Ciprofloxacin (ciprofloxacin hydrochloride 500 mg) Dailymed

Ciprofloxacin tablets are a fluoroquinolone antibacterial indicated in adults (≥ 18 years of age) with the following infections caused by designated, susceptible bacteria and in pediatric patients where indicated.

• Skin and Skin Structure Infections ( 1.1)
• Bone and Joint Infections ( 1.2)
• Complicated Intra-Abdominal Infections ( 1.3)
• Infectious Diarrhea ( 1.4)
• Typhoid Fever (Enteric Fever) ( 1.5)
• Uncomplicated Cervical and Urethral Gonorrhea ( 1.6)
• Inhalational Anthrax post-exposure in adult and pediatric patients ( 1.7)
• Plague in Adult and Pediatric Patients ( 1.8)
• Chronic Bacterial Prostatitis ( 1.9)
• Lower Respiratory Tract Infections ( 1.10)
  • Acute Exacerbation of Chronic Bronchitis
• Urinary Tract Infections ( 1.11)
  • Urinary Tract Infections (UTI)
  • Acute Uncomplicated Cystitis
  • Complicated UTI and Pyelonephritis in Pediatric Patients
• Acute Sinusitis ( 1.12)
•  

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin tablets and other antibacterial drugs, ciprofloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.13)

1.1Skin and Skin Structure Infections

Ciprofloxacin tablets are indicated in adult patients for treatment of skin and skin structure infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.

1.2Bone and Joint Infections

Ciprofloxacin tablets are indicated in adult patients for treatment of bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.

1.3Complicated Intra-Abdominal Infections

Ciprofloxacin tablets are indicated in adult patients for treatment of complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.

1.4 Infectious Diarrhea

Ciprofloxacin tablets are 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 tablets are 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 tablets are indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae [see Warnings and Precautions (5.16)].

1.7 Inhalational Anthrax (Post-Exposure)

Ciprofloxacin tablets are indicated in adults and pediatric patients from birth to 17 years of age for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication. ¹ 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 tablets are 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 tablets are indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis.

1.10 Lower Respiratory Tract Infections

Ciprofloxacin tablets are indicated in adult patients for treatment of lower respiratory tract infections caused by or Ciprofloxacin tablets are indicated in adult patients for treatment of lower respiratory tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae.

Ciprofloxacin tablets are not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to . Ciprofloxacin tablets are not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.

Ciprofloxacin tablets are indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by Ciprofloxacin tablets are indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by Moraxella catarrhalis.

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

1.11 Urinary Tract Infections

Ciprofloxacin tablets are indicated in adult patients for treatment of urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter koseri, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.

Ciprofloxacin tablets are indicated in adult female patients for treatment of acute uncomplicated cystitis caused by or Ciprofloxacin tablets are indicated in adult female patients for treatment of acute uncomplicated cystitis caused by Escherichia coli or Staphylococcus saprophyticus.

Because fluoroquinolones, including ciprofloxacin tablets, have been associated with serious adverse reactions [see Warnings and Precautions (5.1 to 5.15)] 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.

Ciprofloxacin tablets are indicated in pediatric patients aged 1 to 17 years of age for treatment of complicated urinary tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Use in Specific Populations (8.4)] .

• Although effective in clinical trials, ciprofloxacin tablets are not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues . Ciprofloxacin tablets, like other fluoroquinolones, are associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions (5.12), Adverse Reactions (6.1), Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)].

1.12 Acute Sinusitis

Ciprofloxacin tablets are indicated in adult patients for treatment of acute sinusitis caused by or Ciprofloxacin tablets are indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.

Because fluoroquinolones, including ciprofloxacin tablets, have been associated with serious adverse reactions [see Warnings and Precautions (5.1 to 5.15 )] and for some patients acute sinusitis is self-limiting, reserve ciprofloxacin tablets 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 tablets and other antibacterial drugs, ciprofloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with ciprofloxacin tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued.

As with other drugs, some isolates of Pseudomonas aeruginosa 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.

2 Dosage And Administration

Ciprofloxacin tablets should be administered orally as described in the appropriate Dosage Guidelines tables.

Adult Dosage Guidelines
Infection	Dose	Frequency	Duration
Skin and Skin Structure	500 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 (Post-Exposure)	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 and Pyelonephritis (1 to 17 years of age)	10 mg/kg to 20 mg/kg (maximum 750 mg per dose)	Every 12 hours	10 to 21 days
Inhalational Anthrax (Post-Exposure)	15 mg/kg (maximum 500 mg per dose)	Every 12 hours	60 days
Plague	15 mg/kg (maximum 500 mg per dose)	Every 8 to 12 hours	10 to 21 days

2.1Dosage 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.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.

