Pharmacokinetics: Drug concentrations in serum (in subjects with tympanostomy tubes and perforated tympanic membranes), in otorrhea, and in mucosa of the middle ear (in subjects with perforated tympanic membranes) were determined following otic administration of ofloxacin solution. In two single-dose studies, mean ofloxacin serum concentrations were low in adult patients with tympanostomy tubes, with and without otorrhea, after otic administration of a 0.3% solution (4.1 ng/ml (n=3) and 5.4 ng/ml (n=5), respectively). In adults with perforated tympanic membranes, the maximum serum drug level of ofloxacin detected was 10 ng/ml after administration of a 0.3% solution. Ofloxacin was detectable in the middle ear mucosa of some adult subjects with perforated tympanic membranes (11 of 16 subjects). The variability of ofloxacin concentration in middle ear mucosa was high. The concentrations ranged from 1.2 to 602 μg/g after otic administration of a 0.3% solution. Ofloxacin was present in high concentrations in otorrhea (389 - 2850 μg/g, n=13) 30 minutes after otic administration of a 0.3% solution in subjects with chronic suppurative otitis media and perforated tympanic membranes. However, the measurement of ofloxacin in the otorrhea does not necessarily reflect the exposure of the middle ear to ofloxacin.

Microbiology: Ofloxacin hasin vitroactivity against a wide range of gram-negative and gram-positive microorganisms. Ofloxacin exerts its antibacterial activity by inhibiting DNA gyrase, a bacterial topoisomerase. DNA gyrase is an essential enzyme which controls DNA topology and assists in DNA replication, repair, deactivation, and transcription. Cross-resistance has been observed between ofloxacin and other fluoroquinolones. There is generally no cross-resistance between ofloxacin and other classes of antibacterial agents such as beta-lactams or aminoglycosides.

Ofloxacin has been shown to be active against most isolates of the following microorganisms, bothin vitroand clinically in otic infections as described in theINDICATIONS AND USAGEsection.

AEROBES, GRAM-POSITIVE:

Staphylococcus aureus

Streptococcus pneumoniae

AEROBES, GRAM-NEGATIVE:

Escherichia coli

Haemophilus influenzae

Moraxella catarrhalis

Proteus mirabilis

Pseudomonas aeruginosa

General: As with other anti-infective preparations, prolonged use may result in over-growth of nonsusceptible organisms, including fungi. If the infection is not improved after one week, cultures should be obtained to guide further treatment. 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.

The systemic administration of quinolones, including ofloxacin at doses much higher than given or absorbed by the otic route, has led to lesions or erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species.

Young growing guinea pigs dosed in the middle ear with 0.3% ofloxacin otic solution showed no systemic effects, lesions or erosions of the cartilage in weight-bearing joints, or other signs of arthropathy. No drug-related structural or functional changes of the cochlea and no lesions in the ossicles were noted in the guinea pig following otic administration of 0.3% ofloxacin for one month.

No signs of local irritation were found when 0.3% ofloxacin was applied topically in the rabbit eye. Ofloxacin was also shown to lack dermal sensitizing potential in the guinea pig maximization study.

Information for Patients: Avoid contaminating the applicator tip with material from the fingers or other sources. This precaution is necessary if the sterility of the drops is to be preserved. Systemic quinolones, including ofloxacin, have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.

Otitis Externa

Prior to administration of FLOXIN®Otic, the solution 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 solution. The patient should lie with the affected ear upward, and then the drops should be instilled. This position should be maintained for five minutes to facilitate penetration of the drops into the ear canal. Repeat, if necessary, for the opposite ear (seeDOSAGE AND ADMINISTRATION).

Acute Otitis Media and Chronic Suppurative Otitis Media

Prior to administration of FLOXIN®Otic, the solution 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 solution. The patient should lie with the affected ear upward, and then the drops should be instilled. The tragus should then be pumped 4 times by pushing inward to facilitate penetration of the drops into the middle ear. This position should be maintained for five minutes. Repeat, if necessary, for the opposite ear (seeDOSAGE AND ADMINISTRATION).

