INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. CIPRODEX(R) 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 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 months and older), adult and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa.. Acute Otitis Media (AOM) in pediatric patients (age 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 months and older), adult and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa.. CIPRODEX is combination of ciprofloxacin, fluoroquinolone antibacterial and dexamethasone, 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 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 months and older), adult, and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa. (1) Acute Otitis Media (AOM) in pediatric patients (age 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 months and older), adult, and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa. (1).

ADVERSE REACTIONS SECTION.

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)] 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 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 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, 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 TubesThe following adverse reactions occurred in 0.5% or more of the patients with non-intact tympanic membranes.Adverse ReactionsIncidence (N 400)Ear discomfort3.0%Ear pain2.3%Ear precipitate (residue)0.5%Irritability0.5%Taste Perversion0.5%The following adverse reactions were each reported in single patient: tympanostomy tube blockage; ear pruritus; tinnitus; oral moniliasis; crying; dizziness; and erythema.Acute Otitis ExternaThe following adverse reactions occurred in 0.4% or more of the patients with intact tympanic membranes.Adverse ReactionsIncidence (N 537)Ear pruritus1.5%Ear debris0.6%Superimposed ear infection0.6%Ear congestion0.4%Ear pain0.4%Erythema 0.4%The following adverse reactions were each reported in 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 population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions include auricular swelling, headache, hypersensitivity, otorrhea, skin exfoliation, rash erythematous, and vomiting.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-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 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.Long-term studies have not been performed to evaluate the carcinogenic potential of topical otic dexamethasone.MutagenesisEight 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, of the tests were positive, but results of the following in vivo test systems gave negative results:Rat Hepatocyte DNA Repair AssayMicronucleus Test (Mice)Dominant Lethal Test (Mice)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.Impairment of FertilityFertility studies performed in male and female rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 482 times the ROHD of ciprofloxacin based on BSA) revealed no evidence of impairment. Male rats received oral ciprofloxacin for 10 weeks prior to mating and females were dosed for weeks prior to mating through GD 7.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 26-week study in male rats and resulted in changes to the testes, epididymis, sperm duct, prostate, seminal vesicle, Cowpers gland, and accessory glands. The relevance of this study for short-term topical otic use is unknown.. 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). Rat Hepatocyte DNA Repair Assay. Micronucleus Test (Mice). Dominant Lethal Test (Mice).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ciprofloxacin is fluoroquinolone antibacterial [see Microbiology (12.4)].Dexamethasone, 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 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 hours following administration in of patients and of 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 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 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.ResistanceCross-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 ActivityCiprofloxacin 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 BacteriaGram-positive BacteriaStaphylococcus aureusStreptococcus pneumoniaeGram-negative BacteriaHaemophilus influenzaeMoraxella catarrhalisPseudomonas aeruginosa. Staphylococcus aureus. Streptococcus pneumoniae. Haemophilus influenzae. Moraxella catarrhalis. Pseudomonas aeruginosa.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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, 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 TubesThe following adverse reactions occurred in 0.5% or more of the patients with non-intact tympanic membranes.Adverse ReactionsIncidence (N 400)Ear discomfort3.0%Ear pain2.3%Ear precipitate (residue)0.5%Irritability0.5%Taste Perversion0.5%The following adverse reactions were each reported in single patient: tympanostomy tube blockage; ear pruritus; tinnitus; oral moniliasis; crying; dizziness; and erythema.Acute Otitis ExternaThe following adverse reactions occurred in 0.4% or more of the patients with intact tympanic membranes.Adverse ReactionsIncidence (N 537)Ear pruritus1.5%Ear debris0.6%Superimposed ear infection0.6%Ear congestion0.4%Ear pain0.4%Erythema 0.4%The following adverse reactions were each reported in single patient: ear discomfort; decreased hearing; and ear disorder (tingling).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. CIPRODEX is contraindicated in patients with 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 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 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). CIPRODEX is contraindicated in patients with 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).

DESCRIPTION SECTION.

