOC visit were 93% (254/272) for Proquin XR and 90% (225/251) for ciprofloxacin immediate-release tablets. Of the patients with their baseline organism eradicated, new infections were detected in 42/254 (16%) Proquin XR-treated patients and 32/225 (14%) ciprofloxacin-treated patients at the TOC visit. Gram-negative rods were responsible for new infections in 10 Proquin XR-treated patients and 7 ciprofloxacin-treated patients, and Enterococcus species were isolated in 24 Proquin XR-treated patients, and 20 ciprofloxacin-treated patients. REFERENCES Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Eight Edition. Approved Standard CLSI Document M7-A8, Vol. 29, No. 2, CLSI, Wayne, PA, January, 2009. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests. Tenth Edition. Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Wayne, PA, January, 2009.

Find Lowest Prices on Proquin® XR (ciprofloxacin) Extended-Release Tablets, 500 mg* *present as 582 mg of ciprofloxacin hydrochloride monohydrate WARNING TENDONITIS AND TENDON RUPTURE Fluoroquinolones, including Proquin XR (ciprofloxacin hcl) , are associated with an increased risk of tendinitis and tendon rupture in all ages. The risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart and lung transplant recipients [See WARNINGS AND PRECAUTIONS]. Fluroquinolones, including Proquin XR (ciprofloxacin hcl) , may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Proquin XR (ciprofloxacin hcl) in patients with known history of myasthenia gravis (See WARNINGS). DESCRIPTION Proquin XR (ciprofloxacin hydrochloride monohydrate) extended-release tablets contain 582 mg of ciprofloxacin hydrochloride monohydrate, a synthetic broad-spectrum fluoroquinolone antimicrobial agent for oral administration, which is equivalent to 500 mg of ciprofloxacin. Ciprofloxacin hydrochloride monohydrate is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3-quinolinecarboxylic acid hydrochloride monohydrate. The molecular weight of the ciprofloxacin hydrochloride monohydrate is 385.82. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows: Proquin XR is available as 500 mg (ciprofloxacin hydrochloride monohydrate equivalent) tablets, utilizing AcuForm® delivery technology. Proquin XR (ciprofloxacin hcl) tablets are blue film-coated and oval-shaped. The inactive ingredients are povidone, magnesium stearate, polyethylene oxide, and film coating (Opadry® Blue).

INDICATIONS To reduce the development of drug-resistant bacteria and maintain the effectiveness of Proquin XR (ciprofloxacin hcl) and other antibacterial drugs, Proquin XR (ciprofloxacin hcl) should be used only to treat uncomplicated urinary tract infections that are strongly suspected to be caused by 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. Uncomplicated Urinary Tract Infections Proquin XR (ciprofloxacin hcl) is indicated for the treatment of uncomplicated urinary tract infections (acute cystitis) caused by susceptible strains of Escherichia coli and Klebsiella pneumoniae. Limitations of Use Proquin XR is not interchangeable with other ciprofloxacin extended-release or immediate release oral formulations. The safety and efficacy of Proquin XR (ciprofloxacin hcl) in treating pyelonephritis, complicated urinary tract infections, and infections other than uncomplicated urinary tract infections have not been demonstrated. DOSAGE AND ADMINISTRATION Proquin XR (ciprofloxacin hcl) 500 mg tablets should be administered orally once daily for 3 days with a main meal of the day, preferably the evening meal. Proquin XR (ciprofloxacin hcl) tablets should be taken whole and never split, crushed, or chewed. Proquin XR (ciprofloxacin hcl) should be administered at least 4 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, metal cations such as iron, and multivitamin preparations containing zinc [see DRUG INTERACTIONS]. Concomitant administration of ciprofloxacin with milk products or calcium-fortified juices alone should be avoided since decreased absorption is possible [see DRUG INTERACTIONS]. Adequate hydration of patients receiving Proquin XR (ciprofloxacin hcl) should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria has been reported with quinolones [see ADVERSE REACTIONS and PATIENT INFORMATION]. HOW SUPPLIED Dosage Forms And Strengths Extended release tablets: 500 mg* of ciprofloxacin *present as 582 mg of ciprofloxacin hydrochloride monohydrate Storage And Handling Proquin XR (ciprofloxacin hcl) is available as blue film-coated tablets containing 500 mg ciprofloxacin. The tablet is debossed with “500” on one side and “DMI” on the other side. Package Strength NDC Code Bottles of 30: 500 mg 13913-001-30 Blister Packs of 3: 500 mg 13913-001-03 Store Proquin XR (ciprofloxacin hcl) at 25°C (77 °F); excursions permitted to 15-30 °C (59-86 °F) [see USP Controlled Room Temperature]. Revised February 2011. Depomed, Inc. 1360 O'Brien Drive, Menlo Park, CA 94025-1436. 1-866-458-6389

