CIPROFLOXACIN-DEXAMETHASONE (Generic for CIPRODEX)

Ciprofloxacin; dexamethasone otic suspension is a combination of a fluoroquinolone antibacterial and a corticosteroid indicated for the treatment of acute otitis media (AOM) infections due to susceptible isolates of Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa in pediatric patients age 6 months and older who have tympanostomy tubes. It is also used for acute otitis externa (AOE) due to Staphylococcus aureus and Pseudomonas aeruginosa in pediatric patients age 6 months and older and in adult and elderly patients. Ciprofloxacin is a fluoroquinolone antibiotic with in vitro activity against a wide range of gram-positive and gram-negative microorganisms; topical use in the ear is not associated with ototoxicity. Dexamethasone is an anti-inflammatory corticosteroid and is included to aid in the resolution of the inflammatory response associated with the bacterial infection. The FDA approved ciprofloxacin; dexamethasone otic suspension on July 18, 2003.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Otic Administration
-Warm the suspension by holding the bottle in the hand for 1 to 2 minutes to avoid dizziness, which may result from instillation of a cold solution into the ear canal. Shake well immediately before using.
-Administer the drops without touching the tip of the bottle to the ear.
-The patient should lie with the affected ear upward during installation of the drops.
-For pediatric patients with acute otitis media, pump the tragus 5 times by pushing inward to facilitate penetration of the drops into the middle ear.
-The patient should continue to lie with the affected ear upward for 60 seconds to facilitate penetration of the drops into the ear.
-Administration may be repeated, if necessary, for the opposite ear.
-Discard unused portion after therapy is completed.

Ciprofloxacin; dexamethasone contains ciprofloxacin, a fluoroquinolone antibiotic. The widespread use of fluoroquinolone otic drops has resulted in the emergence of fluoroquinolone antimicrobial resistance; patients with recurrent otorrhea unresponsive to topical ciprofloxacin may need further evaluation. Culture and sensitivity testing may help guide management.

Some systemic adverse events noted with the use of the ciprofloxacin; dexamethasone otic suspension include irritability (0.5%) and dysgeusia (0.5%). Oral candidiasis, tinnitus, crying, and dizziness were each reported in a single patient. Headache, hypersensitivity, and vomiting were noted in post-marketing reports.

Local adverse events associated with the ciprofloxacin; dexamethasone otic suspension include ear discomfort (3%), ear pain/otalgia (0.4 to 2.3%), ear precipitate (0.5%), ear pruritus (1.5%), ear debris (0.6%), ear congestion (0.4%), and erythema (0.4%). Tympanostomy tube blockage, decreased hearing/hearing loss, and ear disorder (tingling) were each reported in a single patient. Auricular swelling, otorrhea, skin exfoliation, and erythematous rash were noted in post-marketing reports.

Ciprofloxacin; dexamethasone otic suspension is for otic use only; it is not for ophthalmic administration or parenteral administration.

Ciprofloxacin; dexamethasone otic suspension is contraindicated in persons with a history of hypersensitivity to ciprofloxacin or any member of the quinolone class of antimicrobial agents (quinolone hypersensitivity) or to dexamethasone (corticosteroid hypersensitivity). Discontinue ciprofloxacin; dexamethasone at the first appearance of a skin rash or any other sign of hypersensitivity.

Ciprofloxacin; dexamethasone otic suspension is contraindicated for use by patients with a viral infection of the external canal including a herpes infection. As with other antibiotic preparations, use of ciprofloxacin; dexamethasone may result in overgrowth of nonsusceptible organisms including bacteria and fungi. If the infection is not improved after one week of therapy, cultures should be obtained to guide further treatment. If such infections occur, discontinue use and institute alternative therapy. If otorrhea (ear discharge) 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. The widespread use of fluoroquinolone otic drops has resulted in the emergence of fluoroquinolone antimicrobial resistance; patients with recurrent ear discharge unresponsive to topical ciprofloxacin may need further evaluation. Culture and sensitivity testing may help guide management. In clinical trials of ciprofloxacin; dexamethasone otic suspension, patients were required to be free of fungal infection or mycobacterial infection of the ears, active herpes infection (e.g., herpes simplex), overt viral infection of the tympanic membrane (e.g., varicella), and other related disorders.

There are no available data on ciprofloxacin; dexamethasone topical otic use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, developmental toxicity and embryotoxicity have been observed following ophthalmic and oral administration of dexamethasone. Because of the minimal systemic absorption of ciprofloxacin and dexamethasone after topical otic administration, there is expected to be minimal risk for maternal and fetal toxicity when administered during pregnancy. Animal studies have not been conducted with ciprofloxacin; dexamethasone otic.