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 sterile, preserved suspension for otic use. Each mL of CIPRODEX contains ciprofloxacin hydrochloride (equivalent to mg ciprofloxacin base), mg dexamethasone, and 0.1 mg benzalkonium chloride as 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, 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 C17H18FN3O3.HCl.H2O. The molecular weight is 385.82 g/mol and the structural formula is:Figure 1: Structure of CiprofloxacinDexamethasone, 9-fluoro-11(beta),17,21-trihydroxy-16(alpha)-methylpregna-1,4-diene-3,20-dione, is corticosteroid. The empirical formula is C22H29FO5. The molecular weight is 392.46 g/mol and the structural formula is:Figure 2: Structure of Dexamethasone. Figure 1: Structure of Ciprofloxacin. Figure 2: Structure of Dexamethasone.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. CIPRODEX 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). 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. CIPRODEX is for otic use (ears) only, and not for ophthalmic use, or for injection.Shake well immediately before use.. 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 months and older) With Tympanostomy TubesThe recommended dosage regimen through tympanostomy tubes is as follows: 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.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 cold suspension.The patient should lie with the affected ear upward, and then the drops should be instilled.The tragus should then be pumped times by pushing inward to facilitate 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 months and older)The recommended dosage regimen is as follows: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.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 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.. 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.. 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 cold suspension.. The patient should lie with the affected ear upward, and then the drops should be instilled.. The tragus should then be pumped times by pushing inward to facilitate 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.. 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.. 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 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).For Otic Use OnlyAdvise patients that CIPRODEX is for otic use (ears) only. This product must not be used in the eye [see Dosage and Administration (2.2)].Administration InstructionsInstruct 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 ReactionsAdvise 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 ProductAdvise patients to avoid contaminating the tip with material from the ear, fingers, or other sources [see Instructions for Use].Duration of UseAdvise 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 LightAdvise patients to protect the product from light [see How Supplied/Storage and Handling (16)].Unused ProductAdvise patients to discard unused portion after therapy is completed [see Dosage and Administration (2.2)].Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936T2020-141.

INSTRUCTIONS FOR USE SECTION.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: November 2020INSTRUCTIONS FOR USECIPRODEX(R) (CI-PRO-DEX)(ciprofloxacin and dexamethasone)otic suspensionThis Instructions for Use contains information on how to use CIPRODEX.Important Information You Need to Know Before Using CIPRODEX.Read this Instructions for Use that comes with CIPRODEX before you start using it and each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.Use CIPRODEX exactly as your doctor tells you to use it.CIPRODEX is for use in the ear only (otic use). Do not inject CIPRODEX or use CIPRODEX in the eye.Shake CIPRODEX well before each use.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 use CIPRODEXStep 1. Wash your hands with soap and water (see Figure A). Figure Step 2. Warm the bottle of CIPRODEX by rolling the bottle between your hands for to minutes (see Figure B). Shake the bottle of CIPRODEX well. Figure Step 3. Remove the CIPRODEX cap. Put the cap in 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 C). Figure Step 5. Hold the bottle of CIPRODEX between your thumb and index finger (see Figure D). 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 DStep 6. Gently squeeze the bottle and let drops of CIPRODEX fall into the affected ear. If drop misses your ear, follow the instructions in Step again.Step 7. Stay on your side with the affected ear facing upward (see Figure C).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 middle ear infection, and you have tube in your eardrum known as tympanostomy: Gently press the part of the ear known as the tragus (see Figure E) times using pumping motion (see Figure E). This will allow the drops of CIPRODEX to enter your middle ear.Remain on your side with the affected ear facing upward (see Figure C) for minute. Figure If you use CIPRODEX to treat an outer ear canal infection:Gently pull the outer ear lobe upward and backward (see Figure F). This will allow the drops of CIPRODEX to enter your ear canal.Remain on your side with the affected ear facing upward (see Figure C) for minute.Figure FStep 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 store CIPRODEXStore CIPRODEX at room temperature between 68F to 77F (20C to 25C).Do not freeze CIPRODEX.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 CorporationEast Hanover, New Jersey 07936 (C) NovartisT2020-143. Use CIPRODEX exactly as your doctor tells you to use it.. CIPRODEX is for use in the ear only (otic use). Do not inject CIPRODEX or use CIPRODEX in the eye.. Shake CIPRODEX well before each use.. 