OVERDOSE Only a small amount of ciprofloxacin ( < 10%) is removed from the body after hemodialysis or peritoneal dialysis. In the event of an acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment. Adequate hydration must be maintained. Serious adverse effects were not observed in rats receiving single oral doses of ciprofloxacin as high as 2,000 mg/kg. CONTRAINDICATIONS Proquin XR (ciprofloxacin hcl) is contraindicated in persons with a known hypersensitivity to ciprofloxacin or other quinolone antibacterials [see WARNINGS AND PRECAUTIONS].

SIDE EFFECTS Serious and Otherwise Important Adverse Reactions The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: Tendon Effects [see WARNINGS AND PRECAUTIONS] Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS] Other Serious and Sometimes Fatal Reactions [see WARNINGS AND PRECAUTIONS] Central Nervous System Effects [see WARNINGS AND PRECAUTIONS] Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS] Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS] Photosensitivity/Phototoxicity [see WARNINGS AND PRECAUTIONS] Development of Drug Resistant Bacteria [see WARNINGS AND PRECAUTIONS] Crystalluria and cylindruria have been reported with quinolones, including ciprofloxacin. Therefore, adequate hydration of patients receiving Proquin XR (ciprofloxacin hcl) should be maintained to prevent the formation of highly concentrated urine [see DOSAGE AND ADMINISTRATION]. Clinical Trial Experience 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. The data described below reflect exposure to Proquin XR (ciprofloxacin hcl) in 524 patients in one clinical trial. The population studied had a mean age of 39 years (approximately 93.4% of the population were < 65 years of age), 100% were female, 77% were Caucasian and 7.4% were Black. Patients received Proquin XR (ciprofloxacin hcl) 500 mg once daily for 3 days. Patients were followed for approximately 5 weeks after the end of study drug dosing. Discontinuation of Proquin XR (ciprofloxacin hcl) occurred in 1.4% of patients. Each of the discontinuations were for a different adverse reactions. Refer to Table 1. The most common adverse reactions ( ≥ 2%) were fungal infection, nasopharyngitis, headache, and micturition urgency. Table 1: Adverse reactions (regardless of relationship to study drug) occurring in ≥ 1% of Proquin XR (ciprofloxacin hcl) -treated patients (500 mg once daily for 3 days) during the entire study period compared to ciprofloxacin-immediate release tablets (250 mg twice daily for 3 days) Adverse Reaction Proquin XR Ciprofloxacin-immediate release tablets Nausea 1.4 2.4 Abdominal pain 1.7 1.2 Suprapubic pain 1.4 0.6 Urinary tract infection 10.8 9.8 Fungal infection 2.7 1.8 Upper respiratory tract infection 1.4 2.9 Back pain 1.7 1.6 Headache 2.3 3.9 Micturition urgency 1.9 1.0 Urinary frequency 1.4 1.0 Nasopharyngitis 2.7 1.4 Pharyngitis 1.2 1.0 The incidence of adverse events (regardless of relationship to study drug) reported for at least 1% of patients treated with Proquin XR (ciprofloxacin hcl) during study drug treatment and up to 3 days after study drug was headache (1.5%). Less common reactions, occurring at any time during the study in less than 1% of Proquin XR (ciprofloxacin hcl) -treated patients were: Cardiac Disorders: ventricular bigeminy. Immune System Disorders: hypersensitivity. Gastrointestinal Disorders: abdominal pain, nausea, diarrhea, dyspepsia, aggravated irritable bowel syndrome, lower abdominal pain, vomiting. General Disorders: suprapubic pain, fatigue, pain, rigors, tenderness. Infections and Infestations: urinary tract infection, fungal vaginosis, bacterial vaginitis, vaginal candidiasis, vaginal infection, vaginitis. Investigations: blood bilirubin increased, alanine aminotransferase increased, abdominal aortic bruit, aspartate aminotransferase increased, body temperature increased. Musculoskeletal and Connective Tissue Disorders: joint swelling, muscle spasms, night cramps. Nervous System Disorders: headache, dizziness, disturbance