Table 1: Adult Dosage Guidelines

Infection	Dose	Frequency	Usual Durations 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).
Skin and Skin Structure Skin and Skin Structure	500 mg to 750 mg500 mg to 750 mg	every 12 hoursevery 12 hours	7 to 14 days7 to 14 days
Bone and Joint Bone and Joint	500 mg to 750 mg500 mg to 750 mg	every 12 hoursevery 12 hours	4 to 8 weeks4 to 8 weeks
Complicated Intra–Abdominal Complicated Intra–Abdominal Used in conjunction with metronidazole.	500 mg500 mg	every 12 hoursevery 12 hours	7 to 14 days7 to 14 days
Infectious Diarrhea Infectious Diarrhea	500 mg500 mg	every 12 hoursevery 12 hours	5 to 7 days5 to 7 days
Typhoid Fever Typhoid Fever	500 mg500 mg	every 12 hoursevery 12 hours	10 days10 days
Uncomplicated Urethral and Cervical Gonococcal Infections Uncomplicated Urethral and Cervical Gonococcal Infections	250 mg250 mg	single dosesingle dose	single dosesingle dose
Inhalational Anthrax (Post-Exposure) Inhalational Anthrax (Post-Exposure) Begin drug administration as soon as possible after suspected or confirmed exposure.	500 mg500 mg	every 12 hoursevery 12 hours	60 days60 days
Plague Plague	500 mg to 750 mg500 mg to 750 mg	every 12 hoursevery 12 hours	14 days14 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

Patients whose therapy is started with ciprofloxacin IV may be switched to ciprofloxacin tablets or oral suspension 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  IV Dosage
250 mg Tablet every 12 hours	200 mg intravenous every 12 hours
500 mg Tablet every 12 hours	400 mg intravenous every 12 hours
750 mg Tablet every 12 hours	400 mg intravenous every 8 hours

2.2 Dosage in Pediatric Patients

Dosing and initial route of therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined by the severity of the infection. Ciprofloxacin tablets should be administered as described in Table 3. Dosing and initial route of therapy (that is, IV or oral) for cUTI or pyelonephritis should be determined by the severity of the infection. Ciprofloxacin tablets should be administered as described in Table 3.

Table 3: Pediatric Dosage Guidelines

Infection	Dose	Frequency	Total Duration
Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age)	10 mg/kg to 20 mg/kg (maximum 750 mg per dose; not to be exceeded even in patients weighing more than 51 kg)	Every 12 hours	10 to 21 days 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).
Inhalational Anthrax (Post-Exposure) Begin drug administration as soon as possible after suspected or confirmed exposure.	15 mg/kg (maximum 500 mg per dose)	Every 12 hours	60 days
Plague Begin drug administration as soon as possible after suspected or confirmed exposure to Y. pestis.	15 mg/kg (maximum 500 mg per dose)	Every 8 to 12 hours	10 to 21 days

      

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:

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

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.

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.

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)].

• 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)
• Clostridium difficile-associated diarrhea: Evaluate if colitis occurs. ( 5.10)
• 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. ( 5.11, 7, 8.5)

5.1Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

Fluoroquinolones, including ciprofloxacin tablets, 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 tablets, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2Tendinitis and Tendon Rupture

Fluoroquinolones, including ciprofloxacin tablets, 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 tablets, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture [see Adverse Reactions (6.2)] .

5.3Peripheral Neuropathy

Fluoroquinolones, including ciprofloxacin tablets, 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 tablets. 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 tablets, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6.1, 6.2)] .

5.4Central Nervous System Effects

Fluoroquinolones, including ciprofloxacin tablets, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis. Ciprofloxacin tablets may also cause central nervous system (CNS) events including: nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and psychotic reactions have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin tablets to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care. Ciprofloxacin tablets, like other fluoroquinolones, are known to trigger seizures or lower the seizure threshold. As with all fluoroquinolones, use ciprofloxacin tablets 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). Use ciprofloxacin tablets when the benefits of treatment exceed the risks, since these patients are endangered because of possible undesirable CNS side effects. Cases of status epilepticus have been reported. If seizures occur, discontinue ciprofloxacin tablets [see Adverse Reactions (6.1) and Drug Interactions (7)] .

5.5Exacerbation of Myasthenia Gravis

Fluoroquinolones, including ciprofloxacin tablets, 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 tablets in patients with known history of myasthenia gravis [see Adverse Reactions (6.2)] .

5.6Other 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 tablets. 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)] .

