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doses of ciprofloxacin up to 100 mg/kg/ day revealed no evidence of impairment. This would be over 100 times the maximum recommended clinical dose of ototopical ciprofloxacin based upon body surface area, assuming total absorption of ciprofloxacin from the ear of a patient treated with CIPRODEX® Otic twice per day according to label directions.


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.


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 1.802 mg/kg in a 26-week study in male rats and resulted in changes to the testes, epididymis, sperm duct, prostate, seminal vessicle, Cowper’s gland and accessory glands. The relevance of this study for short term topical otic use is unknown.


Pregnancy: Teratogenic Effects. Pregnancy Category C: Reproduction studies have been performed in rats and mice using oral doses of up to 100mg/kg and IV doses up to 30 mg/kg and have revealed no evidence of harm to the fetus as a result of ciprofloxacin. In rabbits, ciprofloxacin (30 and 100mg/kg orally) produced gastroin- testinal disturbances resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose. After intravenous administration of doses up to 20 mg/kg, no maternal toxicity was produced in the rabbit, and no embryotoxicity or teratogenicity was observed.


Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.


Animal reproduction studies have not been conducted with CIPRODEX® Otic. No ade- quate and well controlled studies have been performed in pregnant women. Caution should be exercised when CIPRODEX® Otic is used by a pregnant woman. © 2015 Novartis 05/15


US-CDX-15-E-0387


Nursing Mothers: Ciprofloxacin and corticosteroids, as a class, appear in milk following oral administration. Dexametha- sone in breast milk could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical otic admin- istration of ciprofloxacin or dexamethasone could result in sufficient systemic absorption to produce detectable quantities in human milk. Because of the potential for unwanted effects in nursing infants, 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.


Pediatric Use: The safety and efficacy of CIPRODEX® Otic have been established in pediatric patients 6 months and older (937 patients) in adequate and well-controlled clinical trials. Although no data are available on patients less than age 6 months, there are no known safety concerns or differences in the disease process in this population that would preclude use of this product (See DOSAGE AND ADMINISTRATION). No clin- ically relevant changes in hearing function were observed in 69 pediatric patients (age 4 to 12 years) treated with CIPRODEX® Otic and tested for audiometric parameters.


ADVERSE REACTIONS In Phases II and III clinical trials, a total of 937 patients were treated with CIPRODEX® Otic. This included 400 patients with acute otitis media with tympanostomy tubes and 537 patients with acute otitis externa. The reported treatment-related adverse events are listed below:


Acute Otitis Media in pediatric patients with tympanostomy tubes: The following treatment-related adverse events occurred in 0.5% or more of the patients with non-intact tympanic membranes.


Adverse Events Ear discomfort Ear pain


Ear precipitate (residue) Irritability


Taste perversion


Incidence (N=400) 3.0% 2.3% 0.5%


0.5% 0.5%


The following treatment-related adverse events were each reported in a single patient: tympanostomy tube blockage; ear pruritus; tinnitus; oral moniliasis; crying; dizziness; and erythema.


Acute Otitis Externa: The following treatment-related adverse events occurred in 0.4% or more of the patients with intact tympanic membranes.


Adverse Events Ear pruritus Ear debris


Superimposed ear infection


Ear congestion Ear pain


Erythema


Incidence (N=537) 1.5% 0.6% 0.6%


0.4% 0.4% 0.4%


The following treatment-related adverse events were each reported in a single patient: ear discomfort; decreased hearing; and ear disorder (tingling).


DOSAGE AND ADMINISTRATION CIPRODEX® OTIC SHOULD BE SHAKEN WELL IMMEDIATELY BEFORE USE.


CIPRODEX® Otic contains 3 mg (3000 ug/mL) ciprofloxacin and 1 mg/mL dexamethasone.


Acute Otitis Media in pediatric patients with tympanostomy tubes: The recom- mended dosage regimen for the treatment of acute otitis media in pediatric patients (age 6 months and older) through tympa- nostomy tubes is: Four drops (0.14 mL, 0.42 mg ciprofloxacin, 0.14 mg dexamethasone) instilled into the affected ear twice daily for seven days. The suspension should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness, which may result from the instillation of a cold suspension. The patient should lie with the affected ear upward, and then the drops should instilled. The tragus should then be pumped 5 times by pushing inward to facili- tate penetration of the drops into the middle ear. This position should be maintained for 60 seconds. Repeat, if necessary, for the opposite ear. Discard unused portion after therapy is completed.


Acute Otitis Externa: The recommended dosage regimen for the treatment of acute otitis externa is: For patients (age 6 months and older): Four drops (0.14 mL, 0.42 mg cip- rofloxacin, 0.14 mg dexamethasone) instilled into the affected ear twice daily for seven days. The suspension should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness, which may result from the instillation of a cold suspension. The patient should lie with the affected ear upward, and then the drops should be instilled. This position should be maintained for 60 seconds to facilitate penetration of the drops into the ear canal. Repeat, if necessary, for the opposite ear. Discard unused portion after therapy is completed.


U.S. Patent Nos. 4,844,902; 6,284,804; 6,359,016 CIPRODEX is a registered trademark of Bayer Intellectual Property GmbH, licensed to Alcon by Bayer Intellectual Property GmbH. Manufactured by Alcon Laboratories, Inc. Rx Only


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