in attention, paresthesia. Renal and Urinary Disorders: micturition urgency, dysuria, urinary frequency, abnormal urine odor, hematuria. Reproductive System and Breast Disorders: female genital pruritus. Respiratory, Thoracic, and Mediastinal Disorders: dyspnea. Skin/Subcutaneous Tissue Disorders: rash, photosensitivity/ phototoxicity reaction, pruritus, urticaria. Adverse Reactions Reported with Other Systemic Formulations of Ciprofloxacin In addition, to the adverse reactions reported with Proquin XR (ciprofloxacin hcl) , the following adverse reactions have been reported during clinical trials and from worldwide post-marketing experience with other systemic formulations of ciprofloxacin (includes all dosages and indications). Because these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or a causal relationship to drug exposure. Abnormal gait, achiness, acidosis, agitation, agranulocytosis, allergic reactions (ranging from urticaria to anaphylactic reactions) [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS], amylase increase, anemia, angina pectoris, angioedema, anosmia, anxiety, arrhythmia, arthralgia, ataxia, atrial flutter, bleeding diathesis, blurred vision, bronchospasm, C. difficile associated diarrhea, candidiasis (cutaneous, oral), candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, cholestatic jaundice, chromatopsia, confusion, convulsion [see WARNINGS AND PRECAUTIONS], delirium, depression, diplopia, drowsiness, dysphagia, dyspnea, edema (conjunctivae, face, hands, laryngeal, lips, lower extremities, neck, pulmonary), epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, fever, fixed eruptions, flushing, gastrointestinal bleeding, gout (flare up), grand mal convulsion, gynecomastia, hallucinations, hearing loss, hematuria, hemolytic anemia, hemoptysis, hemorrhagic cystitis, hepatic failure (including fatal cases) [see WARNINGS AND PRECAUTIONS], hepatic necrosis, hepatitis, hiccup, hyperesthesia, hyperpigmentation, hypertension, hypertonia, hypoesthesia, hypotension, ileus, insomnia, interstitial nephritis, intestinal perforation, jaundice, joint stiffness, lethargy, lightheadedness, lipase increase, lymphadenopathy, malaise, manic reaction, marrow depression, migraine, moniliasis (oral, gastrointestinal, vaginal), mouth dryness, myalgia, myasthenia, myasthenia gravis (possible exacerbation), myocardial infarction, myoclonus, nephritis, nightmares, nystagmus, oral ulceration, pain (arm, back, breast, chest, epigastric, eye, extremities, foot, jaw, neck, oral mucosa), palpitation, pancreatitis, pancytopenia, paranoia, paresthesia [see WARNINGS AND PRECAUTIONS], peripheral neuropathy, perspiration (increased), petechia, phlebitis, phobia, photosensitivity/phototoxicity reaction[see WARNINGS AND PRECAUTIONS] pleural effusion, polyuria, postural hypotension, prothrombin time prolongation, pseudomembranous colitis (the onset of symptoms may occur during or after antimicrobial treatment) [see WARNINGS AND PRECAUTIONS], pulmonary embolism, purpura, renal calculi, renal failure, respiratory arrest, respiratory distress, restlessness, serum sickness-like reaction, Stevens-Johnson syndrome, sweating, syncope, tachycardia, taste loss, tendonitis, tendon rupture [see BOXED WARNING and WARNINGS AND PRECAUTIONS], tinnitus, torsade de pointes, toxic epidermal necrolysis, toxic psychosis, tremor, twitching, unresponsiveness, urethral bleeding, urinary retention, urination (frequent), vaginal pruritus, vasculitis, ventricular ectopy, vesicles, visual acuity (decreased), visual disturbances (flashing lights, change in color perception, overbrightness of lights), weakness. The following adverse laboratory changes, in alphabetical order, regardless of incidence or relationship to drug, have been reported in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and all indications): Decreases in blood glucose, BUN, hematocrit, hemoglobin, leukocyte counts, platelet counts, prothrombin time, serum albumin, serum potassium, total serum protein, uric acid. Increases in alkaline phosphatase, ALT (SGPT), AST (SGOT), atypical lymphocyte counts, blood glucose, blood monocytes, BUN, cholesterol, eosinophils counts, LDH, platelet counts, prothrombin time, sedimentation rate, serum amylase, serum bilirubin, serum calcium, serum cholesterol, serum creatinine phosphokinase, serum creatinine, serum gamma-glutamyl transpeptidase (GGT), serum potassium, serum theophylline (in patients receiving theophylline concomitantly), serum