Drug: Cipro I.V.

CIPRO IV (ciprofloxacin) is a synthetic antimicrobial agent for intravenous (IV) administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-3quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is: Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. CIPRO IV solutions are available as sterile 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. CIPRO IV contains lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6. The plastic container is not made with natural rubber latex.. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, for example, di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. The glucose content for the 200 mL flexible container is 10 g.

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The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
  • Tendon Effects [see WARNINGS AND PRECAUTIONS]
  • Exacerbation of Myasthenia Gravis [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Other Serious and Sometimes Fatal Reactions [see WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Serious Adverse Reactions with Concomitant Theophylline [see WARNINGS AND PRECAUTIONS]
  • Central Nervous System Effects [see WARNINGS AND PRECAUTIONS]
  • Clostridium Difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS]
  • Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS]
  • Prolongation of the QT Interval [see WARNINGS AND PRECAUTIONS]
  • Musculoskeletal Disorders in Pediatric Patients [see WARNINGS AND PRECAUTIONS]
  • Photosensitivity/Phototoxicity [see WARNINGS AND PRECAUTIONS]
  • Development of Drug Resistant Bacteria [see WARNINGS AND PRECAUTIONS]
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 IV, 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 CIPRO IV: 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 Ren al/U rogenital 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 CIPRO (Intravenous and Intravenous/Oral. sequential) with intravenous beta-lactam control antibiotics, the CNS adverse reaction profile of CIPRO 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 Reactions1 as Assessed by the IPSC
  CIPRO Comparator All Patients (within 6 weeks) 31/335 (9.3%)

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CIPRO IV should be administered intravenously at dosages described in the appropriate Dosage Guidelines tables. Dosage 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. Table 1: Adult Dosage Guidelines
Infection1 Dose Frequency Usual Duration Urinary Tract 200 mg to 400 mg

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Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of CIPRO IV 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 coadministered drug. Table 8: Drugs That are Affected by and Affecting CIPRO IV
Drugs That are Affected by CIPRO IV Drug(s) Recommendation Comments Tizanidine Contraindicated Concomitant administration of tizanidine and CIPRO IV is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see CONTRAINDICATIONS] Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of CIPRO IV 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.] Drugs Known to Prolong QT Interval Avoid Use CIPRO IV 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 and Use in Specific Populations]. Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when CIPRO IV 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 ciprofloxacin is co-administered with oral antidiabetic drugs. [See ADVERSE REACTIONS] 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 IV discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO IV with phenytoin. Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin 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 IV 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 IV with an oral anticoagulant (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 IV 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 IV [see WARNINGS AND PRECAUTIONS]. 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 IV 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 Pharmacokinetics). 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 IV inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. Drug(s) Affecting Pharmacokinetics of CIPRO Probenecid Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels) Potentiation of CIPRO IV toxicity may occur. Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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CIPRO IV is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below when the intravenous administration is needed [see DOSAGE AND ADMINISTRATION]. Urinary Tract Infections CIPRO IV 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. Lower Respiratory Tract Infections CIPRO IV 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.* Also, CIPRO IV is indicated for the treatment of acute exacerbations of chronic bronchitis caused by Moraxella catarrhalis [see Limitation of Use]. Nosocomial Pneumonia CIPRO IV is indicated in adult patients for treatment of nosocomial pneumonia caused by caused by Haemophilus influenzae or Klebsiella pneumoniae. Skin And Skin Structure Infections CIPRO IV 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, methicillinsusceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes. Bone And Joint Infections CIPRO IV is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. Complicated Intra-Abdominal Infections CIPRO IV 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. Acute Sinusitis CIPRO IV is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis. Chronic Bacterial Prostatitis CIPRO IV is indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis. Empirical Therapy For Febrile Neutropenic Patients CIPRO IV is indicated in adult patients for the treatment of febrile neutropenia in combination with piperacillin sodium [see Clinical Studies]. Complicated Urinary Tract Infections And Pyelonephritis CIPRO IV is indicated in pediatric patients one to 17 years of age for treatment of complicated urinary tract infections (cUTI) and pyelonephritis due to Escherichia coli [see Limitation of Use, Use in Specific Populations, and Clinical Studies]. Inhalational Anthrax (post-exposure) CIPRO IV is indicated in adults and pediatric patients from birth to 17 years of age for treatment of 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] Plague CIPRO IV 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]. Limitation Of Use Use in Pediatric Patients Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues. CIPRO IV, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, Use In Specific Populations, and Nonclinical Toxicology]. Lower Respiratory Tract Infections CIPRO IV is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO IV and other antibacterial drugs, CIPRO IV 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 CIPRO IV 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.

