5.1 Otic Use Only

CETRAXAL is for otic use only. It should not be used for injection, for inhalation or for topical ophthalmic use.

5.2 Hypersensitivity

CETRAXAL should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity.

5.3 Growth of Resistant Organisms with Prolonged Use

As with other anti-infectives, use of CETRAXAL may result in overgrowth of nonsusceptible organisms, including yeast and fungi. If super-infection occurs, discontinue use and institute alternative therapy.

5.4 Lack of Clinical Response

If the infection is not improved after one week of therapy, cultures may help guide further treatment.

8.1 Pregnancy

8.3 Nursing Mothers

Ciprofloxacin is excreted in human milk with systemic use. It is not known whether ciprofloxacin is excreted in human milk following otic use. Because of the potential for serious adverse reactions 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 effectiveness of CETRAXAL in infants below one year of age have not been established. The efficacy of CETRAXAL in treating otitis externa in pediatric patients one year or older has been demonstrated in controlled clinical trials (see Section14 Clinical Studies).

There is no evidence that the otic administration of quinolones has any effect on weight bearing joints, even though systemic administration of some quinolones has been shown to cause arthropathy in immature animals.

8.5 Geriatric Use

No overall differences in safety and effectiveness have been observed between elderly and younger patients.

12.1 Mechanism of Action

Ciprofloxacin is a fluoroquinolone antimicrobial (see 12.4 Clinical Pharmacology, Microbiology).

12.3 Pharmacokinetics

The plasma concentrations of ciprofloxacin were not measured following administration of 0.25 mL CETRAXAL (total dose: 0.5 mg ciprofloxacin). However, the maximum plasma concentration of ciprofloxacin is anticipated to be less than 5 ng/mL.

12.4 Microbiology

The bactericidal action of ciprofloxacin results from interference with the enzyme DNA gyrase, which is needed for the synthesis of bacterial DNA.

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

The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of macrolides. Therefore, ciprofloxacin may be active against pathogens that are resistant to these antibiotics, and these antibiotics may be active against pathogens that are resistant to ciprofloxacin. In vitro studies demonstrated cross-resistance between ciprofloxacin and some fluoroquinolones.

Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections of acute otitis externa as described in Section 1 Indications and Usage.

        Staphylococcus aureus

        Pseudomonas aeruginosa.

13.1 Carcinogenesis, Mutagenesis, and 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 CETRAXAL 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)
• Escherichia 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).

Two of the 8 in vitro 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 CETRAXAL twice per day.

Store at 15ºC to 25ºC (59ºF to 77ºF). Discard used containers. Store unused containers in pouch to protect from light.

17.1 Directions for Use

Patients should be advised that CETRAXAL is for otic use only. It is not for ophthalmic or inhalation use. It is not for injection.

CETRAXAL should be given 2 times each day (about 12 hours apart) in each infected ear.

CETRAXAL should be used for as long as it is prescribed, even if the symptoms improve. The patient should be advised to follow these directions while on CETRAXAL:

• Wash their hands before use.

• Warm the container in their hands for at least one minute prior to use to minimize dizziness that may result from the instillation of a cold solution into the ear canal. Twist off and discard top of container.

• Lie with the affected ear upward and then instill the contents of one container into the ear. Maintain this position for at least one minute to facilitate penetration of the drops into the ear.

• Repeat, if necessary, for the opposite ear.
• Discard used container.
• Store unused containers in pouch to protect from light.

17.2 Hypersensitivity

Patients should be advised to immediately discontinue CETRAXAL at the first appearance of a skin rash or any other sign of hypersensitivity [see Section 5.1 Warnings and Precautions].