Ciprofloxacin in Dextrose

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS Fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection), have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5.1 )] including: 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 )] Discontinue Ciprofloxacin Injection (in 5% Dextrose Injection) immediately and avoid the use of fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection), in patients who experience any of these serious adverse reactions [see Warnings and Precautions ( 5.1 )]. Fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection), may exacerbate muscle weakness in patients with myasthenia gravis. Avoid Ciprofloxacin Injection in patients with known history of myasthenia gravis [see Warnings and Precautions ( 5.5 )]. Because fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection), have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 to 5.16 )] , reserve Ciprofloxacin Injection (in 5% Dextrose Injection) for use in patients who have no alternative treatment options for the following indications: Acute exacerbation of chronic bronchitis [see Indications and Usage ( 1.9 )] Acute Sinusitis [see Indications and Usage ( 1.11 )] WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning. Fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection) have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together ( 5.1 ), including: Tendinitis and tendon rupture ( 5.2 ) Peripheral neuropathy ( 5.3 ) Central nervous system effects ( 5.4 ) Discontinue Ciprofloxacin Injection immediately and avoid the use of fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection), in patients who experience any of these serious adverse reactions ( 5.1 ) Fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection), may exacerbate muscle weakness in patients with myasthenia gravis. Avoid Ciprofloxacin Injection (in 5% Dextrose Injection) in patients with known history of myasthenia gravis. ( 5.5 ) Because fluoroquinolones, including Ciprofloxacin Injection (in 5% Dextrose Injection), have been associated with serious adverse reactions ( 5.1 to 5.16 ), reserve Ciprofloxacin Injection (in 5% Dextrose Injection) for use in patients who have no alternative treatment options for the following indications: Acute exacerbation of chronic bronchitis ( 1.9 ) Acute sinusitis ( 1.11 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions (for example, anaphylactic reactions) may occur after first or subsequent doses of Ciprofloxacin Injection. Discontinue Ciprofloxacin Injection at the first sign of skin rash, jaundice or any sign of hypersensitivity. ( 4.1 , 5.6 , 5.7 ) Hepatotoxicity: Discontinue immediately if signs and symptoms of hepatitis occur. ( 5.8 ) Clostridioides difficile -Associated Diarrhea: Evaluate if colitis occurs. ( 5.11 ) QT Prolongation: Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval. ( 5.12 , 7 , 8.5 ) 5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ciprofloxacin. 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 immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ciprofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones. 5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.2 )] . This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting ciprofloxacin, 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 immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ciprofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture [see Adverse Reactions ( 6.2 )]. 5.3 Peripheral Neuropathy Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin and may be irreversible in some patients [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 , 6.2 )] . Discontinue ciprofloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ciprofloxacin, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions ( 6.1 , 6.2 )]. 5.4 Central Nervous System Effects Psychiatric Adverse Reactions Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations, or paranoia; depression, or self-injurious behavior such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care [see Adverse Reactions ( 6.1 )]. Central Nervous System Adverse Reactions Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pseudotumor cerebri), dizziness, and tremors. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. As with all fluoroquinolones, use ciprofloxacin with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). If seizures occur, discontinue ciprofloxacin, and institute appropriate care [see Adverse Reactions ( 6.1 ) and Drug Interactions ( 7 )]. 5.5 Exacerbation of Myasthenia Gravis Fluoroquinolones, including ciprofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis [see Adverse Reactions ( 6.2 )]. 5.6 Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome); Vasculitis; arthralgia; myalgia; serum sickness; Allergic pneumonitis; Interstitial nephritis; acute renal insufficiency or failure; Hepatitis; jaundice; acute hepatic necrosis or failure; Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. Discontinue ciprofloxacin 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 ciprofloxacin. 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. 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 [see Adverse Reactions ( 6.2 , 6.3 )]. 5.9 Risk of Aortic Aneurysm and Dissection Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve ciprofloxacin for use only when there are no alternative antibacterial treatments available. 5.10 Serious Adverse Reactions with Concomitant Theophylline Serious and fatal reactions have been reported in patients receiving concurrent administration of Intravenous Ciprofloxacin 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 cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Drug Interactions ( 7 )]. 5.11 Clostridioides difficile -Associated Diarrhea Clostridioides difficile (C. difficile) -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin, 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 two 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 )]. 5.12 Prolongation of the QT Interval Some fluoroquinolones, including ciprofloxacin, 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. Avoid ciprofloxacin 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 ) and Use in Specific Populations ( 8.5 )]. 5.13 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals Ciprofloxacin is 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 ( 1.10 , 1.6 , 1.7 )] . 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 caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinoloneclass 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 )]. 5.14 Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones, including ciprofloxacin, after sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue ciprofloxacin if phototoxicity occurs [see Adverse Reactions ( 6.1 )]. 5.15 Development of Drug Resistant Bacteria Prescribing ciprofloxacin 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. 5.16 Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2 Enzymes Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine, and zolpidem) 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 )]. 5.17 Crystalluria 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 has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving ciprofloxacin. Hydrate patients well to prevent the formation of highly concentrated urine [see Dosage and Administration ( 2.4 )] . 5.18 Periodic Assessment of Organ System Functions As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy. 5.19 Blood Glucose Disturbances Fluoroquinolones, including ciprofloxacin, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (for example, glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs in a patient being treated with ciprofloxacin, discontinue ciprofloxacin and initiate appropriate therapy immediately [see Adverse Reactions ( 6.1 ), Drug Interactions ( 7 )] .

