Ciprofloxacin and Dexamethasone

1 INDICATIONS AND USAGE Ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension USP is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the specific conditions listed below:(1) • Acute Otitis Media (/\OM) in pediatric patients (age 6 months and older with tympanostomy tubes due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa (1) Acute Otitis Externa (AOE) in pediatric (age 6 months and older), adult and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa .(1) Ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension is a combination of ciprofloxacin, a fluoroquinolone antibacterial and dexamethasone, a corticosteroid, indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the specific conditions listed below:(1) • Acute Otitis Media (AOM) in pediatric patients (age 6 months and older with tympanostomy tubes due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa (1) Acute Otitis Externa (AOE) in pediatric (age 6 months and older), adult, and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa . (1)

2 DOSAGE AND ADMINISTRATION Ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension is for otic use (ears) only, not for ophthalmic use, or for injection. (2.1) Shake well immediately before use. (2.1) Instill four drops into the affected ear twice daily, for seven days. (2.2) 2.1 Important Administration Instructions Ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension is for otic use (ears) only, and not for ophthalmic use, or for injection. 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: • Four drops [equivalent to 0.14 ml of ciprofloxacin 0.3% and dexamethasone 0.1 % otic suspension, (consisting of 0.42 mg of ciprofloxacin and 0.14 mg of 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 ortwo minutes to avoid dizziness, which may result from the instillation of acold suspension. • The patient should lie with the affected ear upward, and then the drops should be instilled. • The tragus should then be pumped 5 times by pushing inward to facilltate 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. For the Treatment of Acute Otitis Externa (age 6 months and older) The recommended dosage regimen is as follows: Four drops [equivalent to 0.14 mL of ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension, (consisting of 0.42 mg ciprofloxacin and 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. The tragus should then be pumped 5 times by pushing inward ID facilltate penetration of the drops into the middle ear. 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.

3 DOSAGE FORMS AND STRENGTHS Ciprofloxacin and dexamethasone otic suspension, USP: Each mL contains ciprofloxacin hydrochloride USP, 0.3% (equivalent to 3 mg ciprofloxacin base) and dexamethasone USP, 0.1% (equivalent to 1 mg dexamethasone, USP). Otic Suspension: Each mL of ciprofloxacin and dexamethasone otic suspension, USP contains ciprofloxacin hydrochloride USP, 0.3% (equivalent to 3 mg ciprofloxacin base) and dexamethasone USP, 0.1% (equivalent to 1 mg dexamethasone, USP). ( 3 )

