CIPROFLOXACIN AND FLUOCINOLONE ACETONIDE solution

Ciprofloxacin and Fluocinolone Acetonide by

Drug Labeling and Warnings

Ciprofloxacin and Fluocinolone Acetonide by is a Prescription medication manufactured, distributed, or labeled by Wilshire Pharmaceuticals, The Ritedose Corporation. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution is indicated for the treatment of acute otitis media with tympanostomy tubes (AOMT) in pediatric patients (aged 6 months and older) due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa.

  • 2 DOSAGE AND ADMINISTRATION

    • Ciprofloxacin and Fluocinolone Acetonide Otic Solution is for otic use only. It is not for ophthalmic use, or for injection.

    The recommended dosage regimen is as follows:

    • Instill the contents of one single-dose vial 0.25 mL into the affected ear canal twice daily (approximately every 12 hours) for 7 days. Use this dosing for patients aged 6 months of age and older.
    • Warm the solution by holding the vial in the hand for 1 to 2 minutes. This is to avoid dizziness, which may result from the instillation of a cold solution into the ear canal.
    • The patient should lie with the affected ear upward, and then instill the medication.
    • Pump the tragus 4 times by pushing inward to facilitate penetration of the medication into the middle ear.
    • Maintain this position for 1 minute. Repeat, if necessary, for the opposite ear [see Instructions for Use].
  • 3 DOSAGE FORMS AND STRENGTHS

    Otic Solution: Each single-dose vial of Ciprofloxacin and Fluocinolone Acetonide Otic Solution (ciprofloxacin 0.3 % and fluocinolone acetonide 0.025 %) delivers 0.25 mL of solution equivalent to ciprofloxacin 0.75 mg and fluocinolone acetonide 0.0625 mg.

  • 4 CONTRAINDICATIONS

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution is contraindicated in:

    • Patients with known hypersensitivity to fluocinolone acetonide or other corticosteroids, ciprofloxacin or other quinolones, or to any other components of Ciprofloxacin and Fluocinolone Acetonide Otic Solution.
    • Viral infections of the external ear canal, including varicella and herpes simplex infections and fungal otic infections.
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity Reactions

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

    5.2 Potential for Microbial Overgrowth with Prolonged Use

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

    5.3 Continued or Recurrent Otorrhea

    If otorrhea persists after a full course of therapy, or if two or more episodes of otorrhea occur within 6 months, further evaluation is recommended to exclude an underlying condition such as cholesteatoma, foreign body, or a tumor.

  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are described elsewhere in the labeling:

    Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

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

    In clinical trials, 224 patients with AOMT were treated with Ciprofloxacin and Fluocinolone Acetonide Otic Solution for a median duration of 7 days. All the patients received at least one dose of Ciprofloxacin and Fluocinolone Acetonide Otic Solution. There were 220 patients who received at least one dose of ciprofloxacin (CIPRO) and 213 patients received at least one dose of fluocinolone acetonide (FLUO).

    The most common adverse reactions that occurred in 1 or more patients are as follows:

    Table 1: Selected Adverse Reactions that Occurred in 1 or more Patients in the Ciprofloxacin and Fluocinolone Acetonide Otic Solution Group
    Adverse Reactions*Number (%) of Patients
    Ciprofloxacin and Fluocinolone Acetonide Otic Solution
    N=224    		CIPRO
    N=220    		FLUO
    N=213
  • * Selected adverse reactions that occurred in ≥ 1 patient in the Ciprofloxacin and Fluocinolone Acetonide Otic Solution group derived from all reported adverse events that could be related to the study drug or the drug class.
    		•
    Otorrhea12 (5.4%)9 (4.1%)12 (5.6%)
    Excessive granulation tissue3 (1.3%)0 (0.0%)2 (0.9%)
    Ear infection2 (0.9%)3 (1.4%)1 (0.5%)
    Ear pruritus2 (0.9%)1 (0.5%)1 (0.5%)
    Tympanic membrane disorder2 (0.9%)0 (0.0%)0 (0.0%)
    Auricular swelling1 (0.4%)1 (0.5%)0 (0.0%)
    Balance disorder1 (0.4%)0 (0.0%)0 (0.0%)

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during postapproval use of ciprofloxacin and fluocinolone acetonide otic solution, 0.3% / 0.025% outside the US. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    • Immune system disorders: allergic reaction.
    • Infections and infestations: candidiasis.
    • Nervous system disorders: dysgeusia, paresthesia (tingling in ears), dizziness, headache.
    • Ear and labyrinth disorders: ear discomfort, hypoacusis, tinnitus, ear congestion.
    • Vascular disorders: flushing.
    • Skin and subcutaneous tissue disorders: skin exfoliation.
    • Injury, poisoning and procedural complications: device occlusion (tympanostomy tube obstruction).
  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution is negligibly absorbed following otic administration and maternal use is not expected to result in fetal exposure to ciprofloxacin and fluocinolone acetonide [see Clinical Pharmacology (12.3)].