Drug Interactions:Specific drug interaction studies have not been conducted with FLOXIN®Otic.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies to determine the carcinogenic potential of ofloxacin have not been conducted. Ofloxacin was not mutagenic in the Ames test, the sister chromatid exchange assay (Chinese hamster and human cell lines), the unscheduled DNA synthesis (UDS) assay using human fibroblasts, the dominant lethal assay, or the mouse micronucleus assay. Ofloxacin was positive in the rat hepatocyte UDS assay, and in the mouse lymphoma assay. In rats, ofloxacin did not affect male or female reproductive performance at oral doses up to 360 mg/kg/day. This would be over 1000 times the maximum recommended clinical dose, based upon body surface area, assuming total absorption of ofloxacin from the ear of a patient treated with FLOXIN®Otic twice per day.

Pregnancy

Nursing Mothers: In nursing women, a single 200 mg oral dose resulted in concentrations of ofloxacin in milk which were similar to those found in plasma. It is not known whether ofloxacin is excreted in human milk following topical otic administration. Because of the potential for serious adverse reactions from ofloxacin 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:Safety and efficacy have been demonstrated in pediatric patients of the following ages for the listed indications:

• six months and older; otitis externa with intact tympanic membranes
• one year and older: acute otitis media with tympanostomy tubes.
• Twelve years and older: chronic suppurative otitis media with perforated tympanic membranes

Safety and efficacy in pediatric patients below these ages have not been established.

Although no data are available on patients less than 6 months, there are no know safety concerns or differences in the disease process in this population that will preclude use of this product.

No changes in hearing function occurred in 30 pediatric subjects treated with ofloxacin otic and tested for audiometric parameters. Although quinolones, including ofloxacin, have been shown to cause arthropathy in immature animals after systemic administration, young growing guinea pigs dosed in the middle ear with 0.3% ofloxacin otic solution for one month showed no systemic effects, quinolone-induced lesions, erosions of the cartilage in weight-bearing joints, or other signs of arthropathy.

Subjects with Otitis Externa

In a Phase III clinical trials performed in support of once-daily dosing, 799 subjects with otitis externa and intact tympanic membranes were treated with ofloxacin otic solution. The studies, which served as the basis for approval, were 020 (pediatric, adolescents and adults), 016 (adolescents and adults) and 017 (pediatric). The following treatment-related adverse events occurred in 2 or more of the subjects:

	Incidence Rate
Adverse Event	Studies 002/003† BID (N=229)	Studies 016/017† QD (N=3109)	Studies 002† QD (N=489)
†Studies 002/003 (BID) and 016/017 (QD) were active-controlled and comparative.
Application Site	3%	16.8%	0.6%
Reaction
Pruritus	4%	1.2%	1.0%
Earache	1%	0.6%	0.8%
Dizziness	1%	0.0%	0.6%
Headache	0%	0.3%	0.2%
Vertigo	1%	0.0%	0.0%

Study 020 (QD) was open and non-comparative.

An unexpected increased incidence of application site reaction was seen in studies 016/017 and was similar for both ofloxacin and the active control drug (neomycin-polymyxin B sulfate-hydrocortisone). This finding is believed to be the result of specific questioning of the subjects regarding the incidence of application site reactions.

In once daily dosing studies, there were also single reports of nausea, seborrhea, transient loss of hearing, tinnitus, otitis externa, otitis media, tremor, hypertension and fungal infection.

In twice daily dosing studies, the following treatment-related adverse events were each reported in a single subject: dermatitis, eczema, erythematous rash, follicular rash, hypoaesthesia, tinnitus, dyspepsia, hot flushes, flushing and otorrhagia.

