CIPROFLOXACIN (Page 5 of 13)

6 ADVERSE REACTIONS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

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 * as Assessed by the IPSC
Ciprofloxacin Comparator
*
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)
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.
All Patients (within 6 weeks) 31/335 (9.3%) 21/349 (6%)
95% Confidence Interval (-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 (-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 5–17 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 10–21 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 10–21 days. Periodic musculoskeletal assessments were conducted by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0–93 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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