Sophixin DX

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 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 in pediatric (age 6 months and older), adult and elderly patients due to Staphylococcus aureus and Pseudomonas aeruginosa.

Important Administration Instructions

• CIPRODEX is for otic use only, and not for ophthalmic use, or for injection.
• Shake well immediately before use.

Dosage

For The Treatment Of Acute Otitis Media In Pediatric Patients (Age 6 Months And Older) With Tympanostomy Tubes

The recommended dosage regimen through tympanostomy tubes is as follows:

• Four drops (equivalent to 0.14 mL of 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 a cold suspension.
• The patient should lie with the affected ear upward, and then the drops should be instilled.
• The tragus should then be pumped 5 times by pushing inward 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 6 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 a 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.

• 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity Reactions

CIPRODEX 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.

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.

Continued Or Recurrent Otorrhea

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

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 only. This product is not approved for use in the eye.
• Administration Instructions
  Patients should be instructed to warm the bottle in their hand for one to two minutes prior to use and shake well immediately before using.
• Allergic Reactions
  Advise patients to discontinue use immediately and contact their physician, if rash or allergic reaction occurs.
• Avoid Contamination of the Product
  Advise patients to avoid contaminating the tip with material from the ear, fingers, or other sources.
• Duration of Use
  Advise patients that it is very important to use the ear drops for as long as their doctor has instructed, even if the symptoms improve.
• Protect from Light
  Advise patients to protect the product from light.
• Unused Product
  Advise patients to discard unused portion after therapy is completed.

Nonclinical Toxicology

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 vessicle, Cowper's gland and accessory glands. The relevance of this study for short-term topical otic use is unknown.

Use In Specific Populations

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 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 intravenous administration of doses up to 20 mg/kg, no maternal toxicity was produced in therabbit, 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.

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.

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.

Les effets indésirables graves suivants sont décrits ailleurs dans l'étiquetage:

• Réactions d'hypersensibilité
• Potentiel de prolifération microbienne à usage prolongé

Expérience des essais cliniques

Étant donné que les essais cliniques sont menés dans des conditions très variables, les taux d'effets indésirables observés dans les essais cliniques d'un médicament ne peuvent pas être directement comparés aux taux dans les essais cliniques d'un autre médicament et peuvent ne pas refléter les taux observés dans la pratique.

Dans les essais cliniques des phases II et III, un total de 937 patients ont été traités par CIPRODEX. Cela comprenait 400 patients atteints d'otite moyenne aiguë avec des tubes de tympanostomie et 537 patients atteints d'otite externe aiguë. Les effets indésirables signalés sont répertoriés ci-dessous:

Otite moyenne aiguë chez les patients pédiatriques atteints de tubes de tympanostomie

Les effets indésirables suivants sont survenus chez 0,5% ou plus des patients atteints de membranes tympaniques non intactes.

Les effets indésirables suivants ont été signalés chacun chez un seul patient: blocage du tube de tympanostomie; prurit de l'oreille; acouphènes; moniliasis oral; pleurer; vertiges; et érythème.

Otite externe aiguë

Les effets indésirables suivants sont survenus chez 0,4% ou plus des patients atteints de membranes tympaniques intactes

Les effets indésirables suivants ont chacun été rapportés chez un seul patient: gêne auditive; diminution de l'audition; et trouble de l'oreille (pétilation).

Expérience post-commercialisation

Les effets indésirables suivants ont été identifiés lors de l'utilisation post-approbation de CIPRODEX. Étant donné que ces réactions sont signalées volontairement par une population de taille inconnue, il n'est pas toujours possible d'estimer de manière fiable leur fréquence ou d'établir une relation causale avec l'exposition au médicament. Ces réactions comprennent: gonflement des auriculaires, maux de tête, hypersensibilité, otorrhée, exfoliation cutanée, éruption érythémateuse et vomissements.

En raison des caractéristiques de cette préparation, aucun effet toxique n'est à prévoir avec un surdosage otique de ce produit.

Après un seul bilatéral de 4 gouttes (dose totale = 0,28 ml, 0,84 mg de ciprofloxacine, 0,28 mg de dexaméthasone) dose otique topique de CIPRODEX aux patients pédiatriques après insertion du tube de tympanostomie, des concentrations plasmatiques mesurables de ciprofloxacine et dexaméthasone ont été observées 6 heures après l'administration chez 2 des 9 patients et 5 des 9 patients, respectivement.

Les concentrations plasmatiques maximales moyennes de ± ET de ciprofloxacine étaient de 1,39 ± 0,880 ng / mL (n = 9). Les concentrations plasmatiques maximales variaient de 0,543 ng / ml à 3,45 ng / ml et représentaient en moyenne environ 0,1% des concentrations plasmatiques maximales atteintes avec une dose orale de 250 mg. Des concentrations plasmatiques maximales de ciprofloxacine ont été observées dans les 15 minutes à 2 heures suivant l'application de la dose.

Les concentrations plasmatiques maximales moyennes de ± ET de de dexaméthasone étaient de 1,14 ± 1,54 ng / ml (n = 9). Les concentrations plasmatiques maximales variaient de 0,135 ng / ml à 5,10 ng / ml et représentaient en moyenne environ 14% des concentrations maximales signalées dans la littérature après une dose orale de comprimés de 0,5 mg. Des concentrations plasmatiques maximales de dexaméthasone ont été observées dans les 15 minutes à 2 heures suivant l'application de la dose.

La dexaméthasone a été ajoutée pour aider à la résolution de la réponse inflammatoire accompagnant une infection bactérienne (comme l'orrhée chez les patients pédiatriques atteints d'otite moyenne aiguë avec des tubes de tympanostomie).