Adverse Reactions in Adult Patients
During clinical investigations with oral and parenteral ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1% of orally treated patients.
The most frequently reported drug related events, 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%).
Additional medically important events that occurred in less than 1% of ciprofloxacin patients are listed below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities, injection site reaction (ciprofloxacin intravenous)
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis, phlebitis, tachycardia, migraine, hypotension
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures (including status epilepticus), grand mal convulsion, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide), paresthesia, abnormal gait
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding, cholestatic jaundice, hepatitis
HEMIC/LYMPHATIC: lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase, hyperglycemia, hypoglycemia
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare up of gout, muscle weakness
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary retention, urethral bleeding, vaginitis, acidosis, breast pain
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis, bron-chospasm, pulmonary embolism
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity/phototoxicity reaction, flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum, sweating
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste, chromatopsia
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 tablets (500 mg BID) to cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the control drugs.
Adverse Reactions in Pediatric Patients
Ciprofloxacin, administered IV and /or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were evaluated in a comprehensive fashion and included such conditions as 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. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6 % (21/349) in comparator-treated patients. The majority of these events were mild or moderate in intensity. All musculoskeletal events 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 events. The events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless of whether they received IV or oral therapy. Ciprofloxacin-treated patients were more likely to report more than one event and on more than one occasion compared to control patients. These events occurred in all age groups and the rates were consistently higher in the ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
|All Patients (within 6 weeks)||31/335 (9.3%)||21/349 (6%)|
|95% Confidence Interval*||(-0.8%, +7.2%)|
|≥ 12 months < 24 months||1/36 (2.8%)||0/41|
|≥ 2 years < 6 years||5/124 (4%)||3/118 (2.5%)|
|≥ 6 years < 12 years||18/143 (12.6%)||12/153 (7.8%)|
|≥ 12 years to 17 years||7/32 (21.9%)||6/37 (16.2 %)|
|All Patients (within 1 year)||46/335 (13.7%)||33/349 (9.5%)|
|95% Confidence Interval*||(-0.6%, + 9.1%)|
|*The 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 ciprofloxacin group had findings comparable to the control group.|
The incidence rates of neurological events 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 events regardless of relationship to study drug and 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 events were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events 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 event 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%, accidental injury 3%, rhinitis 3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in adults during clinical trials or postmarketing experience may also occur in pediatric patients.
Postmarketing Adverse Event Reports
The following adverse events have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these events 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. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
Acute generalized exanthematous pustulosis (AGEP), Agitation, agranulocytosis, albuminuria, anaphylactic reactions (including life-threatening anaphylactic shock), anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), International Normalized Ratio (INR) increased (in patients treated with Vitamin K antagonists), jaundice, marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome), peripheral neuropathy that may be irreversible, phenytoin alteration (serum), photosensitivity/phototoxicity reaction, polyneuropathy, potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), QT prolongation, renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis (Lyell's Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, vasculitis and ventricular arrhythmia. (See PRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also Inhalational Anthrax-Additional Information.)
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without regard to drug relationship are listed below:
Hepatic –Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic–Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated blood platelets (0.1%), pancytopenia (0.1%).
Renal–Elevations of serum creatinine (1.1%), BUN (0.9%), crystalluria, cylindruria, and hematuria have been reported.
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, and leukocytosis.