Ciprofloxacin

CIPRO is a fluoroquinolone antibacterial indicated in adults (18 years of age and older) with the following infections caused by designated, susceptible bacteria and in pediatric patients where indicated:

• Skin and Skin Structure Infections ( 1.1 )
• Bone and Joint Infections ( 1.2 )
• Complicated Intra-Abdominal Infections ( 1.3 )
• Infectious Diarrhea ( 1.4 )
• Typhoid Fever (Enteric Fever) ( 1.5 )
• Uncomplicated Cervical and Urethral Gonorrhea ( 1.6 )
• Inhalational Anthrax post-exposure in adult and pediatric patients ( 1.7)
• Plague in adult and pediatric patients ( 1.8 )
• Chronic Bacterial Prostatitis ( 1.9 )
• Lower Respiratory Tract Infections ( 1.10 )
• Acute Exacerbation of Chronic Bronchitis
• Urinary Tract Infections ( 1.11 )
• Urinary Tract Infections (UTI)
• Acute Uncomplicated Cystitis
• Complicated UTI and Pyelonephritis in Pediatric Patients
• Acute Sinusitis ( 1.12 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO and other antibacterial drugs, CIPRO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.13 )

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

1.2 Bone and Joint Infections CIPRO is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.

1.3 Complicated Intra-Abdominal Infections CIPRO is indicated in adult patients for treatment of complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.

1.4 Infectious Diarrhea CIPRO is indicated in adult patients for treatment of infectious diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii † , Shigella dysenteriae, Shigella flexneri or Shigella sonnei † when antibacterial therapy is indicated. † Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients.

1.5 Typhoid Fever (Enteric Fever) CIPRO is indicated in adult patients for treatment of typhoid fever (enteric fever ) caused by Salmonella typhi. The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated.

1.6 Uncomplicated Cervical and Urethral Gonorrhea CIPRO is indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae [see Warnings and Precautions ( 5.17 )].

1.7 Inhalational Anthrax (Post-Exposure) CIPRO is indicated in adults and pediatric patients from birth to 17 years of age for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication. 1 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001 [see Clinical Studies ( 14.2 )].

1.8 Plague CIPRO is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17 years of age. Efficacy studies of ciprofloxacin could not be conducted in humans with plague for feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [see Clinical Studies ( 14.3 )] .

1.9 Chronic Bacterial Prostatitis CIPRO is indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis.

1.10 Lower Respiratory Tract Infections CIPRO is indicated in adult patients for treatment of lower respiratory tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. CIPRO is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. CIPRO is indicated for the treatment of acute exacerbations of chronic bronchitis (AECB) caused by Moraxella catarrhalis. Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1–5.16 )] and for some patients AECB is self-limiting, reserve CIPRO for treatment of AECB in patients who have no alternative treatment options .

1.11 Urinary Tract Infections Urinary Tract Infections in Adults CIPRO is indicated in adult patients for treatment of urinary tract infections caused by Escherichia coli , Klebsiella pneumoniae , Enterobacter cloacae , Serratia marcescens , Proteus mirabilis , Providencia rettgeri , Morganella morganii , Citrobacter koseri , Citrobacter freundii , Pseudomonas aeruginosa , methicillin-susceptible Staphylococcus epidermidis , Staphylococcus saprophyticus , or Enterococcus faecalis . Acute Uncomplicated Cystitis CIPRO is indicated in adult female patients for treatment of acute uncomplicated cystitis caused by Escherichia coli or Staphylococcus saprophyticus. Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions [see Warnings and Precautions ( 5 .1-5.16)] and for some patients acute uncomplicated cystitis is self-limiting, reserve CIPRO for treatment of acute uncomplicated cystitis in patients who have no alternative treatment options. Complicated Urinary Tract Infection and Pyelonephritis in Pediatric Patients CIPRO is indicated in pediatric patients aged one to 17 years of age for treatment of complicated urinary tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Use in Specific Populations ( 8.4 )] . Although effective in clinical trials, CIPRO is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues . CIPRO, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions ( 5.13 ), Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.4 ) and Nonclinical Toxicology ( 13.2 )].

1.12 Acute Sinusitis CIPRO is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis. Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1-5.16 )] and for some patients acute sinusitis is self-limiting, reserve CIPRO 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 CIPRO and other antibacterial drugs, CIPRO 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. […]

• Tablets: 250 mg, functionally scored and 500 mg, functionally scored ( 3 )
• Oral Suspension: 5% (250 mg/5 mL), 10% (500 mg/5 mL) (3 )

3.1 Tablets

• 250 mg, slightly yellowish, film-coated, round, functionally scored, imprinted with “BAYER” on one side and “CIP 250” on the other
• 500 mg, slightly yellowish, film-coated, capsule shaped, functionally scored, imprinted with “BAYER” on one side and “CIP 500” on the other

3.2 Oral Suspension

• 5% Oral Suspension: 250 mg ciprofloxacin per 5 mL after reconstitution
• 10% Oral Suspension: 500 mg ciprofloxacin per 5 mL after reconstitution

• Known hypersensitivity to CIPRO or other quinolones ( 4.1 , 5.6 , 5.7)
• Concomitant administration with tizanidine ( 4.2 )

4.1 Hypersensitivity CIPRO is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components [see Warnings and Precautions ( 5.7 )].

