Besivance

BESIVANCE — besifloxacin suspension
Physicians Total Care, Inc.

1 INDICATIONS AND USAGE

Besivance™ (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

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.

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Topical Ophthalmic Use Only

NOT FOR INJECTION INTO THE EYE.

Besivance™ 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.

5.2 Growth of Resistant Organisms with Prolonged Use

As with other anti-infectives, prolonged use of Besivance™ (besifloxacin ophthalmic suspension) 0.6% may result in overgrowth of non-susceptible organisms, including fungi. If super-infection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, where appropriate, fluorescein staining.

5.3 Avoidance of Contact Lenses

Patients should not wear contact lenses if they have signs or symptoms of bacterial conjunctivitis or during the course of therapy with Besivance™.

6 ADVERSE REACTIONS

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™ 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™ occurring in approximately 1-2% of patients included: blurred vision, eye pain, eye irritation, eye pruritus and headache.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 Cmax 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 (Cmax , 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™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

Besifloxacin has not been measured in human milk, although it can be presumed to be excreted in human milk. Caution should be exercised when Besivance™ is administered to a nursing mother.

8.4 Pediatric Use

The safety and effectiveness of Besivance™ in infants below one year of age have not been established. The efficacy of Besivance™ in treating bacterial conjunctivitis in pediatric patients one year or older has been demonstrated in controlled clinical trials [see 14 CLINICAL STUDIES ].

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.

8.5 Geriatric Use

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

11 DESCRIPTION

Besivance™ (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™ contains 6.63 mg besifloxacin hydrochloride equivalent to 6 mg besifloxacin base. It is an 8-chloro fluoroquinolone anti-infective for topical ophthalmic use.

Besifloxacin hydrochloride (structural formula)

C19 H21 ClFN3 O3 •HCl

Mol Wt 430.30

Chemical Name: (+)-7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-8-chloro-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride.

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

Each mL Contains:

Active: besifloxacin 0.6% (6 mg/mL);

Preservative: benzalkonium chloride 0.01%

Inactives: polycarbophil, mannitol, poloxamer 407, sodium chloride, edetate disodium dihydrate, sodium hydroxide and water for injection.

Besivance™ is an isotonic suspension with an osmolality of approximately 290 mOsm/kg.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Besifloxacin is a fluoroquinolone antibacterial [see 12.4 Clinical Pharmacology, Microbiology ].

12.3 Pharmacokinetics

Plasma concentrations of besifloxacin were measured in adult patients with suspected bacterial conjunctivitis who received Besivance™ bilaterally three times a day (16 doses total). Following the first and last dose, the maximum plasma besifloxacin concentration in each patient was less than 1.3 ng/mL. The mean besifloxacin Cmax was 0.37 ng/mL on day 1 and 0.43 ng/mL on day 6. The average elimination half-life of besifloxacin in plasma following multiple dosing was estimated to be 7 hours.

12.4 Microbiology

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 β -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. In vitro studies demonstrated crossresistance between besifloxacin and some fluoroquinolones.

In vitro resistance to besifloxacin develops via multiple-step mutations and occurs at a general frequency of < 3.3 x 10-10 for Staphylococcus aureus and < 7 x 10-10 for Streptococcus pneumoniae.

Besifloxacin has been shown to be active against most isolates of the following bacteria both in vitro and in conjunctival infections treated in clinical trials as described in the INDICATIONS AND USAGE 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.

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