Ciprofloxacin precautions
| Ciprofloxacin Hydrochloride |
|---|
| CIPRO®,CIPROFLOXACIN®,CILOXAN®,CETRAXAL® FDA Package Insert |
| Description |
| Clinical Pharmacology |
| Microbiology |
| Indications and Usage |
| Contraindications |
| Warnings |
| Precautions |
| Adverse Reactions |
| Overdosage |
| Clinical Studies |
| Dosage and Administration |
| How Supplied |
| Medication Guide |
| Direction For Use |
| Labels and Packages |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Abdurahman Khalil, M.D. [2]
List of precautions
General
Central nervous system
Renal impairment
Photosensitivity/Phototoxicity
Carcinogenesis
Mutagenesis
Impairment of fertility
Pregnancy
Nursing mothers
Pediatric use
- Inhalational Anthrax (Post-Exposure)
- Complicated Urinary Tract Infection and Pyelonephritis
- Cystic fibrosis
General
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. Crystalluria related to Ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving Ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine. Return to top
Central nervous system
Quinolones, including Ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. Return to top
Renal impairment
Alteration of the dosage regimen is necessary for patients with impairment of renal function. Return to top
Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., 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 after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.
Prescribing Ciprofloxacin Tablets USP in the absence of a proven and 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. Return to top
Carcinogenesis
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 and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2).
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 mg/m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32 weeks in mice treated concomitantly with UVA and other quinolones.3
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. Return to top
Mutagenesis
8 in vitro mutagenicity tests have been conducted with Ciprofloxacin. 2 of the 8 tests were positive (Mouse Lymphoma Cell Forward Mutation Assay, Rat Hepatocyte DNA Repair Assay) and 6 were negative (Salmonella/Microsome Test, E. coli DNA Repair Assay, Chinese Hamster V79 Cell HGPRT Test, Syrian Hamster Embryo Cell Transformation Assay, Saccharomyces cerevisiae Point Mutation Assay, Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay). 3 in vivo test systems gave negative results (Rat Hepatocyte DNA Repair Assay, Micronucleus Test (Mice), Dominant Lethal Test (Mice)). Return to top
Impairment of fertility
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 mg/m2) revealed no evidence of impairment. Return to top
Pregnancy
Teratogenic Effects
- Pregnancy category C.
There are no adequate and well-controlled studies in pregnant women. 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.
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to Ciprofloxacin and 68% first trimester exposures) during gestation. 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). 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. 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. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother.
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 mg/m2) 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 mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. Return to top
Nursing mothers
Ciprofloxacin is excreted in human milk. The amount of Ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing from mothers taking Ciprofloxacin, 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. Return to top
Pediatric use
Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing joints of juvenile animals resulting in lameness.
Inhalational Anthrax (Post-Exposure)
Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of Ciprofloxacin to pediatric patients is appropriate.
Complicated Urinary Tract Infection and Pyelonephritis
Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli. 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 the controls, including events related to joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6.0% (21/349) for control agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the Ciprofloxacin arm compared to 31% (109/349) in the control arm.
Cystic fibrosis
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67 patients received Ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by Ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0-93 days). This study was not designed to determine long term effects and the safety of repeated exposure to Ciprofloxacin.
Musculoskeletal adverse events in patients with cystic fibrosis 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 events were similar in nature and frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after a ten day course of treatment with Ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight months after treatment. However, the relationship of this event to the patient's course of Ciprofloxacin can not be definitively determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process. Return to top
Geriatric use
In a retrospective analysis of 23 multiple-dose controlled clinical trials of Ciprofloxacin 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.
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using Ciprofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
Patients over 65 years of age are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Ciprofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendon rupture usually involves the Achilles, hand, or shoulder tendons and can occur during therapy or up to a few months post completion of therapy. Caution should be used when prescribing Ciprofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue therapy and inform their physicians if any tendon symptoms occur. Return to top
References
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019537s075,020780s033lbl.pdf