These highlights do not include all the information needed to useBesivance safely and effectively. See full prescribing information forBesivance.
BesivanceTM (besifloxacin ophthalmic suspension) 0.6%Sterile topical ophthalmic dropsInitial U.S. Approval: 2009
INDICATIONS AND USAGE Besivance™ (besifloxacin ophthalmic suspension) 0.6%, is a quinolone
antimicrobial indicated for the treatment of bacterial conjunctivitis caused bysusceptible 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, Streptococcuspneumoniae, Streptococcus salivarius*
*Efficacy for this organism was studied in fewer than 10 infections. (1) DOSAGE AND ADMINISTRATION
Instill one drop in the affected eye(s) 3 times a day, four to twelve hours apartfor 7 days. (2)
DOSAGE FORMS AND STRENGTHS
7.5 mL size bottle filled with 5 mL of besifloxacin ophthalmic suspension,0.6% (3)
CONTRAINDICATIONS None
WARNINGS AND PRECAUTIONS Topical Ophthalmic Use Only. (5.1)
Growth of Resistant Organisms with Prolonged Use. (5.2)
Avoidance of Contact Lenses. Patients should not wear contact lenses if theyhave signs or symptoms of bacterial conjunctivitis or during the course oftherapy with Besivance™ (5.3)
ADVERSE REACTIONS
The most common adverse event reported in 2% of patients treated withBesivance™ was conjunctival redness. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Bausch &Lomb Incorporated at 1-800-323-0000 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch
To report SUSPECTED ADVERSE REACTIONS, contact at or FDA at1-800-FDA-1088 or www.fda.gov/medwatch
See 17 for PATIENT COUNSELING INFORMATION
Revised: 04/2009
FULL PRESCRIBING INFORMATION: CONTENTS *
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Topical Ophthalmic Use Only
5.2 Growth of Resistant Organisms with Prolonged Use5.3 Avoidance of Contact Lenses6 ADVERSE REACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers8.4 Pediatric Use
8.5 Geriatric Use11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action12.3 Pharmacokinetics12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
* Sections or subsections omitted from the full prescribing information are not listed
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Besivance™ (besifloxacin ophthalmic suspension) 0.6%, is indicated for the treatment of bacterial conjunctivitis caused by susceptibleisolates of the following bacteria:CDC coryneform group G
Corynebacterium pseudodiphtheriticum*Corynebacterium striatum*Haemophilus influenzaeMoraxella lacunata*Staphylococcus aureusStaphylococcus epidermidisStaphylococcus hominis*Staphylococcus lugdunensis*Streptococcus mitis groupStreptococcus oralis
Streptococcus pneumoniaeStreptococcus salivarius*
*Efficacy for this organism was studied in fewer than 10 infections.
2 DOSAGE AND ADMINISTRATIONInvert 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 CONTRAINDICATIONSNone
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 intothe 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 overgrowthof non-susceptible organisms, including fungi. If super-infection occurs, discontinue use and institute alternative therapy. Wheneverclinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, whereappropriate, 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 withBesivance™.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drugcannot be directly compared with the rates in the clinical trials of the same or another drug and may not reflect the rates observed inpractice.
The data described below reflect exposure to Besivance™ in approximately 1,000 patients between 1 and 98 years old with clinicalsigns 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.
page 2 of 6
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 malformationsin rat pups in a study of embryo-fetal development, although this dose was associated with maternal toxicity (reduced body weightgain and food consumption) and maternal mortality. Increased post-implantation loss, decreased fetal body weights, and decreasedfetal ossification were also observed. At this dose, the mean Cmax in the rat dams was approximately 20 mcg/mL, >45,000 timesthe mean plasma concentrations measured in humans. The No Observed Adverse Effect Level (NOAEL) for this embryo-fetaldevelopment 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 ofdevelopmental landmarks and sexual maturation were delayed, although surviving pups from this dose group that were reared tomaturity did not demonstrate deficits in behavior, including activity, learning and memory, and their reproductive capacity appearednormal.
Since there are no adequate and well-controlled studies in pregnant women, Besivance™ should be used during pregnancy only if thepotential 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 beexercised 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 14CLINICAL STUDIES].
There is no evidence that the ophthalmic administration of quinolones has any effect on weight bearing joints, even though systemicadministration 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 besifloxacinhydrochloride equivalent to 6 mg besifloxacin base. It is an 8-chloro fluoroquinolone anti-infective for topical ophthalmic use.
