2.1 Important Administration Instructions

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CIPRODEX is for otic use (ears) only, and not for ophthalmic use, or for injection.

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Shake well immediately before use.

2.2 Dosage

For the Treatment of Acute Otitis Media in Pediatric Patients (age 6 months and older) With Tympanostomy Tubes

The recommended dosage regimen through tympanostomy tubes is as follows:

1.

Four drops [equivalent to 0.14 mL of CIPRODEX, (consisting of 0.42 mg of ciprofloxacin and 0.14 mg of dexamethasone)] instilled into the affected ear twice daily for seven days.

2.

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.

3.

The patient should lie with the affected ear upward, and then the drops should be instilled.

4.

The tragus should then be pumped 5 times by pushing inward to facilitate penetration of the drops into the middle ear.

5.

This position should be maintained for 60 seconds. Repeat, if necessary, for the opposite ear.

6.

Discard unused portion after therapy is completed.

For the Treatment of Acute Otitis Externa (age 6 months and older)

The recommended dosage regimen is as follows:

1.

Four drops [equivalent to 0.14 mL of CIPRODEX, (consisting of 0.42 mg ciprofloxacin and 0.14 mg dexamethasone)] instilled into the affected ear twice daily for seven days.

2.

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.

3.

The patient should lie with the affected ear upward, and then the drops should be instilled.

4.

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.

5.

Discard unused portion after therapy is completed.

5.1 Hypersensitivity Reactions

CIPRODEX should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal, or facial edema), airway obstruction, dyspnea, urticaria, and itching.

5.2 Potential for Microbial Overgrowth With Prolonged Use

Prolonged use of CIPRODEX may result in overgrowth of non-susceptible, bacteria and fungi. If the infection is not improved after one week of treatment, cultures should be obtained to guide further treatment. If such infections occur, discontinue use and institute alternative therapy.

5.3 Continued or Recurrent Otorrhea

If otorrhea persists after a full course of therapy, or if two or more episodes of otorrhea occur within six months, further evaluation is recommended to exclude an underlying condition such as cholesteatoma, foreign body, or a tumor.

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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Phases II and III clinical trials, a total of 937 patients were treated with CIPRODEX. This included 400 patients with acute otitis media with tympanostomy tubes (AOMT) and 537 patients with AOE. The reported adverse reactions are listed below:

Acute Otitis Media in Pediatric Patients With Tympanostomy Tubes

The following adverse reactions occurred in 0.5% or more of the patients with non-intact tympanic membranes.

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

Acute Otitis Externa

The following adverse reactions occurred in 0.4% or more of the patients with intact tympanic membranes.

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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of CIPRODEX. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: auricular swelling, headache, hypersensitivity, otorrhea, skin exfoliation, rash erythematous, and vomiting.

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C:

No adequate and well controlled studies with CIPRODEX have been performed in pregnant women. Caution should be exercised when CIPRODEX is used by a pregnant woman.

Animal reproduction studies have not been conducted with CIPRODEX.

Reproduction studies with ciprofloxacin have been performed in rats and mice using oral doses of up to 100 mg/kg and intravenous (IV) doses up to 30 mg/kg, and have revealed no evidence of harm to the fetus. In rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose. After IV 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.

8.3 Nursing Mothers

Ciprofloxacin and corticosteroids, as a class, appear in milk following oral administration. Dexamethasone in breast milk could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical otic administration 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.

8.4 Pediatric Use

The safety and efficacy of CIPRODEX have been established in pediatric patients 6 months and older (937 patients) in adequate and well-controlled clinical trials.

No clinically relevant changes in hearing function were observed in 69 pediatric patients (age 4 to 12 years) treated with CIPRODEX and tested for audiometric parameters.

12.1 Mechanism of Action

Ciprofloxacin is a fluoroquinolone antibacterial [see Microbiology (12.4)].

Dexamethasone, a corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage and migration of inflammatory cells.

12.3 Pharmacokinetics

Following a single bilateral 4-drop (total dose = 0.28 mL, 0.84 mg ciprofloxacin, 0.28 mg dexamethasone) topical otic dose of CIPRODEX to pediatric patients after tympanostomy tube insertion, measurable plasma concentrations of ciprofloxacin and dexamethasone were observed at 6 hours following administration in 2 of 9 patients and 5 of 9 patients, respectively.

Mean ± SD peak plasma concentrations of ciprofloxacin were 1.39 ± 0.880 ng/mL (n = 9). Peak plasma concentrations ranged from 0.543 ng/mL to 3.45 ng/mL and were on average approximately 0.1% of peak plasma concentrations achieved with an oral dose of 250-mg. Peak plasma concentrations of ciprofloxacin were observed within 15 minutes to 2 hours post dose application.

Mean ± SD peak plasma concentrations of dexamethasone were 1.14 ± 1.54 ng/mL (n = 9). Peak plasma concentrations ranged from 0.135 ng/mL to 5.10 ng/mL and were on average approximately 14% of peak concentrations reported in the literature following an oral 0.5-mg tablet dose. Peak plasma concentrations of dexamethasone were observed within 15 minutes to 2 hours post dose application.

Dexamethasone has been added to aid in the resolution of the inflammatory response accompanying bacterial infection (such as otorrhea in pediatric patients with AOMT).

12.4 Microbiology

Mechanism of Action

The bactericidal action of ciprofloxacin results from interference with the enzyme, DNA gyrase, which is needed for the synthesis of bacterial DNA.

Resistance

Cross-resistance has been observed between ciprofloxacin and other fluoroquinolones. There is generally no cross-resistance between ciprofloxacin and other classes of anti-bacterial agents, such as beta-lactams or aminoglycosides.

Antimicrobial Activity

Ciprofloxacin has been shown to be active against most isolates of the following microorganisms, both in vitro and clinically in otic infections [see Indications and Usage (1)].

Aerobic Bacteria

Gram-positive Bacteria

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Staphylococcus aureus

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Streptococcus pneumoniae

Gram-negative Bacteria

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Haemophilus influenzae

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Moraxella catarrhalis

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Pseudomonas aeruginosa

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:

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Salmonella/Microsome Test (Negative)

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E. coli DNA Repair Assay (Negative)

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Mouse Lymphoma Cell Forward Mutation Assay (Positive)

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Chinese Hamster V79 Cell HGPRT Test (Negative)

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Syrian Hamster Embryo Cell Transformation Assay (Negative)

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Saccharomyces cerevisiae Point Mutation Assay (Negative)

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Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)

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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:

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Rat Hepatocyte DNA Repair Assay

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Micronucleus Test (Mice)

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Dominant Lethal Test (Mice)

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 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 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 vesicle, Cowper's gland, and accessory glands. The relevance of this study for short-term topical otic use is unknown.

13.2 Animal Toxicology and/or Pharmacology

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.