4.2 Tizanidine Concomitant administration with tizanidine is contraindicated [see Drug Interactions ( 7 )].

• Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions (for example, anaphylactic reactions) may occur after the first or subsequent doses of CIPRO. Discontinue CIPRO at the first sign of skin rash, jaundice or any sign of hypersensitivity. ( 4.1 , 5.6 , 5.7 )
• Hepatotoxicity: Discontinue immediately if signs and symptoms of hepatitis occur. ( 5.8 )
• Clostridioides difficile -associated diarrhea: Evaluate if colitis occurs. ( 5.11 )
• QT Prolongation: Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval. ( 5.12 , 7 , 8.5 )

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including CIPRO, 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 CIPRO. 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 CIPRO immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including CIPRO, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including CIPRO, 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 CIPRO, 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 CIPRO immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including CIPRO, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture [see Adverse Reactions ( 6.2 )].

5.3 Peripheral Neuropathy Fluoroquinolones, including CIPRO, 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 CIPRO. Symptoms may occur soon after initiation of CIPRO and may be irreversible in some patients [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 , 6.2 )] . Discontinue CIPRO 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 CIPRO, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions ( 6.1 , 6.2 )].

5.4 Central Nervous System Effects Psychiatric Adverse Reactions Fluoroquinolones, including CIPRO, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations, or paranoia; depression, or self-injurious behavior such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These reactions may occur following the first dose. Advise patients receiving CIPRO to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care. Central Nervous System Adverse Reactions Fluoroquinolones, including CIPRO, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pscudotumor cerebri), dizziness, and tremors. CIPRO, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. As with all fluoroquinolones, use CIPRO with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). If seizures occur, discontinue CIPRO and institute appropriate care [see Adverse Reactions ( 6.1 ) and Drug Interactions ( 7 )].

5.5 Exacerbation of Myasthenia Gravis Fluoroquinolones, including CIPRO, 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 CIPRO in patients with known history of myasthenia gravis [see Adverse Reactions ( 6.2 )].

5.6 Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including CIPRO. 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 CIPRO immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Adverse Reactions ( 6.1 , 6.2 )].

5.7 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including CIPRO. […]

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 )]
• Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions ( 5.9 )]
• Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions ( 5.10) ]
• Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.11 )]
• Prolongation of the QT Interval [see Warnings and Precautions ( 5.12 )]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5.13 )]
• Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.14 )]
• Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.15 )] The most common adverse reactions ≥1% were nausea, diarrhea, liver function tests abnormal, vomiting, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical 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. Adult Patients During clinical investigations with oral and parenteral CIPRO, 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 8: 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 CIPRO tablets [500 mg two times daily (BID)] to cefuroxime axetil (250 mg–500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, CIPRO demonstrated a CNS adverse reaction profile comparable to the control drugs. Pediatric Patients Short (6 weeks) and long term (1 year) musculoskeletal and neurological safety of oral/intravenous ciprofloxacin, was compared to a cephalosporin for treatment of cUTI or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years) in an international multicenter trial. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled. An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse reactions including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6 weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9.3% (31/335) in the ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse reaction and on more than one occasion compared to control patients. The rate of musculoskeletal adverse reactions was consistently higher in the ciprofloxacin group compared to the control group across all age subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated patients (Table 9). Table 9: 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 CIPRO 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 CIPRO 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%. […]

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of CIPRO with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug. Table 11: Drugs That are Affected by and Affecting CIPRO Drugs That are Affected by CIPRO Drug(s) Recommendation Comments Tizanidine Contraindicated Concomitant administration of tizanidine and CIPRO is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 ) ] Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of CIPRO with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions ( 5.10 )]. Drugs Known to Prolong QT Interval Avoid Use CIPRO may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.12 ) and Use in Specific Populations ( 8.5 )]. Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when CIPRO and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when CIPRO is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1 )]. Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO with phenytoin. Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when CIPRO is co-administered with cyclosporine. Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO with an oral anti-coagulant (for example, warfarin). Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO therapy is indicated. Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO [see Warnings and Precautions ( 5.16 )]. Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO are advised. NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology ( 12.3 ) ] . Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life CIPRO inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. Zolpidem Avoid Use Co-administration with ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended Drug(s) Affecting Pharmacokinetics of CIPRO Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) CIPRO should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 )]. Decrease CIPRO absorption, resulting in lower serum and urine levels Probenecid Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels) Potentiation of CIPRO toxicity may occur. Interacting Drug Interaction Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7 ) Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7 ) Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7 ) Phenytoin Monitor phenytoin level ( 7 ) Methotrexate Monitor for methotrexate toxicity ( 7 ) Cyclosporine May increase serum creatinine. Monitor serum creatinine ( 7 ) Multivalent cation-containing products including antacids, metal cations or didanosine Decreased CIPRO absorption. Take CIPRO 2 hours before or 6 hours after administration of multivalent cation containing drugs ( 7 )

