Ciprofloxacin Extended Release Tablets

Ciprofloxacin extended-release tablets are indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below.

Uncomplicated Urinary Tract Infections (Acute Cystitis)

Ciprofloxacin extended-release tablets are indicated for the treatment of uncomplicated urinary tract infections (UTIs) caused by Escherichia coli, Proteus mirabilis, Enterococcus faecalis, or Staphylococcus saprophyticus.

Because fluoroquinolones, including ciprofloxacin extended-release tablets, have been associated with serious adverse reactions [see Warnings and Precautions (5.1 to 5.15)] and for some patients uncomplicated UTI (acute cystitis) is self-limiting, reserve ciprofloxacin extended-release tablets for treatment of uncomplicated UTIs (acute cystitis) in patients who have no alternative treatment options.

Complicated Urinary Tract Infections, and Acute Uncomplicated Pyelonephritis

Ciprofloxacin extended-release tablets are indicated for the treatment of complicated urinary tract infections (cUTI) caused by Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa and acute uncomplicated pyelonephritis (AUP) caused by Escherichia coli.

Limitations of Use

• The safety and efficacy of ciprofloxacin extended-release tablets in treating infections other than urinary tract infections has not been demonstrated. • Ciprofloxacin extended-release tablets are not indicated for pediatric patients.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin extended-release tablets and other antibacterial drugs, ciprofloxacin extended-release tablets should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with ciprofloxacin extended-release tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued.

As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.

Dosage

Ciprofloxacin extended-release tablets and ciprofloxacin immediate-release tablets are not interchangeable. Ciprofloxacin extended-release tablets should be administered orally once daily (Table 1).

Table 1: Dosage Guidelines

Indication	Dose	Frequency	Usual Duration
Uncomplicated Urinary Tract Infection (Acute Cystitis)	500 mg	every 24 hours	3 Days
Complicated Urinary Tract Infection and Acute Uncomplicated Pyelonephritis	1000 mg	every 24 hours	7 to 14 Days

Patients whose therapy is started with ciprofloxacin IV for UTIs may be switched to ciprofloxacin extended-release tablets when clinically indicated at the discretion of the physician.

Administration

• Ciprofloxacin extended-release tablets should be taken whole and not split, crushed, or chewed. • Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate), as well as sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc [see Drug Interactions (7)]. • Concomitant administration of ciprofloxacin extended-release tablets with dairy products (like milk or yogurt) or with calcium-fortified products alone should be avoided since decreased absorption is possible. A 2 hour window between substantial calcium intake (greater than 800 mg) and dosing with ciprofloxacin extended-release tablets is recommended [see Patient Counseling Information (17)]. • Adequate hydration of patients receiving ciprofloxacin extended-release tablets should be maintained to prevent the formation of highly concentrated urine. Crystalluria has been reported with quinolones [see Warnings and Precautions (5.17), Adverse Reactions (6.1) and Patient Counseling Information (17)].

Impaired Renal Function

• In patients with cUTI and acute uncomplicated pyelonephritis with a creatinine clearance of ≤ 30 mL/min, the dose of ciprofloxacin extended-release tablets should be reduced from 1000 mg to 500 mg daily. The use of ciprofloxacin 1000 mg extended-release tablets is not recommended in this patient population. • For patients on hemodialysis or peritoneal dialysis, administer ciprofloxacin extended-release tablets after the dialysis procedure is completed (maximum dose should be ciprofloxacin 500 mg extended-release tablets every 24 hours). The use of ciprofloxacin 1000 mg extended-release tablets is not recommended in this patient population [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. • For patients on continuous ambulatory peritoneal dialysis (CAPD), the maximum dose should be 500 mg every 24 hours.

Uncomplicated Urinary Tract Infections (Acute Cystitis)

Ciprofloxacin extended-release tablets were evaluated for the treatment of uncomplicated UTIs (acute cystitis) in a randomized, double-blind, controlled clinical trial conducted in the U.S. This study compared ciprofloxacin extended-release tablets (500 mg once daily for 3 days) with ciprofloxacin immediate-release tablets (CIPRO® 250 mg two times a day (BID) for 3 days). Of the 905 patients enrolled, 452 were randomly assigned to the ciprofloxacin extended-release tablets treatment group and 453 were randomly assigned to the control group. The primary efficacy variable was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at test-of-cure (Day 4 to 11 Post-therapy).