Subjects with Acute Otitis Media with Tympanostomy Tubes (AOM TT) and Subjects with Chronic Suppurative Otitis Media (CSOM) with Perforated Tympanic Membranes

In Phase III clinical trials which formed the basis for approval, the following treatment-related adverse events occurred in 1% or more of the 656 subjects with non-intact tympanic membranes in AOM TT or CSOM treated twice-daily with ofloxacin otic solution:

Adverse Event	Incidence (N=656)
Taste Perversion	7%
Earache	1%
Pruritus	1%
Paraesthesia	1 %.
Rash	1%
Dizziness	1%

Other treatment-related adverse reactions reported in subjects with non-intact tympanic membranes included: diarrhea (0.6%), nausea (0.3%), vomiting (0.3%), dry mouth (0.5%), headache (0.3%), vertigo (0.5%), otorrhagia (0.6%), tinnitus (0.3%), fever (0.3%). The following treatment-related adverse events were each reported in a single subject: application site reaction, otitis externa, urticaria, abdominal pain, dysaesthesia, hyperkinesia, halitosis, inflammation, pain, insomnia, coughing, pharyngitis, rhinitis, sinusitis, and tachycardia.

Post-Marketing Adverse Events

Cases of uncommon transient neurospsychiatric disturbances have been included in spontaneous post-marketing reports. A casual relationship with ofloxacin otic solution 0.3% is unknown.

Otitis Externa:The recommended dosage regimen for the treatment of otitis externa is:

• For pediatric patients (from 6 months to 13 years old): Five drops (0.25 ml, 0.75 mg ofloxacin) instilled into the affected ear once daily for seven days.
• For patients 13 years and older: Ten drops (0.5 ml, 1.5 mg ofloxacin) instilled into the affected ear once daily for seven days.
• The solution 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 solution. The patient should lie with the affected ear upward, and then the drops should be instilled. This position should be maintained for five minutes to facilitate penetration of the drops into the ear canal. Repeat, if necessary, for the opposite ear.

Acute Otitis Media in pediatric patients with tympanostomy tubes:The recommended dosage regimen for the treatment of acute otitis media in pediatric patients (from 1 to 12 years old) with tympanostomy tubes is:

Five drops (0.25 ml, 0.75 mg ofloxacin) instilled into the affected ear twice daily for ten days. The solution should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness that may result from the instillation of a cold solution. The patient should lie with the affected ear upward, and then the drops should be instilled. The tragus should then be pumped 4 times by pushing inward to facilitate penetration of the drops into the middle ear. This position should be maintained for five minutes. Repeat, if necessary, for the opposite ear.

Chronic Suppurative Otitis Media with perforated tympanic membranes:The recommended dosage regimen for the treatment of chronic suppurative otitis media with perforated tympanic membranes in patients 12 years and older is:

Ten drops (0.5 ml, 1.5 mg ofloxacin) instilled into the affected ear twice daily for fourteen days. The solution should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness that may result from the instillation of a cold solution. The patient should lie with the affected ear upward, before instilling the drops. The tragus should then be pumped 4 times by pushing inward to facilitate penetration into the middle ear. This position should be maintained for five minutes. Repeat, if necessary, for the opposite ear.

How should FLOXIN Otic be given?

1.  Wash hands

The person giving FLOXIN Otic should wash his/her hands with soap and water.

2.  Clean ear and warm bottle

Gently clean any discharge that can be removed easily from the outer ear.

DO NOT INSERT ANY OBJECT OR SWAB INTO THE EAR CANAL.

Hold the bottle of FLOXIN Otic in the hand for one or two minutes to warm the solution.

3.  Add drops

For a Middle Ear Infection:

The person receiving FLOXIN Otic should lie on his/her side with the infected ear up.  Patients (12 and older) should have 10 drops of FLOXIN Otic put into the infected ear.  Pediatric patients under 12 should have 5 drops put into the infected ear.  The tip of the bottle should not touch the fingers or the ear or any other surfaces.

For an Ear Canal Infection ("Swimmer's Ear"):

The person receiving FLOXIN Otic should lie on his/her side with the infected ear up.  Patients (13 and older) should have 10 drops of FLOXIN Otic put into the infected ear.  Pediatric patients under 13 should have 5 drops put into the infected ear.  The tip of the bottle should not touch the fingers or the ear or any other surfaces.