5.7Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including ciprofloxacin tablets. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, including intubation, as indicated [see Adverse Reactions (6.1)] .

5.8 Hepatotoxicity

Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin tablets. Acute liver injury is rapid in onset (range 1 to 39 days), and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic, or mixed. Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment immediately.

There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin tablets [see Adverse Reactions (6.2, 6.3)].

5.9Serious Adverse Reactions with Concomitant Theophylline

Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin tablets and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have also occurred.

Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin tablets cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Drug Interactions (7)] .

5.10 -Associated Diarrhea

Clostridium difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin tablets, 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 isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated [see Adverse Reactions (6.1)] .

5.11Prolongation of the QT Interval

Some fluoroquinolones, including ciprofloxacin tablets have been associated with prolongation of the QT interval on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin tablets.

Avoid ciprofloxacin tablets in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example, congenital long QT syndrome, uncorrected electrolyte imbalance, such as hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients may also be more susceptible to drug-associated effects on the QT interval [see Adverse Reactions (6.2), Use in Specific Populations (8.5)] .

5.12Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

Ciprofloxacin tablets are indicated in pediatric patients (less than 18 years of age) only for cUTI, prevention of inhalational anthrax (post exposure), and plague [see Indications and Usage (1.7, 1.8, 1.11)] . An increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues, has been observed [see Adverse Reactions (6.1)] .

In pre-clinical studies, oral administration of ciprofloxacin tablets caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)] .

5.13Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, bulering, 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 including ciprofloxacin tablets after sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue ciprofloxacin tablets if phototoxicity occurs [see Adverse Reactions (6.1)] .

5.14Development of Drug Resistant Bacteria

Prescribing ciprofloxacin tablets 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.

5.15Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2 Enzymes

Ciprofloxacin tablets are an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of ciprofloxacin tablets and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the co-administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-administered drug [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .

5.16Interference with Timely Diagnosis of Syphilis

Ciprofloxacin tablets have not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. Perform a serologic test for syphilis in all patients with gonorrhea at the time of diagnosis. Perform follow-up serologic test for syphilis 3 months after ciprofloxacin tablets treatment.

5.17Crystalluria

Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline [see Nonclinical Toxicology (13.2)]. Crystalluria related to ciprofloxacin tablets has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving ciprofloxacin tablets. Hydrate patients well to prevent the formation of highly concentrated urine [see Dosage and Administration (2.4)] .

6 Adverse Reactions

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions (5.1)]
• Tendinitis and Tendon Rupture [see Warnings and Precautions (5.2)]
• Peripheral Neuropathy [see Warnings and Precautions (5.3)]
• Central Nervous System Effects [see Warnings and Precautions (5.4)]
• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.5)]
• Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions (5.6)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
• Hepatotoxicity [see Warnings and Precautions (5.8)]
• Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions (5.9)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.10)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.11)]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.12)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.13)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.14)]

The most common adverse reactions ≥ 1% were nausea, diarrhea, liver function tests abnormal, vomiting, and rash. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials 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.

During clinical investigations with oral and parenteral ciprofloxacin, 49,038 patients received courses of the drug.

The most frequently reported adverse reactions, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).

Table 6: Medically Important Adverse Reactions That Occurred In Less Than 1% of Ciprofloxacin Patients

System Organ Class	Adverse Reactions
Body as a Whole	Headache Abdominal Pain/Discomfort Pain
Cardiovascular	Syncope Angina Pectoris Myocardial Infarction Cardiopulmonary Arrest Tachycardia Hypotension
Central Nervous System	Restlessness Dizziness Insomnia Nightmares Hallucinations Paranoia Psychosis (toxic) Manic Reaction Irritability Tremor Ataxia Seizures (including Status Epilepticus) Malaise Anorexia Phobia Depersonalization Depression (potentially culminating in self-injurious behavior (such as suicidal ideations/thoughts and attempted or completed suicide) Paresthesia Abnormal Gait Migraine
Gastrointestinal	Intestinal Perforation Gastrointestinal Bleeding Cholestatic Jaundice Hepatitis Pancreatitis
Hemic/Lymphatic	Petechia
Metabolic/Nutritional	Hyperglycemia Hypoglycemia
Musculoskeletal	Arthralgia Joint Stiffness Muscle Weakness
Renal/Urogenital	Interstitial Nephritis Renal Failure
Respiratory	Dyspnea Laryngeal Edema Hemoptysis Bronchospasm
Skin/Hypersensitivity	Anaphylactic Reactions including life-threatening anaphylactic shock Erythema Multiforme/Stevens-Johnson Syndrome Exfoliative Dermatitis Toxic Epidermal Necrolysis Pruritus Urticaria Photosensitivity/Phototoxicity reaction Flushing Fever Angioedema Erythema Nodosum Sweating
Special Senses	Blurred Vision Disturbed Vision (chromatopsia and photopsia) Decreased Visual Acuity Diplopia Tinnitus Hearing Loss Bad Taste

In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets [500 mg two times daily (BID)] to cefuroxime axetil (250 mg to 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin tablets demonstrated a CNS adverse reaction profile comparable to the control drugs.