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.. Gently press the part of the ear known as the tragus (see Figure E) times using pumping motion (see Figure E). This will allow the drops of CIPRODEX to enter your middle ear.. Remain on your side with the affected ear facing upward (see Figure C) for minute.. Gently pull the outer ear lobe upward and backward (see Figure F). This will allow the drops of CIPRODEX to enter your ear canal.. Remain on your side with the affected ear facing upward (see Figure C) for minute.. Store CIPRODEX at room temperature between 68F to 77F (20C to 25C).. Do not freeze CIPRODEX.. Keep CIPRODEX out of light.. wash. warm. sick. eardrop. up back. tragus.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-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 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.Long-term studies have not been performed to evaluate the carcinogenic potential of topical otic dexamethasone.MutagenesisEight 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, of the tests were positive, but results of the following in vivo test systems gave negative results:Rat Hepatocyte DNA Repair AssayMicronucleus Test (Mice)Dominant Lethal Test (Mice)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.Impairment of FertilityFertility studies performed in male and female rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 482 times the ROHD of ciprofloxacin based on BSA) revealed no evidence of impairment. Male rats received oral ciprofloxacin for 10 weeks prior to mating and females were dosed for weeks prior to mating through GD 7.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 26-week study in male rats and resulted in changes to the testes, epididymis, sperm duct, prostate, seminal vesicle, Cowpers gland, and accessory glands. The relevance of this study for short-term topical otic use is unknown.. 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). Rat Hepatocyte DNA Repair Assay. Micronucleus Test (Mice). Dominant Lethal Test (Mice). 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following 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 hours following administration in of patients and of 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 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 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).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on CIPRODEX use in pregnant women to evaluate for 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 CIPRODEX, 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 CIPRODEX. 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 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.DataAnimal DataCiprofloxacinDevelopmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. The doses used in these studies are, at 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. 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 embryo-fetal toxicity nor fetal malformations were observed. To mitigate maternal toxicity in these studies, groups of rabbits received ciprofloxacin for different day dosing period covering organogenesis (GD 6-18).DexamethasoneDexamethasone has been shown to be teratogenic in mice and rabbits following topical ophthalmic application. In 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: November 2020PATIENT INFORMATIONCIPRODEX(R) (CI-PRO-DEX)(ciprofloxacin and dexamethasone)otic suspensionWhat is CIPRODEXCIPRODEX is prescription medicine used in the ear only (otic use) that contains medicines, quinolone antibiotic medicine called ciprofloxacin and corticosteroid medicine called dexamethasone. CIPRODEX is used in adults and children months of age or older to treat certain types of infections caused by certain germs called bacteria. These bacterial infections include:middle ear infection (known as acute otitis media or AOM) in people who have tube in their eardrum known as tympanostomy to prevent having too much fluid in the middle earouter ear canal infection (known as acute otitis externa or AOE)It is not known if CIPRODEX is safe and effective in children under months of age.Who should not use CIPRODEXDo not use CIPRODEX if you:are allergic to ciprofloxacin, quinolones, or any of the ingredients in CIPRODEX. See the end of this Patient Information leaflet for complete list of ingredients in CIPRODEX.have an outer ear canal infection caused by certain viruses, including the herpes simplex virus.have an ear infection caused by fungus.What should tell my doctor before using CIPRODEXBefore using CIPRODEX, tell your doctor about all of your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if CIPRODEX will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if CIPRODEX passes into your breast milk. Talk to your doctor about the best way to feed your baby during treatment with CIPRODEX. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use CIPRODEXRead the detailed Instructions for Use that come with CIPRODEX.Use CIPRODEX exactly as your doctor tells you to.CIPRODEX is for use in the ear only (otic use). Do not use CIPRODEX in the eye or inject CIPRODEX.Apply drops of CIPRODEX into the affected ear times day for days.Do not stop using CIPRODEX unless your doctor tells you to, even if your symptoms improve.If your symptoms do not improve after days of treatment with CIPRODEX, call your doctor.Call your doctor right away if:you have fluid that continues to drain from your ear (otorrhea) after you have finished your treatment with CIPRODEXyou have fluid that drains from your ear or more times within months after you stop treatment with CIPRODEX What are the possible side effects of CIPRODEXCIPRODEX may cause serious side effects, including:allergic reactions. Stop using CIPRODEX