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 )] 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, central nervous system disturbance, local intravenous site reactions eosinophilia, headache, restlessness, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1 ‑ 800 ‑ 441-4100 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 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%). In clinical trials the following adverse reactions were reported in greater than 1% of patients treated with intravenous ciprofloxacin: nausea, diarrhea, central nervous system disturbance, local intravenous site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash. Local intravenous site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen. Table 5: Medically Important Adverse Reactions That Occurred in less than 1% Ciprofloxacin Patients System Organ Class Adverse Reactions Body as a Whole Abdominal Pain/Discomfort Pain Cardiovascular Cardiopulmonary Arrest Myocardial Infarction Tachycardia Syncope Hypertension Angina Pectoris Vasodilation Central Nervous System Restlessness Seizures (including Status Epilepticus) Paranoia Psychosis (toxic) Depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide) Phobia Depersonalization Manic Reaction Unresponsiveness Ataxia Hallucinations Dizziness Paresthesia Tremor Insomnia Nightmares Irritability Malaise Abnormal Gait Migraine Gastrointestinal Ileus Gastrointestinal Bleeding Pancreatitis Hepatic Necrosis Intestinal Perforation Dyspepsia Constipation Oral Ulceration Mouth Dryness Anorexia Flatulence Hepatitis Hemic/Lymphatic Agranulocytosis Prolongation of Prothrombin Time Petechia Metabolic/Nutritional Hyperglycemia Hypoglycemia Musculoskeletal Arthralgia Joint Stiffness Muscle Weakness Renal/Urogenital Renal Failure Interstitial Nephritis Hemorrhagic Cystitis Renal Calculi Frequent Urination Gynecomastia Crystalluria Cylindruria Hematuria Albuminuria Respiratory Respiratory Arrest Dyspnea Laryngeal Edema Hemoptysis Bronchospasm Skin/Hypersensitivity Allergic Reactions Anaphylactic Reactions including life-threatening anaphylactic shock Erythema Multiforme/Stevens-Johnson Syndrome Exfoliative Dermatitis Toxic Epidermal Necrolysis Vasculitis Angioedema Extremities Purpura Fever Pruritus Urticaria Increased Perspiration Erythema Nodosum Thrombophlebitis Burning Photosensitivity/Phototoxicity Reaction Special Senses Decreased Visual Acuity Blurred Vision Disturbed Vision (diplopia, chromatopsia, and photopsia) Anosmia Hearing Loss Tinnitus Nystagmus Bad Taste In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin. In randomized, double-blind controlled clinical trials comparing ciprofloxacin (Intravenous and Intravenous/Oral sequential) with intravenous beta-lactam control antibiotics, the CNS adverse reaction profile of ciprofloxacin was comparable to that of 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 6 ). Table 6: Musculoskeletal Adverse Reactions 1 as Assessed by the IPSC 1 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) 2 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. Ciprofloxacin Comparator All Patients (within 6 weeks) 31/335 (9.3%) 21/349 (6%) 95% Confidence Interval 2 (-0.8%, +7.2%) Age Group 12 months to 24 months 1/36 (2.8%) 0/41 2 years to <6 years 5/124 (4%) 3/118 (2.5%) 6 years to <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 2 (-0.6%, +9.1%) The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3% (9/335) in the ciprofloxacin 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 events 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, doubleblind 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 one 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 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. 6.2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. 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 7 ). Table 7: 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 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 Nystagmus Taste loss 6.3 Adverse Laboratory Changes Changes in laboratory parameters while on ciprofloxacin therapy are listed below: Hepatic-Elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, and serum bilirubin Hematologic-Elevated eosinophil and platelet counts, decreased platelet counts, hemoglobin and/or hematocrit Renal-Elevations of serum creatinine, BUN, and uric acid Other elevations of serum creatine phosphokinase, serum theophylline (in patients receiving theophylline concomitantly), blood glucose, and triglycerides Other changes occurring were: decreased leukocyte count, elevated atypical lymphocyte count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (gGT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes occurring during administration of ciprofloxacin were: elevation of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin, decreased prothrombin time, hemolytic anemia, and bleeding diathesis.