BE SURE TO FOLLOW THE INSTRUCTIONS BELOW FOR THE PATIENT'S SPECIFIC EAR INFECTION.

4.  Press ear or pull ear

For a Middle Ear Infection:

While the person receiving FLOXIN Otic lies on his/her side, the person giving the drops should gently press the TRAGUS (see diagram) 4 times in a pumping motion.  This will allow the drops to pass through the hole or tube in the eardrum and into the middle ear.

For an Ear Canal Infection ("Swimmer's Ear"):

While the person receiving the drops lies on his/her side, the person giving the drops should gently pull the outer ear upward and backward.  This will allow the ear drops to flow down into the ear canal.

5.  Stay on side

The person who received the ear drops should remain on his/her side for at least 5 minutes.

Repeat Steps 2-5 for the other ear if both ears are infected.

How often should FLOXIN Otic be given?

In patients with an Ear Canal Infection ("Swimmer's Ear"), FLOXIN Otic ear drops should be given once daily at about the same time each day (for example, 8 AM or 8 PM) in each infected ear unless the doctor has instructed otherwise.

In patients with a Middle Ear Infection, FLOXIN Otic ear drops should be given 2 times each day (about 12 hours apart, for example 8 AM and 8 PM) in each infected ear unless the doctor has instructed otherwise.  The best times to use the ear drops are in the morning and at night.

It is very important to use the ear drops for as long as the doctor has instructed, even if the symptoms improve.  If FLOXIN Otic ear drops are not used for as long as the doctor has instructed, the infection may be more likely to return.

What if a dose is missed?

In patients with an Ear Canal Infection ("Swimmer's Ear"), it is important that you take the drops every day.  If you miss a dose which may have been scheduled for earlier in the day, (for example, 8:00 AM), you should take that day's dose as soon as possible and then go back to your regular daily dosing schedule.

In patients with a Middle Ear Infection, if a dose of FLOXIN Otic is missed, it should be given as soon as possible  However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule.

Do not use a double dose unless the doctor has instructed you to do so.  If the infection is not improved after one week, you should consult your doctor.  If you have two or more episodes of drainage with six months, it is recommended that you see your doctor for further evaluation.

What activities should be avoided while using FLOXIN Otic?

During the testing of FLOXIN Otic in external ear infections, the most common side effect was discomfort upon application which happened in 7% of patients.  If the pain is severe, the medication should be stopped and you should contact your doctor.  Other side effects were:  itching (1%), earache (0.8%), and dizziness (0.4%).

During the testing of FLOXIN Otic in middle ear infections, the most common side effect was a bitter taste which happened in 7% of patients with a middle ear infection.  This may occur when some of the medications passes from the middle ear to the back of the mouth.  This side effect is not serious and there is no need to stop the medicine if this should happen.  Other side effects which were found in 1% of the patients were:  earache, itching, abnormal sensation, rash, and dizziness.

Call your doctor about these or other side effects if they occur.

If a rash or an allergic reaction to FLOXIN Otic occurs, stop using the product and contact your doctor.

DO NOT TAKE FLOXIN Otic BY MOUTH.

If FLOXIN Otic is accidentally swallowed or an overdose occurs, call the doctor immediately.  This medicine is available only with a doctor's prescription.  Use only as directed.  Do not use this medicine if outdated.

If you wish to learn more about FLOXIN Otic, ask the doctor or pharmacist.  Complete prescribing information is printed on the reverse side.

HOW SUPPLIED.

Plastic dropper bottles containing 5 mL and 10 mL

Storage Conditions:  Store at 25 C (77 F), excursions permitted to 15-30 C (59-86 F).  Protect from light.

FLOXIN Otic is manufactured for:

Daiichi Sankyo Pharma Development, a division of Daiichi Sankyo, Inc.

Edison, N.J.  08837 USA

This Patient Information has been approved by the U.S. Food and Drug Administration.

Rev:  November 2006

Copyright  2006 Daiichi Sankyo, Inc.. All rights reserved.

Covered by U.S. Patent No. 5,401,741