CIPRODEX

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: 1. Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 2. 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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 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. Adverse Reactions Incidence (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. Adverse Reactions Incidence (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 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.

4 CONTRAINDICATIONS • CIPRODEX 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. • CIPRODEX 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 )

11 DESCRIPTION CIPRODEX (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 CIPRODEX contains ciprofloxacin hydrochloride (equivalent to 3 mg ciprofloxacin base), 1 mg dexamethasone, and 0.1 mg benzalkonium chloride as a preservative. The inactive ingredients are acetic acid, boric acid, edetate disodium, hydroxyethyl cellulose , purified water, sodium acetate, sodium chloride, and tyloxapol. 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 empirical 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: Dexamethasone, 9-fluoro-11(beta),17,21-trihydroxy-16(alpha)-methylpregna-1,4-diene-3,20-dione, is a corticosteroid. The empirical formula is C 22 H 29 FO 5 . The molecular weight is 392.46 g/mol and the structural formula is: ciprofloxacin chemical diagram dexamethasone chemical diagram

2 DOSAGE AND ADMINISTRATION CIPRODEX is for otic use (ears) only, not for ophthalmic use, or for injection. ( 2.1 ) 3. Shake well immediately before use. ( 2.1 ) 4. Instill four drops into the affected ear twice daily, for seven days. ( 2 ) 2.1 Important Administration Instructions • CIPRODEX 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: 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.

1 INDICATIONS AND USAGE CIPRODEX is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the specific conditions listed below: 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 . Acute Otitis Externa (AOE) in pediatric (age 6 months and older), adult and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa . CIPRODEX 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: • 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)

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

12 CLINICAL PHARMACOLOGY 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 • Staphylococcus aureus • Streptococcus pneumoniae Gram-negative Bacteria • Haemophilus influenzae • Moraxella catarrhalis • Pseudomonas aeruginosa

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).

20200301

3

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

CIPRODEX ciprofloxacin and dexamethasone Ciprofloxacin Hydrochloride Ciprofloxacin Dexamethasone Dexamethasone Benzalkonium Chloride Boric Acid Sodium Chloride Hydroxyethyl Cellulose (1500 Mpa.s At 1%) Tyloxapol Acetic Acid Sodium Acetate Edetate Disodium Water Sodium Hydroxide Hydrochloric Acid

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.

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: • 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) 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 NONCLINICAL TOXICOLOGY 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: • 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) 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.

NDA021537

CIPRODEX

ciprofloxacin and dexamethasone

71205-309

HUMAN PRESCRIPTION DRUG

AURICULAR (OTIC)

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 • Staphylococcus aureus • Streptococcus pneumoniae Gram-negative Bacteria • Haemophilus influenzae • Moraxella catarrhalis • Pseudomonas aeruginosa

PRINCIPAL DISPLAY PANEL NDC 71205-309-75 Rx Only CIPRODEX ® (ciprofloxacin 0.3% and dexamethasone 0.1%) STERILE OTIC SUSPENSION 7.5 mL Alcon ® a Novartis company 71205-309-75

Dosage and Administration, Important Administration Instructions ( 2.1 ) 2/2019

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). For Otic Use Only Advise patients that CIPRODEX is for otic use (ears) only. This product must not be used in the eye. Administration Instructions Instruct patients to warm the bottle in their hand for one to two minutes prior to use and shake well immediately before using [see Dosage and Administration (2.1, 2.2)] . Allergic Reactions Advise patients to discontinue use immediately and contact their physician, if rash or allergic reaction occurs [see Warnings and Precautions (5.1)] . Avoid Contamination of the Product Advise patients to avoid contaminating the tip with material from the ear, fingers, or other sources [see Instructions for Use] . Duration of Use Advise patients that it is very important to use the eardrops for as long as their doctor has instructed, even if the symptoms improve [see Patient Information] . Protect From Light Advise patients to protect the product from light [see How Supplied/Storage and Handling (16)] . Unused Product Advise patients to discard unused portion after therapy is completed [see Dosage and Administration (2.2)] . DROP-TAINER is a trademark of Alcon. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Relabeled by: Proficient Rx LP Thousand Oaks, CA 91320 T2019-37

