Source: Health Products and Food Branch (CA) Revision Year: 2017
Ciprofloxacin, a fluoroquinolone antibiotic, has in vitro activity against a wide range of grampositive and gram-negative microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzyme, DNA gyrase, which is required for the synthesis of bacterial DNA.
Dexamethasone, a potent corticosteroid, has been shown to aid in the resolution of inflammation.
Following a single bilateral 4-drop topical otic dose of CIPRODEX to pediatric patients following tympanostomy tube insertion, measurable plasma concentrations of ciprofloxacin and dexamethasone were observed up to 6 hours. In 25 patients, the mean (± SD) peak plasma concentrations of ciprofloxacin and dexamethasone were 1.14 ± 0.98 ng/mL and 0.86 ± 1.19 ng/mL, respectively, and were observed typically within 15 minutes to 2 hours postdose. For ciprofloxacin, these levels were approximately 650-fold lower than levels achieved with an oral dose of 250 to 1000 mg.1 This bilateral exposure resulted in a peak dexamethasone concentration approximately 9-fold lower than reported by following an oral 0.5mg dose.2 Estimates of half-life averaged 3.1 hours for ciprofloxacin and 4.5 hours for dexamethasone. Both values are similar to those reported after oral doses in adults.1,3 While systemic exposure was assessed with bilateral administration, most AOMT patients in the clinical trials for this product had unilateral infections (77%).
Ciprofloxacin has in vitro activity against a wide range of gram-positive and gram-negative microorganisms. The bactericidal action of ciprofloxacin results from interference with the enzyme, DNA gyrase, which is needed for the synthesis of bacterial DNA.
The following table shows the in vitro activity of ciprofloxacin.
Acute Otitis Media with Otorrhea:
| Pathogen | N | MIC range μg/mL | MIC50 μg/mL | MIC90 μg/mL |
|---|---|---|---|---|
| Aerobic, Gram-Positive | ||||
| Staphylococcus aureus | 54 | 0.13-16 | 0.25 | 1.0 |
| Streptococcus pneumoniae | 48 | 0.25-4.0 | 1.0 | 2.0 |
| Aerobic, Gram-Negative | ||||
| Haemophilus influenzae | 36 | 0.004-0.13 | 0.008 | 0.016 |
| Moraxella catarrhalis | 11 | 0.013-0.06 | 0.03 | 0.06 |
| Pseudomonas aeruginosa | 48 | 0.06-2.0 | 0.25 | 0.50 |
Acute Otitis Externa:
| Pathogen | N | MIC range μg/mL | MIC50 μg/mL | MIC90 μg/mL |
|---|---|---|---|---|
| Aerobic, Gram-Positive | ||||
| Staphylococcus aureus | 41 | 0.13-2.0 | 0.25 | 1.0 |
| Staphylococcus haemolyticus | 13 | 0.13-16 | 0.25 | 16 |
| Enterococcus faecalis | 29 | 0.50-2.0 | 1.0 | 2.0 |
| Aerobic, Gram-Negative | ||||
| Acinetobacter genospecies 3 | 15 | 0.06-4.0 | 0.13 | 4.0 |
| Enterobacter aerogenes | 20 | 0.008-0.13 | 0.016 | 0.03 |
| Enterobacter cloacae | 12 | 0.004-0.03 | 0.016 | 0.03 |
| Klebsiella pneumoniae | 18 | 0.016-0.06 | 0.03 | 0.06 |
| Proteus mirabilis | 10 | 0.016-0.03 | 0.03 | 0.03 |
| Pseudomonas aeruginosa | 235 | 0.016-1.0 | 0.13 | 0.25 |
| Pseudomonas stutzeri | 10 | 0.016-0.25 | 0.13 | 0.25 |
| Serratia marcescens | 15 | 0.03-1.0 | 0.06 | 0.50 |
Cross-resistance has been observed between ciprofloxacin and other fluoroquinolones. There is generally no cross-resistance between quinolones and other classes of antibacterial agents such as β-lactams or aminoglycosides.
The single-dose toxicity of ciprofloxacin has been established in several species. The oral LD50 in rats and mice is >5000 mg/kg, and about 2500 mg/kg in rabbits. Emesis in dogs and cats precluded determination of oral LD50s in these species. However, in cats it was shown to be greater than 150 mg/kg. The intramuscular LD50 was >1000 mg/kg in rats and mice.
Several routes of administration have been used to determine the single-dose toxicity of dexamethasone. The oral LD50 of dexamethasone in rats is >3000 mg/kg. Subcutaneous LD50s are 14 mg/kg, 4400 mg/kg and 7200 μg/kg in rats, mice and rabbits, respectively. Intraperitoneal LD50s are 54 mg/kg in rats and 410 mg/kg in mice.
The single dose exposure to ciprofloxacin and dexamethasone from the instillation of four drops of the CIPRODEX into the affected ear is 0.42 mg ciprofloxacin and 0.14 mg dexamethasone. Administration of this product to a 10 kg child twice daily in both ears would result in exposures of 0.168 mg/kg ciprofloxacin and 0.056 mg/kg dexamethasone. These doses are >800 and >50,000 fold lower than the lowest oral LD50s reported for ciprofloxacin and dexamethasone, respectively. In the event that a 10 kg child should accidentally ingest the entire contents of a 7.5 ml vial of CIPRODEX they would receive a dose of 2.25 mg/kg ciprofloxacin and 0.75 mg/kg dexamethasone. These doses are 66 and 4,000 fold lower that the lowest oral LD50s for ciprofloxacin and dexamethasone respectively.
Eight 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 V79 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 mice and rats have been completed for ciprofloxacin. After daily oral doses of 750 mg/kg (mice) and 250 mg/kg (rats) were administered for up to 2 years, there was no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects in these species. No long term studies of CIPRODEX have been performed to evaluate carcinogenic potential.
Long term studies have not been performed to evaluate the carcinogenic potential of topical otic dexamethasone. Dexamethasone has been tested for in vitro and in vivo genotoxic potential and shown to be positive in the following assays; chromosomal aberrations, sister-chromatid exchange in human lymphocytes and micronuclei and sister-chromatid exchanges in mouse bone marrow. However, the Ames/Salmonella assay, both with and without S9 mix, did not show any increase in His+ revertants.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg/day revealed no evidence of impairment. This would be over 1000 times the maximum recommended clinical dose of ototopical ciprofloxacin, assuming total absorption of ciprofloxacin from the ear of a 10kg child treated with CIPRODEX twice per day according to label directions.
The effect of dexamethasone on fertility has not been investigated following topical otic application. However, the lowest toxic dose of dexamethasone identified following topical dermal application was 1802 μg/kg in a 26-week study in male rats and resulted in changes to the testes, epididymis, sperm duct, prostate, seminal vesicle, Cowper’s gland and accessory glands. The relevance of this study for topical otic use is unknown; however this dose is >150 fold higher than the exposure which would occur if a 50 kg adult used CIPRODEX in both ears twice a day as indicated.
Guinea pigs dosed in the middle ear with CIPRODEX for one month exhibited no drug-related structural or functional changes of the cochlear hair cells and no lesions in the ossicles. CIPRODEX was also shown to lack dermal sensitizing potential in the guinea pig when tested according to the method of Buehler.
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