<table ID="t5" width="100%"><caption>Table 5: Medically Important Adverse Reactions That Occurred in less than 1% Ciprofloxacin Patients</caption><col width="40.700%" align="left"/><col width="59.300%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">System Organ Class</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Adverse Reactions</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Body as a Whole</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Abdominal Pain/Discomfort Pain</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Cardiopulmonary Arrest Myocardial Infarction Tachycardia Syncope Hypertension Angina Pectoris Vasodilation </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Central Nervous System</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Restlessness Seizures (including Status Epilepticus) Paranoia Psychosis (toxic) Depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide) Phobia Depersonalization Manic Reaction Unresponsiveness Ataxia Hallucinations Dizziness Paresthesia Tremor Insomnia Nightmares Irritability Malaise Abnormal Gait Migraine </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Ileus Gastrointestinal Bleeding Pancreatitis Hepatic Necrosis Intestinal Perforation Dyspepsia Constipation Oral Ulceration Mouth Dryness Anorexia Flatulence Hepatitis </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Hemic/Lymphatic</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Agranulocytosis Prolongation of Prothrombin Time Petechia </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Metabolic/Nutritional</content></td><td align="left" styleCode="Botrule Rrule" valign="middle">Hyperglycemia Hypoglycemia</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Arthralgia Joint Stiffness Muscle Weakness </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Renal/Urogenital</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Renal Failure Interstitial Nephritis Hemorrhagic Cystitis Renal Calculi Frequent Urination Gynecomastia Crystalluria Cylindruria Hematuria Albuminuria </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Respiratory</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Respiratory Arrest Dyspnea Laryngeal Edema Hemoptysis Bronchospasm </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Skin/Hypersensitivity</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Allergic Reactions Anaphylactic Reactions including life-threatening anaphylactic shock Erythema Multiforme/Stevens-Johnson Syndrome Exfoliative Dermatitis Toxic Epidermal Necrolysis Vasculitis Angioedema Extremities Purpura Fever Pruritus Urticaria Increased Perspiration Erythema Nodosum Thrombophlebitis Burning Photosensitivity/Phototoxicity Reaction </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Special Senses</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Decreased Visual Acuity Blurred Vision Disturbed Vision (diplopia, chromatopsia, and photopsia) Anosmia Hearing Loss Tinnitus Nystagmus Bad Taste </td></tr></tbody></table>

<table ID="t6" width="100%"><caption>Table 6: Musculoskeletal Adverse Reactions ¹as Assessed by the IPSC </caption><col width="39.900%" align="left"/><col width="25.133%" align="left"/><col width="34.967%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹Included: 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) </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">²The 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. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Ciprofloxacin</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Comparator</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">All Patients (within 6 weeks)</td><td align="left" styleCode="Botrule Rrule" valign="top">31/335 (9.3%)</td><td align="left" styleCode="Botrule Rrule" valign="top">21/349 (6%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">95% Confidence Interval ²</td><td colspan="2" align="left" styleCode="Botrule Rrule" valign="top">(-0.8%, +7.2%)</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top">Age Group</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">12 months to 24 months</td><td align="left" styleCode="Botrule Rrule" valign="top">1/36 (2.8%)</td><td align="left" styleCode="Botrule Rrule" valign="top">0/41</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">2 years to &lt;6 years</td><td align="left" styleCode="Botrule Rrule" valign="top">5/124 (4%)</td><td align="left" styleCode="Botrule Rrule" valign="top">3/118 (2.5%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">6 years to &lt;12 years</td><td align="left" styleCode="Botrule Rrule" valign="top">18/143 (12.6%)</td><td align="left" styleCode="Botrule Rrule" valign="top">12/153 (7.8%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">12 years to 17 years</td><td align="left" styleCode="Botrule Rrule" valign="top">7/32 (21.9%)</td><td align="left" styleCode="Botrule Rrule" valign="top">6/37 (16.2%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">All Patients (within 1 year)</td><td align="left" styleCode="Botrule Rrule" valign="top">46/335 (13.7%)</td><td align="left" styleCode="Botrule Rrule" valign="top">33/349 (9.5%)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">95% Confidence Interval ²</td><td colspan="2" align="left" styleCode="Botrule Rrule" valign="top">(-0.6%, +9.1%)</td></tr></tbody></table>

<table ID="t7" width="100%"><caption>Table 7: Postmarketing Reports of Adverse Drug Reactions</caption><col width="39.000%" align="left"/><col width="61.000%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">System Organ Class</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Adverse Reactions</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular</content></td><td align="left" styleCode="Botrule Rrule" valign="top">QT prolongation Torsade de Pointes Vasculitis and ventricular arrhythmia </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Central Nervous System</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Hypertonia Myasthenia Exacerbation of myasthenia gravis Peripheral neuropathy Polyneuropathy Twitching </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Pseudomembranous colitis</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Hemic/Lymphatic</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Pancytopenia (life threatening or fatal outcome) Methemoglobinemia </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Hepatobiliary</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Hepatic failure (including fatal cases)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Infections and Infestations</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Candidiasis (oral, gastrointestinal, vaginal)</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Investigations</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Prothrombin time prolongation or decrease Cholesterol elevation (serum) Potassium elevation (serum) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Myalgia Myoclonus Tendinitis Tendon rupture </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Psychiatric Disorders</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Agitation Confusion Delirium </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Skin/Hypersensitivity</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Acute generalized exanthematous pustulosis (AGEP) Fixed eruption Serum sickness-like reaction </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Special Senses</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Anosmia Hyperesthesia Hypesthesia Nystagmus Taste loss </td></tr></tbody></table>