The bacteriologic eradication and clinical success rates were similar between ciprofloxacin extended-release tablets and the control group. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (ciprofloxacin extended-release tablets minus control group) are given in Table 8:

Table 8: Bacteriological Eradication and Clinical Cure Rates at the Test-of-Cure (TOC) Visit

* The presence of a pathogen at a level of ≥ 105 CFU/mL was required for microbiological evaluability criteria, except for S. saprophyticus (≥ 104 CFU/mL). † n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients ‡ n/N = patients with specified baseline organism eradicated/patients with specified baseline organism § n/N = patients with clinical success/total number of patients
	Ciprofloxacin Extended-Release Tablets 500 mg QD x 3 Days	Ciprofloxacin 250 mg BID x 3 Days
Randomized Patients	452	453
Per Protocol Patients*	199	223
Bacteriologic Eradication at TOC (n/N)†	188/199 (94.5%)	209/223 (93.7%)
	CI [-3.5%, 5.1%]
Bacteriologic Eradication (by organism) at TOC (n/N)‡
E. coli	156/160 (97.5%)	176/181 (97.2%)
E. faecalis	10/11 (90.9%)	17/21 (81%)
P. mirabilis	11/12 (91.7%)	7/7 (100%)
S. saprophyticus	6/7 (85.7%)	9/9 (100%)
Clinical Response at TOC (n/N)§	189/199 (95%)	204/223 (91.5%)
	CI [-1.1%, 8.1%]

Complicated Urinary Tract Infections and Acute Uncomplicated Pyelonephritis

Ciprofloxacin extended-release tablets were evaluated for the treatment of cUTI and acute uncomplicated pyelonephritis (AUP) in a randomized, double-blind, controlled clinical trial conducted in the U.S. and Canada. The study enrolled 1,042 patients (521 patients per treatment arm) and compared ciprofloxacin extended-release tablets (1000 mg once daily for 7 to 14 days) with immediate-release ciprofloxacin (500 mg BID for 7 to 14 days). The primary efficacy endpoint for this trial was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at 5 to 11 days post-therapy (test-of-cure or TOC) for the Per Protocol and Modified Intent-To-Treat (MITT) populations.

The Per Protocol population was defined as patients with a diagnosis of cUTI or AUP, a causative organism(s) at baseline present at ≥ 105 CFU/mL, no inclusion criteria violation, a valid test-of-cure urine culture within the TOC window, an organism susceptible to study drug, no premature discontinuation or loss to follow-up, and compliance with the dosage regimen (among other criteria). More patients in the ciprofloxacin extended-release tablets arm than in the control arm were excluded from the Per Protocol population and this should be considered in the interpretation of the study results. Reasons for exclusion with the greatest discrepancy between the two arms were no valid test-of-cure urine culture, an organism resistant to the study drug, and premature discontinuation due to adverse events.

An analysis of all patients with a causative organism(s) isolated at baseline and who received study medication, defined as the MITT population, included 342 patients in the ciprofloxacin extended-release tablets arm and 324 patients in the control arm. Patients with missing responses were counted as failures in this analysis. In the MITT analysis of cUTI patients, bacteriologic eradication was 160/271 (59%) vs. 156/248 (62.9%) in ciprofloxacin extended-release tablets and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was 184/271 (67.9%) for ciprofloxacin extended-release tablets and 182/248 (73.4%) for control arm, respectively [97.5% CI* (-14.4%, 3.5%)]. Bacterial eradication in the MITT analysis of patients with AUP at TOC was 47/71 (66.2%) and 58/76 (76.3%) for ciprofloxacin extended-release tablets and control arm, respectively [97.5% CI* (-26.8%, 6.5%)]. Clinical cure at TOC was 50/71 (70.4%) for ciprofloxacin extended-release tablets and 58/76 (76.3%) for the control arm [97.5% CI* (-22%, 10.4%)].

* confidence interval of the difference in rates (ciprofloxacin extended-release tablets minus control).

In the Per Protocol population, the differences between ciprofloxacin extended-release tablets and the control arm in bacteriologic eradication rates at the TOC visit were not consistent between AUP and cUTI patients. The bacteriologic eradication rate for cUTI patients was higher in the ciprofloxacin extended-release tablets arm than in the control arm. For AUP patients, the bacteriologic eradication rate was lower in the ciprofloxacin extended-release tablets arm than in the control arm. This inconsistency was not observed between the two treatment groups for clinical cure rates. Clinical cure rates were 96.1% (198/206) and 92.1% (211/229) for ciprofloxacin extended-release tablets and the control arm, respectively [difference: 4% with a two-sided 97.5% CI (-1.3%, 9.4%)].

The bacterial eradication and clinical cure rates by infection type for ciprofloxacin extended-release tablets and the control arm at the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates (ciprofloxacin extended-release tablets minus control arm) are given in Table 9 for the Per Protocol population analysis.