4 CONTRAINDICATIONS Ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to other quinolones, or to any of the components in this medication. Use of this product is contraindicated in viral infections of the external canal, including herpes simplex infections and fungal otic infections. • Ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to other quinolones, or to any of the components in this medication. ( 4 ) • Use of this product is contraindicated in viral infections of the external canal, including herpes simplex infections and fungal otic infections. (4)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] • Potential for Microbial Overgrowth with Prolonged Use [see Warnings and Precautions ( 5.2)] Most common adverse reactions were ear discomfort (3%), ear pain (2.3%), and ear pruritus (1.5%). (6) To report SUSPECTED ADVERSE REACTIONS, contact Dr. REDDY’S LABORATORIES Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension. 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. Ad v erse Reactions In cidence (N=400) Ear discomfort 3.0% Ear pain 2.3% Ear precipitate (residue) 0.5% Irritability 0.5% Taste Perversion 0.5% 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. Ad v erse Reactions In cidence (N=537) Ear pruritus 1.5% Ear debris 0.6% Superimposed ear infection 0.6% Ear congestion 0.4% Ear pain 0.4% Erythema 0.4% 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 ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension. 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Because of the minimal systemic absorption of ciprofloxacin and dexamethasone following topical otic administration of ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension, this product is expected to be of minimal risk for maternal and fetal toxicity when administered to pregnant women [see Clinical Pharmacology ( 12.3 )]. Animal reproduction studies have not been conducted with ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension. Oral administration of ciprofloxacin during organogenesis at doses up to 100 mg/kg to pregnant mice and rats, and up to 30 mg/kg to pregnant rabbits did not cause fetal malformations (see Data). These doses were at least 200 times the recommended otic human dose (ROHD in mice, rats, and rabbits, respectively, based on body surface area (BSA). With dexamethasone, malformations have been observed in animal studies after ocular and systemic administration. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20% respectively. Data Animal Data Ciprofloxacin Developmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. The doses used in these studies are, at a minimum, approximately 200 times greater than the recommended otic human dose based on body surface area. In rats and mice, oral doses up to 100 mg/kg administered during organogenesis (Gestation Days (GD), 6-17) were not associated with adverse developmental outcomes, including embryofetal toxicity or malformations. A 30 mg/kg oral dose was associated with suppression of maternal and fetal body weight gain, but fetal malformations were not observed. Intravenous administration of doses up to 20 mg/kg to pregnant rabbits was not maternally toxic and neither embryofetal toxicity nor fetal malformations were observed. To mitigate maternal toxicity in these studies, groups of rabbits received ciprofloxacin for a different 5 day dosing period covering organogenesis (GD 6-18). Dexamethasone Dexamethasone has been shown to be teratogenic in mice and rabbits following topical ophthalmic application. In a rat oral developmental toxicity study, no adverse effects were observed at 0.01 mg/kg/day (0.1 times the ROHD based on BSA), although embryotoxicity was observed at higher doses. 8.2 Lactation Risk Summary It is not known whether ciprofloxacin and dexamethasone are present in human milk following topical otic administration. Published literature reports the presence of ciprofloxacin in human milk after oral administration to lactating women. However, because of the minimal systemic absorption of ciprofloxacin following topical otic administration of ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension, breastfeeding is not expected to result in the exposure of the infant to ciprofloxacin [see Clinical Pharmacology ( 12.3 )]. Systemically administered corticosteroids appear in human milk. Dexamethasone in breast milk could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. However, it is not known whether topical otic administration of ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension could result in systemic absorption that is sufficient to produce detectable quantities of dexamethasone in human milk. There are no data on the effects of ciprofloxacin or dexamethasone on milk production. The developmental and health benefits of breastfeeding should b …

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.

11 DESCRIPTION Ciprofloxacin and dexamethasone (ciprofloxacin 0.3% and dexamethasone 0.1%) sterile otic suspension contains the quinolone antimicrobial, ciprofloxacin hydrochloride, combined with the corticosteroid, dexamethasone, in a sterile, preserved suspension for otic use. Each mL of ciprofloxacin and dexamethasone otic suspension, USP contains ciprofloxacin hydrochloride, USP (equivalent to 3 mg ciprofloxacin base), 1 mg dexamethasone, USP, and 0.2 mg benzalkonium chloride (50%) as a preservative. The inactive ingredients are boric acid, sodium chloride, hydroxyl ethyl cellulose, tyloxapol, acetic acid, sodium acetate trihydrate, edetate disodium, and water for injection. Sodium hydroxide or hydrochloric acid may be added for adjustment of pH. Ciprofloxacin, a quinolone antimicrobial is available as the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid. The molecular formula is C 17 H 18 FN 3 O 3 •HCl•H 2 O. The molecular weight is 385.82 g/mol and the structural formula is: Figure 1: Structure of Ciprofloxacin Dexamethasone, 9-fluoro-11(beta),17,21-trihydroxy-16(alpha)-methylpregna-1,4-diene-3,20-dione, is a corticosteroid. The molecular formula is C 22 H 29 FO 5 . The molecular weight is 392.46 g/mol and the structural formula is: Figure 2: Structure of Dexamethasone spl-ciprofoxacin-structure spl-dexamethasone-structure

10 OVERDOSAGE Due to the characteristics of this preparation, no toxic effects are to be expected with an otic overdose of this product.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied: Ciprofloxacin 0.3% and Dexamethasone 0.1% Otic Suspension USP, is white to off-white suspension supplied as follows: 7.5 mL fill in 10 mL low density polyethylene bottle. The packaging system consists of a 10 mL low density polyethylene plastic squeeze bottle, a natural low density polyethylene dropper tip and a high density polyethylene tamper evident screw cap for dropper bottle. 7.5 mL fill, NDC 85766-245-75 (relabeled from NDC 43598-326-75) Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [see USP Controlled Room Temperature]. Avoid freezing. Protect from light.