triglycerides, uric acid. Others: albuminuria, change in serum phenytoin, crystalluria, cylindruria, immature WBCs, leukocytosis, methemaglobinemia, pancytopenia. DRUG INTERACTIONS Theophylline As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline, which may result in an increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, serum concentrations of theophylline should be monitored and dosage adjustments made as appropriate [see WARNINGS AND PRECAUTIONS]. Antacids and Other Products Containing Multivalent Cations Concurrent administration of quinolones, including ciprofloxacin, with multivalent cation-containing products such as magnesium or aluminum antacids, sucralfate, VIDEX® chewable/buffered tablets or pediatric powder, or products containing calcium, iron, or zinc may substantially decrease the absorption of ciprofloxacin. Proquin XR (ciprofloxacin hcl) should be given either 2 hours after or at least 4 hours before these products. This time window is different than for other oral formulations of ciprofloxacin, which are usually administered 2 hours before or 6 hours after antacids [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Calcium-containing Beverages Concomitant administration of ciprofloxacin with milk products or calcium-fortified juices alone should be avoided since decreased absorption of Proquin XR is possible [see DOSAGE AND ADMINISTRATION]. Warfarin Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be monitored if Proquin XR (ciprofloxacin hcl) is administered concomitantly with warfarin or other oral anticoagulants. Patients should also be monitored for evidence of bleeding [see ADVERSE REACTIONS  and CLINICAL PHARMACOLOGY]. Cyclosporine Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly. Cyclosporine whole blood trough concentrations should be monitored when given concomitantly with Proquin XR (ciprofloxacin hcl) . Methotrexate Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma concentrations of methotrexate. This might increase the risk of methotrexate toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated. Phenytoin Altered serum concentrations of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin. Phenytoin serum concentrations should be monitored when given concomitantly with Proquin XR (ciprofloxacin hcl) . Glyburide The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia. Non-steroidal Anti-inflammatory Drugs (NSAIDs), but not Aspirin NSAIDs in combination with very high doses of quinolones have been shown to provoke convulsions in nonclinical studies [see Nonclinical Toxicology. Caffeine Some quinolones, including ciprofloxacin, have been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and prolongation of the serum half-life of caffeine. Probenecid Probenecid interferes with renal tubular secretion of ciprofloxacin and produces increased concentrations of ciprofloxacin in serum.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Tendinopathy and Tendon Rupture Fluoroquinolones, including Proquin XR (ciprofloxacin hcl) , are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Proquin XR (ciprofloxacin hcl) should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug [see ADVERSE REACTIONS]. Exacerbation of Myasthenia Gravis Fluoroquinolones, including Proquin XR (ciprofloxacin hcl) , have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Proquin XR (ciprofloxacin hcl) in patients with known history of myasthenia gravis. [See PATIENT INFORMATION and ADVERSE REACTIONS/Reported Post-Marketing Adverse Events with Other Formulations of Ciprofloxacin]. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including ciprofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. Proquin XR (ciprofloxacin hcl) should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated [see ADVERSE REACTIONS]. Other Serious and Sometimes Fatal Reactions Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis inertstitial nephritis; acute renal insufficiency or failure; hepatitis; jaundice; acute hepatic necrosis or failure; anemia, including hemolytic and apalstic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hemtologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see ADVERSE REACTIONS]. Theophylline Serious and fatal reactions have been reported in patients receiving theophylline concurrently with fluoroquinolones, including ciprofloxacin. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by Proquin XR (ciprofloxacin hcl) cannot be eliminated. If concomitant use cannot be avoided, serum concentrations of theophylline should be monitored and dosage adjustments made as appropriate [see DRUG INTERACTIONS]. Central Nervous System Effects Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause CNS events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. The reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction) [see ADVERSE REACTIONS, DRUG INTERACTIONS]. Clostridium difficile-Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Proquin XR (ciprofloxacin hcl) , and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who represent with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see ADVERSE REACTIONS]. Peripheral Neuropathy Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dyesthesias, and weakness have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position, sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition [see ADVERSE REACTIONS]. Arthropathic Effects in Animals Ciprofloxacin, as with other members of the quinolone class, causes arthropathy and/or chondroplasia in immature dogs. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. The relevance of these findings to the clinical use of ciprofloxacin is unknown. [see Use In Specific Populations, Nonclinical Toxicology]. Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs [see ADVERSE REACTIONS]. Development of Drug Resistant Bacteria Prescribing Proquin XR (ciprofloxacin hcl) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patient Counseling Information See FDA-Approved Medication Guide Use Only for Uncomplicated Urinary Tract Infection Inform patients that Proquin XR (ciprofloxacin hcl) is only approved to treat uncomplicated urinary tract infections and to contact their healthcare provider if they do not feel better or if they develop fever and back pain while or after taking Proquin XR. Tendon Disorders Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue Proquin XR (ciprofloxacin hcl) treatment. The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Myasthenia Gravis Syndrome Fluoroquinolones like Proquin XR (ciprofloxacin hcl) may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if you have any worsening muscle weakness or breathing problems. Hypersensitivity Inform patients that ciprofloxacin may be associated with hypersensitivity reactions; even following a single dose. Instruct patients to discontinue Proquin XR and contact their healthcare provider at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction [see WARNINGS AND PRECAUTIONS]. Convulsions Inform patients that convulsions have been reported in patients taking fluoroquinolones, including ciprofloxacin and to notify their physician before taking this drug if they have a history of convulsions [see WARNINGS AND PRECAUTIONS]. Neurologic Adverse Effects (e.g., dizziness, lightheadedness) Instruct patients to wait to see how they react to Proquin XR (ciprofloxacin hcl) before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination [see WARNINGS AND PRECAUTIONS]. Clostridium difficile-Associated Diarrhea Inform patients that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible [see WARNINGS AND PRECAUTIONS]. Peripheral Neuropathies Advise patients if symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physician [see WARNINGS AND PRECAUTIONS]. Photosensitivity Advise to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking Proquin XR (ciprofloxacin hcl) . If patients need to be outdoors when taking Proquin XR (ciprofloxacin hcl) , instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn like reaction or skin eruption occurs, instruct patients to contact their physician [see WARNINGS AND PRECAUTIONS]. Administration with Food, Fluids, and Concomitant Medications Instruct patients to: Take Proquin XR (ciprofloxacin hcl) with a main meal of the day, preferably the evening meal and not to take more than one Proquin XR (ciprofloxacin hcl) tablet per day, even if a dose is missed. Take Proquin XR (ciprofloxacin hcl) tablets whole. Never split, crush, or chew tablets. Drink fluids liberally while taking Proquin XR (ciprofloxacin hcl) to avoid formation of a highly concentrated urine and crystal formation in the urine. Take Proquin XR (ciprofloxacin hcl) at least 4 hours before or 2 hours after antacids and other multivalent cation-containing products. Aluminum or magnesium-containing antacids, sucralfate, VIDEX® (didanosine) chewable buffered tablets or pediatric powder, metal cations such as