Table 9: Bacteriological Eradication and Clinical Cure Rates at the Test-of-Cure (TOC) Visit

* Patients excluded from the Per Protocol population were primarily those with no causative organism(s) at baseline or no organism present at ≥ 105 CFU/mL at baseline, inclusion criteria violation, no valid test-of-cure urine culture within the TOC window, an organism resistant to study drug, premature discontinuation due to an adverse event, lost to follow-up, or non-compliance with dosage regimen (among other criteria). † n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients ‡ n/N = patients with specified baseline organism eradicated/patients with specified baseline organism § n/N = patients with clinical success/total number of patients
	Ciprofloxacin Extended-Release Tablets 1000 mg QD	Ciprofloxacin 500 mg BID
Randomized Patients	521	521
Per Protocol Patients*	206	229
cUTI Patients
Bacteriologic Eradication at TOC (n/N)†	148/166 (89.2%)	144/177 (81.4%)
	CI [-0.7%, 16.3%]
Bacteriologic Eradication (by organism) at TOC (n/N)‡
E. coli	91/94 (96.8%)	90/92 (97.8%)
K. pneumoniae	20/21 (95.2%)	19/23 (82.6%)
E. faecalis	17/17 (100%)	14/21 (66.7%)
P. mirabilis	11/12 (91.6%)	10/10 (100%)
P. aeruginosa	3/3 (100%)	3/3 (100%)
Clinical Cure at TOC (n/N)§	159/166 (95.8%)	161/177 (91%)
	CI [-1.1%, 10.8%]
AUP Patients
Bacteriologic Eradication at TOC (n/N)†	35/40 (87.5%)	51/52 (98.1%)
	CI [-34.8%, 6.2%]
Bacteriologic Eradication of E. coli	35/36 (97.2%)	41/41 (100%)
Clinical Cure at TOC (n/N)§	39/40 (97.5%)	50/52 (96.2%)
	CI [-15.3%, 21.1%]

Of the 166 cUTI patients treated with ciprofloxacin extended-release tablets, 148 (89%) had the causative organism(s) eradicated, 8 (5%) had persistence, 5 (3%) patients developed superinfections and 5 (3%) developed new infections. Of the 177 cUTI patients treated in the control arm, 144 (81%) had the causative organism(s) eradicated, 16 (9%) patients had persistence, 3 (2%) developed superinfections and 14 (8%) developed new infections. Of the 40 patients with AUP treated with ciprofloxacin extended-release tablets, 35 (87.5%) had the causative organism(s) eradicated, 2 (5%) patients had persistence and 3 (7.5%) developed new infections. Of the five ciprofloxacin extended-release tablets AUP patients without eradication at TOC, four were considered clinical cures and did not receive alternative antibiotic therapy. Of the 52 patients with AUP treated in the control arm, 51 (98%) had the causative organism(s) eradicated. One patient (2%) had persistence.

• It is used to treat or prevent bacterial infections.

• If you have an allergy to ciprofloxacin or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Long QTc on ECG or other heartbeat that is not normal, slow heartbeat, or low potassium or magnesium levels.
• If you have kidney problems.
• If you have heart failure (weak heart).
• If you have had a recent heart attack.
• If you have ever had any of these health problems: Nerve problems or tendon problems.
• If you have had tendons get irritated or torn when taking this medicine (ciprofloxacin extended-release tablets) or an alike drug in the past.
• If you have been taking any drugs to treat a heartbeat that is not normal.
• If you are taking any drugs that can cause a certain type of heartbeat that is not normal (prolonged QT interval). There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are taking any of these drugs: Duloxetine, theophylline, tizanidine, or zolpidem.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine (ciprofloxacin extended-release tablets) with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine (ciprofloxacin extended-release tablets) affects you.
• Have your blood work checked if you are on this medicine for a long time. Talk with your doctor.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Tell your doctor if you have signs of high or low blood sugar like breath that smells like fruit, dizziness, fast breathing, fast heartbeat, feeling confused, feeling sleepy, feeling weak, flushing, headache, more thirsty or hungry, passing urine more often, shaking, or sweating.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this medicine (ciprofloxacin extended-release tablets) with your other drugs.
• Do not use longer than you have been told. A second infection may happen.
• Tell your doctor if you take a drug that has caffeine, or you eat or drink products that have caffeine, like tea, coffee, cola, or chocolate.
• You may get sunburned more easily. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.
• Very bad and sometimes deadly allergic side effects have rarely happened. Talk with your doctor.
• Rarely, very bad and sometimes deadly effects have happened with this medicine. These include muscle or joint, kidney, liver, blood, and other problems. Talk with the doctor if you have questions.
• A type of abnormal heartbeat (prolonged QT interval) can happen with this medicine (ciprofloxacin extended-release tablets). Call your doctor right away if you have a fast heartbeat, a heartbeat that does not feel normal, or if you pass out.
• If you are over the age of 60, use this medicine with care. You could have more side effects.
• Use care in children younger than 18 years of age. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine (ciprofloxacin extended-release tablets) while you are pregnant.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.