    8.2 Lactation

    Risk Summary

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution is negligibly absorbed by the mother following otic administration and breastfeeding is not expected to result in exposure of the infant to ciprofloxacin and fluocinolone acetonide [see Clinical Pharmacology (12.3)].

    8.4 Pediatric Use

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution has been studied in patients as young as 6 months in adequate and well-controlled clinical trials. No major differences in safety and effectiveness have been observed between adult and pediatric patients [see Indications and Usage (1) and Dosage and Administration (2)].

    8.5 Geriatric Use

    Clinical studies of Ciprofloxacin and Fluocinolone Acetonide Otic Solution did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

  • 10 OVERDOSAGE

    Due to the characteristics of this preparation, no toxic effects are to be expected with an otic overdose of Ciprofloxacin and Fluocinolone Acetonide Otic Solution.

  • 11 DESCRIPTION

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution, 0.3% / 0.025% is a sterile, preservative-free, clear otic solution containing the fluoroquinolone antibacterial, ciprofloxacin hydrochloride, combined with the corticosteroid, fluocinolone acetonide. Each single-dose vial contains a deliverable volume of 0.25 mL solution of ciprofloxacin hydrochloride equivalent to 0.75 mg ciprofloxacin and 0.0625 mg fluocinolone acetonide. The pH of the solution ranges from 3.5 to 5.0. The inactive ingredients are polysorbate 80, glycerin, povidone K90F and water for injection.

    Ciprofloxacin is available as the monohydrochloride, monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its molecular formula is C17H18FN3O3∙HCl∙H2O.

    The chemical structure of ciprofloxacin hydrochloride is:

    Chemical Structure

    The chemical name of fluocinolone acetonide is (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy- 16,17[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione, cyclic 16,17 acetal with acetone[67-73-2]. Its molecular formula is C24H30F2O6.

    The chemical structure of fluocinolone acetonide is:

    Chemical Structure

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

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

    Fluocinolone acetonide, a corticosteroid, inhibits the local biosynthesis of prostaglandins, which explains part of its anti-inflammatory efficacy. At the cellular level, corticosteroids induce peptides called lipocortins. Lipocortins antagonize phospholipase A2, an enzyme which causes the breakdown of leukocyte lysosomal membranes to release arachidonic acid. This action decreases the subsequent formation and release of endogenous inflammatory mediators including prostaglandins, kinins, histamine, liposomal enzymes and the complement system.

    12.3 Pharmacokinetics

    In two studies in children with AOMT aged ≥ 6 months to 12 years, blood samples were taken in subgroups of 16 and 14 patients, at Visit 1 (prior to the first dose) and Visit 3 (within 1 and 2 hours after the last dose) respectively, to determine the plasma concentrations of ciprofloxacin and/or fluocinolone acetonide following administration of Ciprofloxacin and Fluocinolone Acetonide Otic Solution at the recommended dosage regimen of 0.25 mL twice daily. Pharmacokinetic (PK) analysis resulted in only 1 sample showing a detectable concentration of ciprofloxacin in plasma of 3.0 mcg/L after 7 days of treatment, and no detectable concentrations in plasma of fluocinolone acetonide were observed. However, the sample with detectable ciprofloxacin concentrations was from a patient who had bilateral AOMT (protocol deviation because all patients participating in the PK study were to have unilateral otorrhea) and who received treatment in both ears with ciprofloxacin 0.3% otic solution, the active comparator.

    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

    Bacterial resistance to quinolones can develop through chromosomal or plasmid-mediated mechanisms.

    In vitro studies demonstrated cross-resistance between ciprofloxacin and some fluoroquinolones. There is generally no cross-resistance between ciprofloxacin and other classes of antibacterial agents such as beta-lactams or aminoglycosides.

    Antimicrobial Activity

    Ciprofloxacin has been shown to be active against most isolates of the following bacteria, 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:
    Pseudomonas aeruginosa
    Haemophilus influenzae
    Moraxella catarrhalis

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    No long term studies of Ciprofloxacin and Fluocinolone Acetonide Otic Solution have been performed to evaluate carcinogenic potential.