iron and calcium, and multivitamin preparations containing zinc reduces the absorption of ciprofloxacin. Avoid taking Proquin XR (ciprofloxacin hcl) with dairy products (like milk or yogurt) or calcium-fortified juices alone, since the absorption of ciprofloxacin may be significantly reduced by these products. However, Proquin XR (ciprofloxacin hcl) may be taken with a meal that contains these products. Drug Interactions Instruct patients to inform their healthcare provider if they are taking theophylline. Proquin XR (ciprofloxacin hcl) may increase the effects of theophylline and some other prescription or over-the-counter medications, when taken concurrently with ciprofloxacin. Instruct patients to inform their healthcare provider if they are taking antacids and other multivalent cation containing prescription or over-the-counter medications. Such products can reduce the absorption of ciprofloxacin [see Administration with Food, Fluids and Concomitant Medications]. Use of Proquin XR (ciprofloxacin hcl) Sample Pack Advise the patient that the sample pack contains only one dose for the first day of treatment with Proquin® XR (ciprofloxacin hcl) . Complete treatment requires 3 doses. The patient must fill a prescription for the remaining two doses. Human Milk Feeding Advise women to avoid feeding their infants with their milk during treatment with Proquin XR (ciprofloxacin hcl) . Women should either discontinue feeding or pump and discard their milk during treatment and for 24 hours after the last dose [see Use in Specific Populations]. Antibacterial Resistance Antibacterial drugs including Proquin XR (ciprofloxacin hcl) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Proquin XR (ciprofloxacin hcl) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Proquin XR (ciprofloxacin hcl) or other antibacterial drugs in the future [see WARNINGS AND PRECAUTIONS]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Rodent carcinogenicity studies were not required. Two in vitro mutagenicity tests were conducted with ciprofloxacin: Bacterial Reverse Mutation Assay; negative for mutagenicity in the presence and absence of an S9 metabolic activation system. Chinese Hamster Ovary (CHO) Chromosomal Aberration Assay; positive for inducing chromosomal aberrations. In addition to the in vitro genotoxicity assays, an in vivo rat micronucleus study with ciprofloxacin was negative. Fertility studies performed with male and female rats at oral doses of ciprofloxacin up to 600 mg/kg/day (approximately 10-fold the recommended 500 mg therapeutic dose based upon body surface area) revealed no evidence of impairment. Use In Specific Populations Pregnancy (Teratogenic Effects. Pregnancy Category C) There are no adequate and well-controlled studies of Proquin XR (ciprofloxacin hcl) in pregnant women. However, human data on more than 500 infants from two controlled cohort studies do not show an increased risk for major congenital malformations overall in infants exposed to ciprofloxacin during the first trimester of pregnancy or at other times during pregnancy. The risks to a developing musculoskeletal system were not fully evaluated. Animal studies in rats and rabbits demonstrated variations or anomalies in fetal skeletal development and increased embryo-fetal mortality. These effects occurred at clinically relevant doses but also in the presence of maternal toxicity. Proquin XR (ciprofloxacin hcl) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A controlled, prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. Following in-utero exposure to fluoroquinolones during embryogenesis, there was no associated 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. Rates of spontaneous abortions, prematurity and low birth weight did not differ between the study groups, and there were no clinically significant musculoskeletal dysfunctions up to one year of age in ciprofloxacin exposed children. A controlled, retrospective cohort study of more than 30,000 infants enrolled in Medicaid included 588 infants exposed to ciprofloxacin during pregnancy (average 8 day exposure), and 439 exposures occurred during the first trimester. Compared to a control group with no antibiotic exposure and a control group with exposure to a nonteratogenic antibiotic commonly used during pregnancy, infants exposed to ciprofloxacin during the first trimester (or other times during pregnancy) did not demonstrate an increased risk for major congenital malformations overall. The