Besivance (Besifloxacin hydrochloride) ™ (besifloxacin ophthalmic suspension) 0.6%, is indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following bacteria:

CDC coryneform group G

*Efficacy for this organism was studied in fewer than 10 infections.

Invert closed bottle and shake once before use.

Instill one drop in the affected eye(s) 3 times a day, four to twelve hours apart for 7 days.

7.5 mL bottle filled with 5 mL of besifloxacin ophthalmic suspension, 0.6%.

None

NOT FOR INJECTION INTO THE EYE.

Besivance (Besifloxacin hydrochloride) ™ is for topical ophthalmic use only, and should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with the rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Besivance (Besifloxacin hydrochloride) ™ in approximately 1,000 patients between 1 and 98 years old with clinical signs and symptoms of bacterial conjunctivitis.

The most frequently reported ocular adverse event was conjunctival redness, reported in approximately 2% of patients.

Other adverse events reported in patients receiving Besivance (Besifloxacin hydrochloride) ™ occurring in approximately 1-2% of patients included: blurred vision, eye pain, eye irritation, eye pruritus and headache.

Pregnancy Category C. Oral doses of besifloxacin up to 1000 mg/kg/day were not associated with visceral or skeletal malformations in rat pups in a study of embryo-fetal development, although this dose was associated with maternal toxicity (reduced body weight gain and food consumption) and maternal mortality. Increased post-implantation loss, decreased fetal body weights, and decreased fetal ossification were also observed. At this dose, the mean C in the rat dams was approximately 20 mcg/mL, >45,000 times the mean plasma concentrations measured in humans. The No Observed Adverse Effect Level (NOAEL) for this embryo-fetal development study was 100 mg/kg/day (C, 5 mcg/mL, >11,000 times the mean plasma concentrations measured in humans).

In a prenatal and postnatal development study in rats, the NOAELs for both fetal and maternal toxicity were also 100 mg/kg/day. At 1000 mg/kg/day, the pups weighed significantly less than controls and had a reduced neonatal survival rate. Attainment of developmental landmarks and sexual maturation were delayed, although surviving pups from this dose group that were reared to maturity did not demonstrate deficits in behavior, including activity, learning and memory, and their reproductive capacity appeared normal.

Since there are no adequate and well-controlled studies in pregnant women, Besivance (Besifloxacin hydrochloride) ™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The safety and effectiveness of Besivance (Besifloxacin hydrochloride) ™ in infants below one year of age have not been established. The efficacy of Besivance (Besifloxacin hydrochloride) ™ in treating bacterial conjunctivitis in pediatric patients one year or older has been demonstrated in controlled clinical trials [].

There is no evidence that the ophthalmic 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.

Besivance (Besifloxacin hydrochloride) ™ (besifloxacin ophthalmic suspension) 0.6%, is a sterile ophthalmic suspension of besifloxacin formulated with DuraSite®* (polycarbophil, edetate disodium dihydrate and sodium chloride). Each mL of Besivance (Besifloxacin hydrochloride) ™ contains 6.63 mg besifloxacin hydrochloride equivalent to 6 mg besifloxacin base. It is an 8-chloro fluoroquinolone anti-infective for topical ophthalmic use.

CHClFNO•HCl

Mol Wt 430.30

Besifloxacin hydrochloride is a white to pale yellowish-white powder.

Besivance (Besifloxacin hydrochloride) ™ is an isotonic suspension with an osmolality of approximately 290 mOsm/kg.

Besifloxacin is an 8-chloro fluoroquinolone with a N-1 cyclopropyl group. The compound has activity against Gram-positive and Gram-negative bacteria due to the inhibition of both bacterial DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme required for replication, transcription and repair of bacterial DNA. Topoisomerase IV is an essential enzyme required for partitioning of the chromosomal DNA during bacterial cell division. Besifloxacin is bactericidal with minimum bactericidal concentrations (MBCs) generally within one dilution of the minimum inhibitory concentrations (MICs).

The mechanism of action of fluoroquinolones, including besifloxacin, is different from that of aminoglycoside, macrolide, and -lactam antibiotics. Therefore, besifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to besifloxacin. studies demonstrated crossresistance between besifloxacin and some fluoroquinolones.

Besifloxacin has been shown to be active against most isolates of the following bacteria both and in conjunctival infections treated in clinical trials as described in the section:

CDC coryneform group G

Corynebacterium pseudodiphtheriticum*
Corynebacterium striatum*
Haemophilus influenzae
Moraxella lacunata*
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus hominis*
Staphylococcus lugdunensis*
Streptococcus mitis group
Streptococcus oralis
Streptococcus pneumoniae
Streptococcus salivarius*
*Efficacy for this organism was studied in fewer than 10 infections.

In a randomized, double-masked, vehicle controlled, multicenter clinical trial, in which patients 1-98 years of age were dosed 3 times a day for 5 days, Besivance (Besifloxacin hydrochloride) ™ was superior to its vehicle in patients with bacterial conjunctivitis. Clinical resolution was achieved in 45% (90/198) for the Besivance (Besifloxacin hydrochloride) ™ treated group versus 33% (63/191) for the vehicle treated group (difference 12%, 95% CI 3% - 22%). Microbiological outcomes demonstrated a statistically significant eradication rate for causative pathogens of 91% (181/198) for the Besivance (Besifloxacin hydrochloride) ™ treated group versus 60% (114/191) for the vehicle treated group (difference 31%, 95% CI 23% - 40%). Microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.

Besivance (Besifloxacin hydrochloride) ™ (besifloxacin ophthalmic suspension) 0.6%, is supplied as a sterile ophthalmic suspension in a white low density polyethylene (LDPE) bottle with a controlled dropper tip and tan polypropylene cap. Tamper evidence is provided with a shrink band around the cap and neck area of the package.

5 mL in 7.5 mL bottle

Invert closed bottle and shake once before use.

Rx Only

Patients should be advised to avoid contaminating the applicator tip with material from the eye, fingers or other source.

Although Besivance (Besifloxacin hydrochloride) ™ is not intended to be administered systemically, quinolones administered systemically have been associated with hypersensitivity reactions, even following a single dose. Patients should be advised to discontinue use immediately and contact their physician at the first sign of a rash or allergic reaction.

Patients should be told that although it is common to feel better early in the course of the therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Besivance (Besifloxacin hydrochloride) ™ or other antibacterial drugs in the future.

Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis or during the course of therapy with Besivance (Besifloxacin hydrochloride) ™.

Patients should be advised to thoroughly wash hands prior to using Besivance (Besifloxacin hydrochloride) ™.

Patients should be instructed to invert closed bottle (upside down) and shake once before each use. Remove cap with bottle still in the inverted position. Tilt head back, and with bottle inverted, gently squeeze bottle to instill one drop into the affected eye(s).

Manufactured by: Bausch & Lomb IncorporatedTampa, Florida 33637©Bausch & Lomb Incorporated

U.S. Patent No. 6,685,958U.S. Patent No. 6,699,492U.S. Patent No. 5,447,926

Besivance (Besifloxacin hydrochloride) ™ is a trademark of Bausch & Lomb Incorporated

*DuraSite is a trademark of InSite Vision Incorporated

April 2009

9142602 (flat)

9142702 (folded)

NDC 24208-446-05

Bausch & Lomb

Besivance (Besifloxacin hydrochloride)

besifloxacin ophthalmic suspension, 0.6%

Rx only Sterile

FOR OPHTHALMIC USE ONLY.

5 mL