and call your doctor or go to the nearest emergency room if you have any of the following signs or symptoms of an allergic reaction:hives (urticaria)swelling of your face, lips, mouth, or tonguerashitchingtrouble breathingdizziness, fast heartbeat, or pounding in your chestThe most common side effects of CIPRODEX include:ear discomfortear painear itching (pruritus)These are not all the possible side effects of CIPRODEX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store CIPRODEXStore CIPRODEX at room temperature between 68F to 77F (20C to 25C).Do not freeze CIPRODEX.Keep CIPRODEX out of light.Keep CIPRODEX and all medicines out of the reach of children.General information about the safe and effective use of CIPRODEX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use CIPRODEX for condition for which it was not prescribed. Do not give CIPRODEX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about CIPRODEX that is written for health professionals.What are the ingredients in CIPRODEX Active ingredients: ciprofloxacin hydrochloride, dexamethasone, and benzalkonium chloride as preservative Inactive ingredients: 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. Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936 (C) NovartisT2020-142. middle ear infection (known as acute otitis media or AOM) in people who have tube in their eardrum known as tympanostomy to prevent having too much fluid in the middle ear. outer ear canal infection (known as acute otitis externa or AOE). are allergic to ciprofloxacin, quinolones, or any of the ingredients in CIPRODEX. See the end of this Patient Information leaflet for complete list of ingredients in CIPRODEX.. have an outer ear canal infection caused by certain viruses, including the herpes simplex virus.. have an ear infection caused by fungus.. are pregnant or plan to become pregnant. It is not known if CIPRODEX will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if CIPRODEX passes into your breast milk. Talk to your doctor about the best way to feed your baby during treatment with CIPRODEX. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.. Read the detailed Instructions for Use that come with CIPRODEX.. Use CIPRODEX exactly as your doctor tells you to.. CIPRODEX is for use in the ear only (otic use). Do not use CIPRODEX in the eye or inject CIPRODEX.. Apply drops of CIPRODEX into the affected ear times day for days.. Do not stop using CIPRODEX unless your doctor tells you to, even if your symptoms improve.. Call your doctor right away if:you have fluid that continues to drain from your ear (otorrhea) after you have finished your treatment with CIPRODEXyou have fluid that drains from your ear or more times within months after you stop treatment with CIPRODEX you have fluid that continues to drain from your ear (otorrhea) after you have finished your treatment with CIPRODEX. you have fluid that drains from your ear or more times within months after you stop treatment with CIPRODEX. allergic reactions. Stop using CIPRODEX and call your doctor or go to the nearest emergency room if you have any of the following signs or symptoms of an allergic reaction:. hives (urticaria). swelling of your face, lips, mouth, or tongue. rash. itching. trouble breathing. dizziness, fast heartbeat, or pounding in your chest. ear discomfort. ear pain. ear itching (pruritus). Store CIPRODEX at room temperature between 68F to 77F (20C to 25C).. Do not freeze CIPRODEX.. Keep CIPRODEX out of light.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on CIPRODEX use in pregnant women to evaluate for 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 CIPRODEX, 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 CIPRODEX. 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 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.DataAnimal DataCiprofloxacinDevelopmental toxicology studies have been performed with ciprofloxacin in rats, mice, and rabbits. The doses used in these studies are, at 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. 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 embryo-fetal toxicity nor fetal malformations were observed. To mitigate maternal toxicity in these studies, groups of rabbits received ciprofloxacin for different day dosing period covering organogenesis (GD 6-18).DexamethasoneDexamethasone has been shown to be teratogenic in mice and rabbits following topical ophthalmic application. In 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 SummaryIt 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 CIPRODEX, 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 CIPRODEX 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 be considered along with the mothers clinical need for CIPRODEX and any potential adverse effects on the breast-fed child from CIPRODEX.. 8.4 Pediatric Use. The safety and efficacy of CIPRODEX have been established in pediatric patients 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 to 12 years) treated with CIPRODEX and tested for audiometric parameters.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity and anaphylaxis have been reported with systemic use of quinolones. Discontinue use if this occurs with use of CIPRODEX. (5.1)Prolonged use may result in overgrowth of non-susceptible bacteria and fungi. (5.2). Hypersensitivity and anaphylaxis have been reported with systemic use of quinolones. Discontinue use if this occurs with use of CIPRODEX. (5.1). Prolonged use may result in overgrowth of non-susceptible bacteria and fungi. (5.2). 5.1 Hypersensitivity Reactions. CIPRODEX should be discontinued at the first appearance of 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 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 tumor.