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Hypersensitivity Ciprofloxacin 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]. Tizanidine Concomitant administration with tizanidine is contraindicated [see DRUG INTERACTIONS]. Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis. In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous doses of ciprofloxacin between 125mg/kg and 300 mg/kg.

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Dosage Forms And Strengths Injection (200 mL in 5% Dextrose, 400 mg, 0.2%) Premix in Flexible Containers, for intravenous infusion Storage And Handling CIPRO IV (ciprofloxacin) is available as a clear, colorless to slightly yellowish solution in flexible containers not made with natural rubber latex. SIZE STRENGTH NDC NUMBER 200 mL 5% Dextrose 400 mg, 0.2%

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Tendinopathy And Tendon Rupture Fluoroquinolones, including CIPRO IV, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Inflammation and tendon rupture can occur, sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. CIPRO IV should be used with caution in patients with a history of tendon disorders. CIPRO IV should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. [See ADVERSE REACTIONS] Exacerbation Of Myasthenia Gravis Fluoroquinolones, including CIPRO IV, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis. [See ADVERSE REACTIONS] Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including CIPRO IV. 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]. Other Serious And Sometimes Fatal Reactions Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including CIPRO IV. 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 IV immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see ADVERSE REACTIONS]. Hepatotoxicity Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with CIPRO IV. Acute liver injury is rapid in onset (range 1–39 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 CIPRO IV. [See ADVERSE REACTIONS] Serious Adverse Reactions With Concomitant Theophylline Serious and fatal reactions have been reported in patients receiving concurrent administration of Intravenous CIPRO 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 CIPRO cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See DRUG INTERACTIONS] Central Nervous System Effects Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones, including CIPRO IV. CIPRO IV 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 CIPRO IV to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care. CIPRO IV, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. 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). Use CIPRO IV 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 CIPRO. [See ADVERSE REACTIONS and DRUG INTERACTIONS] Clostridium Difficile-Associated Diarrhea Clostridium Difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CIPRO IV, 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] 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 IV. Symptoms may occur soon after initiation of CIPRO IV and may be irreversible. Discontinue CIPRO IV 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. [See ADVERSE REACTIONS] Prolongation Of The QT Interval Some fluoroquinolones, including CIPRO IV, 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 CIPRO IV. Avoid CIPRO IV 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 and Use in Specific Populations] Musculoskeletal Disorders In Pediatric Patients And Arthropathic Effects In Animals CIPRO IV 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]. An increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues, has been observed [see ADVERSE REACTIONS]. In pre-clinical studies, oral administration of CIPRO IV 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 and Nonclinical Toxicology] 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]. 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 CIPRO IV. Hydrate patients well to prevent the formation of highly concentrated urine [see DOSAGE AND ADMINISTRATION]. 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 CIPRO IV, after sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue CIPRO IV if phototoxicity occurs. [See ADVERSE REACTIONS] Development Of Drug Resistant Bacteria Prescribing CIPRO IV 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. Potential Risks With Concomitant Use Of Drugs Metabolized By Cytochrome P450 1A2 Enzymes Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of CIPRO IV and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic adverse reactions of the coadministered drug. [See DRUG INTERACTIONS and CLINICAL PHARMACOLOGY] 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. Patient Counseling Information Advise the patient to read the FDA-Approved patient labeling (Medication Guide) Antibacterial Resistance Inform patients that antibacterial drugs including CIPRO IV should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When CIPRO IV prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CIPRO IV or other antibacterial drugs in the future. Administration Inform patients to drink fluids liberally while taking CIPRO to avoid formation of highly concentrated urine and crystal formation in the urine. Serious and Potentially Serious Adverse Reactions Inform patients of the following serious adverse reactions that have been associated with CIPRO or other fluoroquinolone use:
  • Tendon Disorders Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue CIPRO treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
  • Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
  • Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
  • Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking CIPRO IV. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
  • Convulsions: Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions.
  • Neurologic Adverse Effects (for example, dizziness, lightheadedness, increased intracranial pressure): Inform patients that they should know how they react to CIPRO IV before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
  • Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, Instruct patients to contact their physician as soon as possible.
  • Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with ciprofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue CIPRO IV and contact their physician.
  • Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
  • Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child's physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child's physician of any joint-related problems that occur during or following ciprofloxacin therapy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
  • Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine. Ciprofloxacin increases the effects of tizanidine (Zanaflex®).
  • Theophylline: Inform patients that ciprofloxacin CIPRO IV may increase the effects of theophylline. Life-threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek medical help if they experience seizures, palpitations, or difficulty breathing.
  • Caffeine: Inform patients that ciprofloxacin may increase the effects of caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
  • Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.
Drug Interactions Oral Antidiabetic Agents Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were co-administered; if low blood sugar occurs with CIPRO IV, instruct them toconsult their physician and that their antibacterial medicine may need to be changed. Anthrax and Plague Studies Inform patients given CIPRO IV for this condition that efficacy studies could not be conducted in humans for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility A total of 8 in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:
  • Salmonella/Microsome Test (Negative)
  • E. coli DNA Repair Assay (Negative)
  • Mouse Lymphoma Cell Forward Mutation Assay (Positive)
  • Chinese Hamster V 79 Cell HGPRT Test (Negative)
  • Syrian Hamster Embryo Cell Transformation Assay (Negative)
  • Saccharomyces cerevisiae Point Mutation Assay (Negative)
  • Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
  • Rat Hepatocyte DNA Repair Assay (Positive)
  • Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:
  • Rat Hepatocyte DNA Repair Assay
  • Micronucleus Test (Mice)
  • Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively (approximately 1.7-times and 2.5-times the highest recommended therapeutic dose based upon body surface area, respectively). Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to32 weeks in mice treated concomitantly with UVA and other quinolones.9 In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown. Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times the highest recommended therapeutic dose based upon body surface area) revealed no evidence of impairment. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. CIPRO IV should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.2 A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.3 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).4 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.2,3 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. Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4-and 1.3-times the highest recommended therapeutic dose based upon body surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon body surface area), no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. Nursing Mothers Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking CIPRO IV, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Although effective in clinical trials, CIPRO IV 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 IV, cause arthropathy in juvenile animals [see WARNINGS AND PRECAUTIONS and Nonclinical Toxicology]. Complicated Urinary Tract Infection and Pyelonephritis CIPRO IV is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric patients 1 to 17 years of age. Although effective in clinical trials, CIPRO IV is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to the controls, including events related to joints and/or surrounding tissues. [See ADVERSE REACTIONS and Clinical Studies] Inhalational Anthrax (Post-Exposure) CIPRO IV is indicated in pediatric patients from birth to 17 years of age for inhalational anthrax (postexposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see DOSAGE AND ADMINISTRATION and Clinical Studies]. Plague CIPRO IV is indicated in pediatric patients from birth to 17 years of age, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of CIPRO IV could not be conducted in humans with pneumonic plague for feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of CIPRO to pediatric patients is appropriate. [See INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, and Clinical Studies] Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as CIPRO IV. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing CIPRO IV to elderly patients especially those on corticosteroids. Patients should be informed of this potential adverse reaction and advised to discontinue CIPRO and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur. [See BOXED WARNING, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS] In a retrospective analysis of 23 multiple-dose controlled clinical trials of CIPRO encompassing over 3500 ciprofloxacin-treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using CIPRO IV with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia). [See WARNINGS AND PRECAUTIONS] 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. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] Hepatic Impairment In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been studied. REFERENCES 2. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 3. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339. 4. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89. Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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