Lactation: Breastfeeding is not recommended during treatment, but a lactating woman may pump and discard breastmilk during treatment and an additional 2 days after the last dose. In patients treated for inhalational anthrax (post exposure), consider the risks and benefits of continuing breastfeeding. ( 8.2 ) See full prescribing information for use in pediatric and geriatric patients ( 8.4 , 8.5 )

8.1 Pregnancy Risk Summary Prolonged experience with ciprofloxacin in pregnant women over several decades, based on available published information from case reports, case control studies and observational studies on ciprofloxacin administered during pregnancy, have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data) . Oral administration of ciprofloxacin during organogenesis at doses up to 100 mg/kg to pregnant mice and rats, and up to 30 mg/kg to pregnant rabbits did not cause fetal malformations (see Data). These doses were up to 0.3, 0.6, and 0.4 times the maximum recommended clinical oral dose in mice, rats, and rabbits, respectively, based on body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective observational studies over several decades have not established an association with ciprofloxacin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available studies have methodological limitations including small sample size and some of them are not specific for ciprofloxacin. A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children. Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin. No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. Animal Data Developmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. In rats and mice, oral doses up to 100 mg/kg administered during organogenesis (Gestation Days, GD, 6-17) were not associated with adverse developmental outcomes, including embryofetal toxicity or malformations. In rats and mice, a 100 mg/kg dose is approximately 0.6 and 0.3 times the maximum daily human oral dose (1500 mg/day) based upon body surface area, respectively. In a series of rabbit developmental toxicology studies, does received oral or intravenous ciprofloxacin for one of the following 5 day periods: GD 6 to 10, GD 10 to 14, or GD 14 to 18, intended to cover the period of organogenesis. This was an attempt to mitigate the gastrointestinal intolerance observed in rabbits that receive antibacterials manifested by reduced maternal food consumption and weight loss, that can lead to embryofetal resorption or spontaneous abortion. An oral ciprofloxacin dose of 100 mg/kg (approximately 1.3 times the highest recommended clinical oral dose based on body surface area) caused excessive maternal toxicity confounding evaluation of the fetuses. A 30 mg/kg oral dose (approximately 0.4 times the highest recommended clinical oral dose) was associated with suppression of maternal and fetal body weight gain, but fetal malformations were not observed. Intravenous administration of doses up to 20 mg/kg (approximately 0.3 times the highest recommended clinical oral dose based upon body surface area) to pregnant rabbits was not maternally toxic and neither embryofetal toxicity nor fetal malformations were observed. In peri- and post-natal studies, rats received ciprofloxacin doses up to 200 mg/kg/day (oral) or up to 30 mg/kg/day (subcutaneous) from GD 16 to 22 days postpartum. The 200 mg/kg dose is approximately 1.3-times the maximum recommended clinical oral dose based on body surface area. Neither maternal toxicity nor adverse effects on growth and development of the pups were observed, including no sign of arthropathy on the rear leg joints of the pups. Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested when administered directly [see Warnings and Precautions ( 5.13 ) and Nonclinical Toxicology 13.2 ] .

8.2 Lactation Risk Summary Published literature reports that ciprofloxacin is present in human milk following intravenous and oral administration . There is no information regarding effects of CIPRO on milk production or the breastfed infant. Because of the potential risk of serious adverse reactions in breastfed infants, including arthropathy shown in juvenile animal studies [see Use in Specific Populations (8.4), (Clinical Considerations)], for most indications a lactating woman may consider pumping and discarding breast milk during treatment with CIPRO and an additional two days (five half-lives) after the last dose. Alternatively, advise a woman that breastfeeding is not recommended during treatment with CIPRO and for an additional two days (five half-lives) after the last dose. However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on CIPRO may be acceptable [see Dosage and Administration ( 2.2 ), Pediatric Use ( 8.4 ), and Clinical Studies ( 14.2 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CIPRO and any potential adverse effects on the breastfed child from CIPRO or from the underlying maternal condition. Clinical Considerations Ciprofloxacin may cause intestinal flora alteration of the breastfeeding infant. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash).

8.4 Pediatric Use Although effective in clinical trials, CIPRO is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. Quinolones, including CIPRO, cause arthropathy (arthralgia, arthritis), in juvenile animals [see Warnings and Precautions ( 5.13 ) and Nonclinical Toxicology ( 13.2 )] . […]

Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12.4 )].

Mechanism of Action The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.