C19H21ClFN3O3•HClMol 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 forinjection.
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 receivedBesivance™ bilaterally three times a day (16 doses total). Following the first and last dose, the maximum plasma besifloxacin
page 3 of 6
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 day6. 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 andGram-negative bacteria due to the inhibition of both bacterial DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzymerequired for replication, transcription and repair of bacterial DNA. Topoisomerase IV is an essential enzyme required for partitioningof 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 antibioticsmay be active against pathogens that are resistant to besifloxacin. In vitro studies demonstrated crossresistance between besifloxacinand some fluoroquinolones.
In vitro resistance to besifloxacin develops via multiple-step mutations and occurs at a general frequency of < 3.3 x 10-10 forStaphylococcus 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 infectionstreated in clinical trials as described in the INDICATIONS AND USAGE section:CDC coryneform group G
Corynebacterium pseudodiphtheriticum*Corynebacterium striatum*Haemophilus influenzaeMoraxella lacunata*Staphylococcus aureusStaphylococcus epidermidisStaphylococcus hominis*Staphylococcus lugdunensis*Streptococcus mitis groupStreptococcus oralis
Streptococcus pneumoniaeStreptococcus salivarius*
*Efficacy for this organism was studied in fewer than 10 infections.13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to determine the carcinogenic potential of besifloxacin have not been performed.
No in vitro mutagenic activity of besifloxacin was observed in an Ames test (up to 3.33 mcg/plate) on bacterial tester strainsSalmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA. However, it was mutagenic in S.typhimurium strain TA102 and E. coli strain WP2(pKM101). Positive responses in these strains have been observed with otherquinolones and are likely related to topoisomerase inhibition.
Besifloxacin induced chromosomal aberrations in CHO cells in vitro and it was positive in an in vivo mouse micronucleus assayat oral doses ≥ 1500 mg/kg. Besifloxacin did not induce unscheduled DNA synthesis in hepatocytes cultured from rats given thetest compound up to 2,000 mg/ kg by the oral route. In a fertility and early embryonic development study in rats, besifloxacindid not impair the fertility of male or female rats at oral doses of up to 500 mg/kg/day. This is over 10,000 times higher than therecommended total daily human ophthalmic dose.
14 CLINICAL STUDIES
In a randomized, double-masked, vehicle controlled, multicenter clinical trial, in which patients 1-98 years of age were dosed 3times a day for 5 days, Besivance™ was superior to its vehicle in patients with bacterial conjunctivitis. Clinical resolution was
achieved in 45% (90/198) for the Besivance™ 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™ 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
Besivance™ (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 bandaround the cap and neck area of the package.5 mL in 7.5 mL bottle
page 4 of 6
NDC 24208-446-05
Storage: Store at 15°- 25°C (59° - 77°F). Protect from Light.Invert closed bottle and shake once before use.Rx Only
17 PATIENT COUNSELING INFORMATION
Patients should be advised to avoid contaminating the applicator tip with material from the eye, fingers or other source.
Although Besivance™ is not intended to be administered systemically, quinolones administered systemically have been associatedwith hypersensitivity reactions, even following a single dose. Patients should be advised to discontinue use immediately and contacttheir 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 takenexactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediatetreatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Besivance™ or otherantibacterial 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 oftherapy with Besivance™.
Patients should be advised to thoroughly wash hands prior to using Besivance™.
Patients should be instructed to invert closed bottle (upside down) and shake once before each use. Remove cap with bottle still in theinverted position. Tilt head back, and with bottle inverted, gently squeeze bottle to instill one drop into the affected eye(s).MANUFACTURER INFORMATION
Manufactured by: Bausch & Lomb IncorporatedTampa, Florida 33637
©Bausch & Lomb IncorporatedU.S. Patent No. 6,685,958U.S. Patent No. 6,699,492U.S. Patent No. 5,447,926
Besivance™ is a trademark of Bausch & Lomb Incorporated*DuraSite is a trademark of InSite Vision IncorporatedApril 20099142602 (flat)9142702 (folded)
page 5 of 6
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 24208-446-05Bausch & LombBesivance
besifloxacin ophthalmic suspension, 0.6%Rx onlySterile
FOR OPHTHALMIC USE ONLY.5 mL
page 6 of 6
因篇幅问题不能全部显示，请点此查看更多更全内容