    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.

    Long-term animal studies have not been performed to evaluate the carcinogenic potential of fluocinolone acetonide.

    Mutagenesis

    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)

    Studies have not been performed to evaluate the mutagenic potential of fluocinolone acetonide. Some corticosteroids have been found to be genotoxic.

    Impairment of Fertility

    No reproduction toxicity studies were conducted with Ciprofloxacin and Fluocinolone Acetonide Otic Solution. Absorption of ciprofloxacin and fluocinolone acetonide following otic administration of Ciprofloxacin and Fluocinolone Acetonide Otic Solution at the recommended dosage is negligible [see Clinical Pharmacology (12.3)].

  • 14 CLINICAL STUDIES

    Two phase 3 multicenter, randomized, double-blind, active-controlled, parallel group trials were conducted in 662 pediatric patients in total (aged 6 months to 12 years old) with AOMT, to assess the efficacy and safety of Ciprofloxacin and Fluocinolone Acetonide Otic Solution compared to ciprofloxacin otic solution and to fluocinolone acetonide otic solution (Trial 1 and Trial 2).

    In both trials, the Ciprofloxacin and Fluocinolone Acetonide Otic Solution treatment arms showed significantly shorter times to cessation of otorrhea in comparison to both the ciprofloxacin and fluocinolone acetonide alone arms demonstrating the contribution of both components of Ciprofloxacin and Fluocinolone Acetonide Otic Solution. The results are presented in the table below:

    Table 2: Results of the Primary Endpoint: Time to Cessation of Otorrhea (Trial 1 and Trial 2)
    Treatment arm
    n.e.: not estimable because the number of censored patients was greater than the number of patients with cessation of otorrhea
  • * Kaplan-Meier median estimate censored all subjects who did not have a cessation of otorrhea at the maximum time point of 22 days.
  • † Log-rank test stratified by age (patients younger than 3 years versus 3 years and older)
    		•
    Trial 1Ciprofloxacin and Fluocinolone Acetonide Otic Solution
    (N=112)    		CIPRO
    (N=109)     		FLUO
    (N=110)
    Number (%) with cessation of otorrhea by Day 2288 (78.6%)73 (67.0%)53 (48.2%)
    Median time to cessation* (days)3.757.69n.e.
    p-value vs Ciprofloxacin and Fluocinolone Acetonide Otic Solution†<0.001<0.001
     
    Trial 2Ciprofloxacin and Fluocinolone Acetonide Otic Solution
    (N=111)    		CIPRO
    (N=112)    		FLUO
    (N=108)
    Number (%) with cessation of otorrhea by Day 2287 (78.4%)77 (68.8%)47 (43.5%)
    Median time to cessation* (days)4.946.83n.e.
    p-value vs Ciprofloxacin and Fluocinolone Acetonide Otic Solution†0.028<0.001
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    How supplied

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution, 0.3 %/0.025 %, is a sterile, preservative-free, clear otic solution supplied in blue translucent single-dose 0.25 mL vials. Fourteen single-dose vials are packaged in a protective foil pouch contained in a carton (NDC: 52536-080-14).

    Storage

    Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from light; store unused vials in pouch and discard 7 days after opening the pouch. Do not open until ready to use. Discard vial after use.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

    Administration Instructions

    • Advise patients that Ciprofloxacin and Fluocinolone Acetonide Otic Solution is for otic use only. It is not to be used in the eyes.
    • Advise patients to warm the otic solution by holding the vial in the hand for 1 to 2 minutes before instilling it in the ear, to avoid dizziness.

    Hypersensitivity Reactions

    • Advise patients to immediately discontinue Ciprofloxacin and Fluocinolone Acetonide Otic Solution at the first appearance of a skin rash or any other sign of hypersensitivity [see Warnings and Precautions (5.1)]
  • SPL UNCLASSIFIED SECTION

    Ciprofloxacin and Fluocinolone Acetonide Otic Solution is:

    Distributed by:
    Wilshire Pharmaceuticals, Inc.
    Atlanta, GA 30328

    Under license of Laboratorios SALVAT, S.A.

    U.S. Patent No: 8,932,610

    OTO-PIAG-00

  • INSTRUCTIONS FOR USECIPROFLOXACIN AND FLUOCINOLONE ACETONIDE(sip-roh-flok-suh-sin and floo-oh-SIN-oh-lone uh-SEET-oh-nide)Otic Solution

    Read this Instructions for Use that comes with Ciprofloxacin and Fluocinolone Acetonide Otic Solution 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 healthcare provider about your medical condition or treatment.