Short (6 weeks) and long term (1 year) musculoskeletal and neurological safety of oral/intravenous ciprofloxacin, was compared to a cephalosporin for treatment of cUTI or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years) in an international multicenter trial. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled.

An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse reactions including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6 weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9.3% (31/335) in the ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse reaction and on more than one occasion compared to control patients. The rate of musculoskeletal adverse reactions was consistently higher in the ciprofloxacin group compared to the control group across all age subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated patients (Table 7).

Table 7: Musculoskeletal Adverse Reactions Included: arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint (knee, elbow, ankle, hip, wrist, and shoulder) as Assessed by the IPSC

	Ciprofloxacin Tablets	Comparator
All Patients (within 6 weeks)	31/335 (9.3%)	21/349 (6%)
95% Confidence Interval The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could not be concluded that the ciprofloxacin group had findings comparable to the control group.	(-0.8%, +7.2%)
Age Group
12 months < 24 months	1/36 (2.8%)	0/41
2 years < 6 years	5/124 (4%)	3/118 (2.5%)
6 years < 12 years	18/143 (12.6%)	12/153 (7.8%)
12 years to 17 years	7/32 (21.9%)	6/37 (16.2%)
All Patients (within 1 year)	46/335 (13.7%)	33/349 (9.5%)
95% Confidence Interval	(-0.6%, + 9.1%)

The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3% (9/335) in the ciprofloxacin tablets group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence.

In this trial, the overall incidence rates of adverse reactions within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most frequent adverse reactions were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse reactions were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse reaction was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other adverse reactions that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.

Short-term safety data for ciprofloxacin was also collected in a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 to 17 years). Sixty seven patients received ciprofloxacin IV 10 mg/kg/dose every 8 hours for 1 week followed by ciprofloxacin tablets 20 mg/kg/dose every 12 hours to complete 10 to 21 days treatment and 62 patients received the combination of ceftazidime intravenous 50 mg/kg/dose every 8 hours and tobramycin intravenous 3 mg/kg/dose every 8 hours for a total of 10 to 21 days. Periodic musculoskeletal assessments were conducted by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0 to 93 days). Musculoskeletal adverse reactions were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse reactions were similar in nature and frequency between treatment arms. The efficacy of ciprofloxacin tablets for the treatment of acute pulmonary exacerbations in pediatric cystic fibrosis patients has not been established.

In addition to the adverse reactions reported in pediatric patients in clinical trials, it should be expected that adverse reactions reported in adults during clinical trials or postmarketing experience may also occur in pediatric patients.

6.2Postmarketing Experience

The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure (Table 8).

Table 8: Postmarketing Reports of Adverse Drug Reactions

System Organ Class	Adverse Reactions
Cardiovascular	QT prolongation Torsade de Pointes Vasculitis and ventricular arrhythmia
Central Nervous System	Hypertonia Myasthenia Exacerbation of myasthenia gravis Peripheral neuropathy Polyneuropathy Twitching
Eye Disorders	Nystagmus
Gastrointestinal	Pseudomembranous colitis
Hemic/Lymphatic	Pancytopenia (life-threatening or fatal outcome) Methemoglobinemia
Hepatobiliary	Hepatic failure (including fatal cases)
Infections and Infestations	Candidiasis (oral, gastrointestinal, vaginal)
Investigations	Prothrombin time prolongation or decrease Cholesterol elevation (serum) Potassium elevation (serum)
Musculoskeletal	Myalgia Myoclonus Tendinitis Tendon rupture
Psychiatric Disorders	Agitation Confusion Delirium
Skin/Hypersensitivity	Acute generalized exanthematous pustulosis (AGEP) Fixed eruption Serum sickness-like reaction
Special Senses	Anosmia Hyperesthesia Hypesthesia Taste loss

6.3Adverse Laboratory Changes

Changes in laboratory parameters while on ciprofloxacin tablets are uled below:

Hepatic: Elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin.

Hematologic: Eosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, pancytopenia.

Renal: Elevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have been reported.

Other changes occurring were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, and leukocytosis.