study was powered to rule out a two fold increased risk for major malformations. The study was not designed to fully assess abnormal musculoskeletal development. Another prospective observational 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 the background rates for congenital malformations in the general population. There was no specific patterns of congenital abnormalities and no clear adverse reactions due to in-utero exposure to ciprofloxacin. Published data do not suggest increased rates of prematurity, spontaneous abortions, or birth weight in women exposed to ciprofloxacin during pregnancy, but these data are very limited. In embryo/fetal developmental toxicity studies, pregnant rats and rabbits received oral doses of ciprofloxacin up to 600 mg/kg/day in rats and 30 mg/kg/day in rabbits. In rats, fetal skeletal variations occurred at the maternally toxic dose of 600 mg/kg/day (approximately 1.8-fold the recommended 500 mg therapeutic dose based upon plasma AUC measure of systemic exposure). In pregnant rabbits, the maternally toxic 30 mg/kg/day dose resulted in abortions and reductions in body weight gain. Embryo/fetal lethality and skeletal developmental effects also occurred in rabbits at this dose level (approximately 1.2-fold the recommended therapeutic dose based upon body surface area), while the maternally toxic 10 mg/kg/day dose level did not induce embryo/fetal developmental effects. A peri/postnatal developmental toxicity study conducted in pregnant/lactating female rats exhibited no developmental effects in offspring at the highest dose level of 600 mg/kg/day. Both the 300 and 600 mg/kg/day dose levels were maternally toxic to the pregnant dams based upon slight body weight gain reduction. There was no evidence of compound-related fetal malformation in any of the reproductive toxicity studies. Nursing Mothers Ciprofloxacin is excreted in human milk. In one study, ten lactating women received oral ciprofloxacin 750 mg every 12 hours. Peak human milk concentrations of ciprofloxacin following the third dose averaged 3.79 mcg/mL (S.D. 1.26), and these levels decreased to a mean of 0.02 mcg/mL at 24 hours after the third dose. Based on these concentrations, the maximum daily infant dose of ciprofloxacin through human milk is about 0.569 mg/kg per day, about 2.8% of the approved 20 mg/kg dose in children one year of age or older. Because of the potential for serious adverse reactions in infants from ciprofloxacin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of ciprofloxacin to the mother. During short courses of therapy, nursing mothers may express and discard milk. Human milk feeding can resume 24 hours after the last dose of Proquin XR (ciprofloxacin hcl) . Pediatric Use The safety and effectiveness of Proquin XR (ciprofloxacin hcl) in pediatric patients and adolescents less than 18 years of age have not been established. Quinolones, including ciprofloxacin, cause arthropathy in juvenile animals [see Nonclinical Toxicology] Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Proquin XR. 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 Proquin XR (ciprofloxacin hcl) to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue Proquin XR (ciprofloxacin hcl) and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]. Clinical experience with Proquin XR (ciprofloxacin hcl) did not include sufficient number of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Reported clinical experience with other formulations of ciprofloxacin has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is 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 [see CLINICAL PHARMACOLOGY]. In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using Proquin XR with concomitant drugs that can result in prolongation of the QT interval (e.g. class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia). 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 alternate pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. No dosage adjustment is required for patients with mild to moderate renal impairment. The efficacy of Proquin XR (ciprofloxacin hcl) has not been studied in patients with severe renal impairment [see CLINICAL PHARMACOLOGY]. Hepatic Impairment No dosage adjustment is required with Proquin XR (ciprofloxacin hcl) in patients with stable chronic cirrhosis. However, the pharmacokinetics of ciprofloxacin in patients with acute hepatic impairment has not been fully elucidated [see CLINICAL PHARMACOLOGY].