Ciprofloxacin (Page 5 of 11)

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. Co-administration 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)]

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/DiscomfortPain
Cardiovascular Cardiopulmonary ArrestMyocardial InfarctionTachycardiaSyncopeHypertensionAngina PectorisVasodilation
Central Nervous System RestlessnessSeizures (including Status Epilepticus) ParanoiaPsychosis (toxic)Depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide)PhobiaDepersonalizationManic ReactionUnresponsivenessAtaxiaHallucinationsDizzinessParesthesiaTremorInsomniaNightmaresIrritabilityMalaiseAbnormal GaitMigraine
Gastrointestinal IleusGastrointestinal BleedingPancreatitisHepatic NecrosisIntestinal PerforationDyspepsiaConstipationOral UlcerationMouth DrynessAnorexiaFlatulenceHepatitis
Hemic/Lymphatic AgranulocytosisProlongation of Prothrombin TimePetechia
Metabolic/Nutritional HyperglycemiaHypoglycemia
Musculoskeletal ArthralgiaJoint StiffnessMuscle Weakness
Renal/Urogenital Renal FailureInterstitial NephritisHemorrhagic CystitisRenal CalculiFrequent UrinationGynecomastiaCrystalluriaCylindruriaHematuriaAlbuminuria
Respiratory Respiratory ArrestDyspneaLaryngeal EdemaHemoptysisBronchospasm
Skin/Hypersensitivity Allergic ReactionsAnaphylactic Reactions including life-threatening anaphylactic shockErythema Multiforme/Stevens-Johnson SyndromeExfoliative DermatitisToxic Epidermal NecrolysisVasculitisAngioedemaExtremitiesPurpuraFeverPruritusUrticariaIncreased PerspirationErythema NodosumThrombophlebitisBurningPhotosensitivity/Phototoxicity Reaction
Special Senses Decreased Visual AcuityBlurred VisionDisturbed Vision (diplopia, chromatopsia, and photopsia)AnosmiaHearing LossTinnitusNystagmusBad 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 Reactions1 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 Interval2 (-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 Interval2 (-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, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 to 17 years). Sixty-seven patients received ciprofloxacin 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.

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