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: February 2019 Instructions for Use CIPRODEX (CI-PRO-DEX) (ciprofloxacin and dexamethasone) otic suspension Read this Instructions for Use that comes with CIPRODEX before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. Important information about CIPRODEX: 1. Use CIPRODEX exactly as your doctor tells you to use it. 2. CIPRODEX is for use in the ear only (otic use). Do not inject CIPRODEX or use CIPRODEX in the eye. 3. Shake CIPRODEX well before each use. 4. Do not touch your ear, fingers, or other surfaces with the tip of the CIPRODEX bottle. You may get bacteria on the tip of the bottle that can cause you to get another infection. How should I use CIPRODEX? Step 1. Wash your hands with soap and water. Step 2. Warm the bottle of CIPRODEX by rolling the bottle between your hands for 1 to 2 minutes (See Figure A). Shake the bottle of CIPRODEX well. Figure A Step 3. Remove the CIPRODEX cap. Put the cap in a clean and dry area. Do not let the tip of the bottle touch your ear, fingers or other surfaces. Step 4. Lie down on your side so that the affected ear faces upward (See Figure B). Figure B Step 5 . Hold the bottle of CIPRODEX between your thumb and index finger ( See Figure C ). Place the tip of the bottle close to your ear. Be careful not to touch your fingers or ear with the tip of the bottle . Figure C Step 6 . Gently squeeze the bottle and let 4 drops of CIPRODEX fall into the affected ear. If a drop misses your ear, follow the instructions in Step 5 again. Step 7. Stay on your side with the affected ear facing upward (See Figure B). It is important that you follow the instructions below for your specific ear infection, to allow CIPRODEX to enter the affected part of your ear. Step 8. If you use CIPRODEX to treat a middle ear infection, and you have a tube in your eardrum known as a tympanostomy: 1. Gently press the part of the ear known as the tragus (See Figure D) 5 times using a pumping motion ( See Figure D ). This will allow the drops of CIPRODEX to enter your middle ear. 2. Remain on your side with the affected ear facing upward ( See Figure B ) for 1 minute . Figure D If you use CIPRODEX to treat an outer ear canal infection: 1. Gently pull the outer ear lobe upward and backward ( See Figure E ). This will allow the drops of CIPRODEX to enter your ear canal. 2. Remain on your side with the affected ear facing upward ( See Figure B ) for 1 minute . Figure E Step 9 . If your doctor has told you to use CIPRODEX in both ears, repeat steps 5-8 for your other ear. Step 10 . Put the cap back on the bottle and close it tightly. Step 11 . After you have used all of your CIPRODEX doses, there may be some CIPRODEX left in the bottle. Throw the bottle away. How should I store CIPRODEX? 1. Store CIPRODEX at room temperature between 68°F to 77°F (20°C to 25°C). 2. Do not freeze CIPRODEX. 3. Keep CIPRODEX out of light. Keep CIPRODEX and all medicines out of the reach of children. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for more information about CIPRODEX that is written for health professionals. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Relabeled by: Proficient Rx LP Thousand Oaks, CA 91320 © Novartis T2019-39 wash warm sick eardrop tragus up back

14 CLINICAL STUDIES In a randomized, multicenter, controlled clinical trial, CIPRODEX dosed 2 times per day for 7 days demonstrated clinical cures in the per protocol analysis in 86% of AOMT patients compared to 79% for ofloxacin solution, 0.3%, dosed 2 times per day for 10 days. Among culture positive patients, clinical cures were 90% for CIPRODEX compared to 79% for ofloxacin solution, 0.3%. Microbiological eradication rates for these patients in the same clinical trial were 91% for CIPRODEX compared to 82% for ofloxacin solution, 0.3%. In 2 randomized multicenter, controlled clinical trials, CIPRODEX dosed 2 times per day for 7 days demonstrated clinical cures in 87% and 94% of per protocol evaluable AOE patients, respectively, compared to 84% and 89%, respectively, for otic suspension containing neomycin 0.35%, polymyxin B 10,000 units/mL, and hydrocortisone 1.0% (neo/poly/HC). Among culture positive patients clinical cures were 86% and 92% for CIPRODEX compared to 84% and 89%, respectively, for neo/poly/HC. Microbiological eradication rates for these patients in the same clinical trials were 86% and 92% for CIPRODEX compared to 85% and 85%, respectively, for neo/poly/HC.

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.

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 USE IN SPECIFIC POPULATIONS 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied: CIPRODEX (ciprofloxacin 0.3% and dexamethasone 0.1%) Sterile Otic Suspension is a white-to off-white suspension supplied as follows: 7.5 mL fill in a DROP-TAINER ® system. The DROP-TAINER system consists of a natural polyethylene bottle and natural plug, with a white polypropylene closure. Tamper evidence is provided with a shrink band around the closure and neck area of the package. 7.5 mL fill NDC 71205-309-75 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.