    Important information about Ciprofloxacin and Fluocinolone Acetonide Otic Solution:

    • Ciprofloxacin and Fluocinolone Acetonide Otic Solution is for use in the ear only (otic use). Do not inject Ciprofloxacin and Fluocinolone Acetonide Otic Solution or use Ciprofloxacin and Fluocinolone Acetonide Otic Solution in the eye.
    • Use Ciprofloxacin and Fluocinolone Acetonide Otic Solution exactly as your healthcare provider tells you to use it.

    How should I use Ciprofloxacin and Fluocinolone Acetonide Otic Solution?

    Step 1.You or your caregiver should wash their hands with soap and water.Image
    Step 2.Gently clean any fluid (discharge) from the outer ear using a clean cloth or tissue. Do not put a cotton swab or any other object in the ear canal.Image
    Step 3.Remove Ciprofloxacin and Fluocinolone Acetonide Otic Solution from the protective foil pouch. Pull apart 1 single-dose vial of Ciprofloxacin and Fluocinolone Acetonide Otic Solution as shown, by tearing along the dotted lines (perforations) until it is fully separated.Image
    Step 4.Warm the dose of Ciprofloxacin and Fluocinolone Acetonide Otic Solution by holding the vial in your hand for 1 to 2 minutes.Image
    Step 5.Twist off the vial cap in the direction of the arrow as shown.Image
    Step 6.The person receiving Ciprofloxacin and Fluocinolone Acetonide Otic Solution should be on his/her side with the infected ear up as shown. Image
    Step 7.Hold the vial of Ciprofloxacin and Fluocinolone Acetonide Otic Solution in your hand and place the vial close to the ear. Let the entire dose of Ciprofloxacin and Fluocinolone Acetonide Otic Solution fall into the affected ear.Image
    Step 8.Gently press the part of the ear known as the tragus 4 times using a pumping motion as shown. This will allow the drops of Ciprofloxacin and Fluocinolone Acetonide Otic Solution to enter the middle ear.Image
    Step 9.Remain on your side with the affected ear facing upward for 1 minute.Image
    Step 10.If your healthcare provider has told you to use Ciprofloxacin and Fluocinolone Acetonide Otic Solution in both ears, repeat Steps 2-9 for the other ear.
    Step 11.Safely throw away Ciprofloxacin and Fluocinolone Acetonide Otic Solution vials after use.

    This Instructions for Use has been approved by the Food and Drug Administration.

    Rev. 05/2019

  • PRINCIPAL DISPLAY PANEL - 0.25 mL Vial Pouch Carton

    NDC: 52536-080-14
    Rx Only

    Ciprofloxacin 0.3% and
    Fluocinolone Acetonide 0.025%

    Otic solution

    Sterile
    Preservative-free

    FOR USE IN THE EAR ONLY

    Contents:
    14 vials
    0.25 mL each
    (Deliverable volume)

    WILSHIRE®
    PHARMACEUTICALS, INC

    Salvat

    PRINCIPAL DISPLAY PANEL - 0.25 mL Vial Pouch Carton
  • INGREDIENTS AND APPEARANCE
    CIPROFLOXACIN AND FLUOCINOLONE ACETONIDE 
    ciprofloxacin and fluocinolone acetonide solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 52536-080
    Route of AdministrationAURICULAR (OTIC)
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ciprofloxacin (UNII: 5E8K9I0O4U) (ciprofloxacin - UNII:5E8K9I0O4U) ciprofloxacin0.75 mg  in 0.25 mL
    fluocinolone acetonide (UNII: 0CD5FD6S2M) (fluocinolone acetonide - UNII:0CD5FD6S2M) fluocinolone acetonide0.0625 mg  in 0.25 mL
    Inactive Ingredients
    Ingredient NameStrength
    glycerin (UNII: PDC6A3C0OX)  
    polysorbate 80 (UNII: 6OZP39ZG8H)  
    povidone K90 (UNII: RDH86HJV5Z)  
    water (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 52536-080-141 in 1 CARTON11/01/2019
    114 in 1 POUCH
    10.25 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20825111/01/2019
    Labeler - Wilshire Pharmaceuticals (078657245)
    Establishment
    NameAddressID/FEIBusiness Operations
    The Ritedose Corporation837769546MANUFACTURE(52536-080) , PACK(52536-080)
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