It is not known whether ciprofloxacin and dexamethasone are present in human breast milk after topical otic administration. Ciprofloxacin is present in human milk after oral administration; however, because of the minimal systemic absorption of ciprofloxacin after topical otic administration, breast-feeding is not expected to result in the exposure of the infant to ciprofloxacin. Systemically administered corticosteroids appear in human milk and dexamethasone in breast milk could suppress growth, interfere with endogenous corticosteroid production, or cause untoward effects. However, it is not known whether topical otic administration could result in systemic absorption that is sufficient to product detectable quantities of dexamethasone in human milk. There are no data of the effects of ciprofloxacin or dexamethasone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ciprofloxacin; dexamethasone and any potential adverse effects on the breast-fed child.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Moraxella catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus (MSSA), Streptococcus pneumoniae
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of acute otitis media in children with tympanostomy tubes:
Otic dosage:
Infants and Children 6 months and older: 4 drops in the affected ear(s) twice daily for 7 days.

For the treatment of acute otitis externa due to susceptible organisms:
Otic dosage:
Adults: 4 drops instilled into the affected ear(s) twice daily for 7 days.
Infants, Children, and Adolescents 6 months to 17 years: 4 drops instilled into the affected ear(s) twice daily for 7 days.

Maximum Dosage Limits:
-Adults
8 drops/day to affected ear(s).
-Geriatric
8 drops/day to affected ear(s).
-Adolescents
8 drops/day to affected ear(s).
-Children
8 drops/day to affected ear(s).
-Infants
6 months and older: 8 drops/day to affected ear(s).
younger than 6 months: Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.

Patients with Renal Impairment Dosing
No dosage adjustments are needed.

*non-FDA-approved indication

There are no drug interactions associated with Ciprofloxacin; Dexamethasone products.

Mechanism of Action:-Ciprofloxacin: Ciprofloxacin is bactericidal via inhibition of DNA gyrase (topoisomerase II), an enzyme responsible for counteracting the excessive supercoiling of DNA during replication or transcription, and topoisomerase IV, an enzyme that helps separate the daughter DNA molecules. In gram-negative bacteria, the primary target is the DNA gyrase A subunit, while the primary target in gram-positive bacteria is generally topoisomerase IV.
-Dexamethasone: Dexamethasone is a potent glucocorticoid. Glucocorticoids prevent or suppress inflammation and immune responses when administered at pharmacological doses. At the molecular level, unbound glucocorticoids readily cross cell membranes and bind with high affinity to specific cytoplasmic receptors. This binding induces a response by modifying transcription and, ultimately, protein synthesis to achieve the steroid's intended action. Such actions can include inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, and suppression of humoral immune responses. Some of the net effects include reduction in edema or scar tissue and a general suppression in immune response. The anti-inflammatory actions of corticosteroids are thought to involve phospholipase A2 inhibitory proteins, collectively called lipocortins. Lipocortins, in turn, control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid.

Ciprofloxacin; dexamethasone otic suspension is administered topically to the ear. The half-life of ciprofloxacin was 3 +/- 1.2 hours and dexamethasone was 3.9 +/- 2.9 hours after administration of 4 drops of ciprofloxacin; dexamethasone through tympanostomy tubes in each ear (8 drops/child) to pediatric patients 1 to 14 years of age.


-Route-Specific Pharmacokinetics
Other Route(s)
Otic Route
-Ciprofloxacin: After tympanostomy tube insertion and 6 hours after administration of 4 drops to each ear, measurable plasma concentrations of ciprofloxacin were observed in 2 of 9 pediatric patients. Peak plasma ciprofloxacin concentrations were noted within 2 hours of administration, the mean was 1.39 +/- 0.880 ng/mL (range, 0.543 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. Serum drug concentrations were measured 6 hours after administration of 4 drops of ciprofloxacin; dexamethasone through tympanostomy tubes in each ear (8 drops/child) to pediatric patients 1 to 14 years of age; 4 of 25 children had ciprofloxacin concentrations 0.5 ng/mL or greater. In 10 adults, no measurable ciprofloxacin (lowest detectable limit of 0.5 mcg/mL) in the labyrinthine fluid, cerebrospinal fluid, or serum was noted after installation of 0.5 mL of 0.3% ciprofloxacin solution into the middle ear. The time interval between the ciprofloxacin application to the round window membrane and sampling of labyrinthine fluid and plasma ranged from 9 to 120 minutes. The data suggest a lack of absorption through the round window membrane.
-Dexamethasone: After tympanostomy tube insertion and 6 hours after administration of 4 drops to each ear, measurable plasma concentrations of dexamethasone were noted in 5 of 9 pediatric patients. Peak plasma dexamethasone concentrations were noted within 2 hours of administration, the mean was 1.14 +/- 1.54 ng/mL (range, 0.135 to 5.1 ng/mL), and were on average approximately 14% of peak plasma concentrations reported in the literature after an oral 0.5 mg tablet dose. Serum drug concentrations were measured 6 hours after administration of 4 drops of ciprofloxacin; dexamethasone through tympanostomy tubes in each ear (8 drops/child) to pediatric patients 1 to 14 years of age; 14 of 24 pediatric patients had dexamethasone concentrations 0.05 ng/mL or greater.