FLOXIN® Otic (ofloxacin otic) solution 0.3% is a sterile aqueous anti-infective (anti-bacterial) solution for otic use. Chemically, ofloxacin has three condensed 6-membered rings made up of a fluorinated carboxyquinolone with a benzoxazine ring. The chemical name of ofloxacin is: (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. The empirical formula of ofloxacin is C₁₈H₂₀FN₃O₄ and its molecular weight is 361.38. The structural formula is:

FLOXIN® Otic contains 0.3% (3 mg/mL) ofloxacin with benzalkonium chloride (0.0025%), sodium chloride (0.9%), and water for injection. Hydrochloric acid and sodium hydroxide are added to adjust the pH to 6.5±0.5.

FLOXIN® Otic (ofloxacin otic) solution 0.3% is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the specific conditions listed below:

Otitis Externa in adults and pediatric patients, 6 months and older, due to Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus.

Chronic Suppurative Otitis Media in patients 12 years and older with perforated tympanic membranes due to Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus.

Acute Otitis Media in pediatric patients one year and older with tympanostomy tubes due to Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.

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

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:

FLOXIN® Otic (ofloxacin otic) solution 0.3% is supplied in plastic dropper bottles containing 5 mL and 10 mL.

NDC 63395-101-05 FLOXIN® Otic 5 mL

NDC 63395-101-10 FLOXIN® Otic 10 mL

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

Daiichi Pharmaceutical Corporation., Montvale, NJ 07645. Revised: April 2005. FDA revision date: 5/4/2005

Subjects with Otitis Externa

In the 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 two or more of the subjects.

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:

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 neuropsychiatric disturbances have been included in spontaneous post-marketing reports. A causal relationship with ofloxacin otic solution 0.3% is unknown.

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

NOT FOR OPHTHALMIC USE.

NOT FOR INJECTION.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching. If an allergic reaction to ofloxacin is suspected, stop the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management, including intubation, should be administered as clinically indicated.

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 weightbearing 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.

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 micro-nucleus 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

Teratogenic effects: Pregnancy Category C.

Ofloxacin has been shown to have an embryocidal effect in rats at a dose of 810 mg/kg/day and in rabbits at 160 mg/kg/day.

These dosages resulted in decreased fetal body weights and increased fetal mortality in rats and rabbits, respectively. Minor fetal skeletal variations were reported in rats receiving doses of 810 mg/kg/day. Ofloxacin has not been shown to be teratogenic at doses as high as 810 mg/kg/day and 160 mg/kg/day when administered to pregnant rats and rabbits, respectively.

Ofloxacin has not been shown to have any adverse effects on the developing embryo or fetus at doses relevant to the amount of ofloxacin that will be delivered ototopically at the recommended clinical doses.

Nonteratogenic Effects: Additional studies in the rat demonstrated that doses up to 360 mg/kg/day during late gestation had no adverse effects on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. There are, however, no adequate and well-controlled studies in pregnant women. FLOXIN® Otic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 age 6 months, there are no known 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, quinoloneinduced lesions, erosions of the cartilage in weight-bearing joints, or other signs of arthropathy.

No information provided.

FLOXIN® Otic (ofloxacin otic) solution 0.3% is contraindicated in patients with a history of hypersensitivity to ofloxacin, to other quinolones, or to any of the components in this medication.

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 µ g/g after otic administration of a 0.3% solution. Ofloxacin was present in high concentrations in otorrhea (389-2850 µ g/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 has in vitro activity against a wide range of gramnegative 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, both in vitro and clinically in otic infections as described in the INDICATIONS AND USAGEsection.

Aerobic and facultative gram-positive microorganisms

Aerobic and facultative gram-negative microorganisms

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 (see DOSAGE 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 (see DOSAGE AND ADMINISTRATION).

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

OFLOXACIN - EAR SOLUTION

(oh-FLOX-uh-sin)

COMMON BRAND NAME(S): Floxin

USES: Ofloxacin is used to treat outer ear infections (swimmer's ear or ear canal infections) and middle ear infections. It works by stopping the growth of bacteria. This medication belongs to a class of drugs called quinolone antibiotics.

This medication treats only bacterial ear infections. It will not work for other types of ear infections. Unnecessary use or overuse of any antibiotic can lead to its decreased effectiveness.

HOW TO USE: Read the Patient Information Leaflet that comes with this product. Consult your doctor or pharmacist if you have any questions.

For accuracy and to avoid contamination, have another person give the drops if possible. Hold the container in your hand for a few minutes to warm it. This will minimize dizziness.

To apply ear drops, wash your hands first. To avoid contamination, do not touch the dropper tip or let it touch your ear or any other surface.

Lie on your side or tilt the affected ear upward. Place the dropper directly over your ear and administer the prescribed number of drops. If you are using the single-use containers, empty the contents of the prescribed number of containers into your ear. For outer ear infections, to help the drops roll into the ear, adults should hold the earlobe up and back. In children, hold the earlobe down and back. For middle ear infections, gently press down several times on the cartilage that partially covers your ear opening to allow the drops to enter your middle ear (see Patient Information Leaflet).

Keep your head tilted for about 5 minutes, or insert a soft cotton plug if so directed. Repeat the above steps for your other ear if so directed.

Do not rinse the dropper. Replace the dropper cap on the bottle after each use. If you are using the single-dose containers, discard any unused solution after each application. Do not reuse.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time(s) each day. Continue using it for the full time prescribed, even if symptoms disappear after a few days. Stopping this medication too early may allow bacteria to continue to grow, which may result in a relapse of the infection.

Inform your doctor if your condition does not improve in 1 week. Report any ear discharge that occurs after the treatment period is completed.

Do not use in the eye.

SIDE EFFECTS: Mild irritation/discomfort in the ear, dizziness, headache, earache, or changes in taste may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: tingling/numbness.

Tell your doctor immediately if any of these rare but very serious side effects occur: hearing changes.

Use of this medication for prolonged or repeated periods may result in a new fungal ear infection. Do not use it for longer than prescribed. Contact your doctor if you notice new or worsening symptoms.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking ofloxacin, tell your doctor or pharmacist if you are allergic to it; or to other quinolone antibiotics (e.g., ciprofloxacin, levofloxacin); or to preservatives (e.g., benzalkonium chloride); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other ear problems, two or more ear infections within 6 months.

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this medication passes into breast milk. Breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. This medicine may be harmful if swallowed.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.

It is important to keep the infected ear(s) clean and dry. Try not to get the infected ear(s) wet when bathing. Avoid swimming unless your doctor tells you otherwise.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature (77 degrees F or 25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.