NDA 21598/S-024
`Page 3
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`VIGAMOX safely and effectively. See full prescribing information for
`VIGAMOX.
`
`------------------------------CONTRAINDICATIONS------------------------------­
`VIGAMOX is contraindicated in patients with a history of hypersensitivity to
`moxifloxacin, to other quinolones, or to any of the components in this
`medication. (4)
`
`VIGAMOX® (moxifloxacin ophthalmic solution), for topical
`ophthalmic use
`Initial U.S. Approval: 1999
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`Dosage and Administration (2)
` 6/2020
`
`Warnings and Precautions, Topical Ophthalmic Use (5.1) Removed 6/2020
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`VIGAMOX is a topical fluoroquinolone anti-infective indicated for the
`treatment of bacterial conjunctivitis caused by susceptible strains of the
`following organisms:
`Corynebacterium species*, Micrococcus luteus*, Staphylococcus aureus,
`
`Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus
`hominis, Staphylococcus warneri*, Streptococcus pneumoniae, Streptococcus
`viridans group, Acinetobacter lwoffii*, Haemophilus influenzae, Haemophilus
`parainfluenzae*, Chlamydia trachomatis
`*Efficacy for this organism was studied in fewer than 10 infections. (1)
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`Instill one drop in the affected eye 3 times a day for 7 days. (2)
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`Ophthalmic solution containing moxifloxacin 0.5%. (3)
`
`•
`
`-------------------------WARNINGS AND PRECAUTIONS---------------------­
`• Hypersensitivity Reactions: Hypersensitivity and anaphylaxis have been
`reported with systemic use of moxifloxacin. (5.1)
`Prolonged Use: May result in overgrowth of non-susceptible organisms,
`including fungi. If superinfection occurs, discontinue use and institute
`alternative therapy. (5.2)
`• Avoid Contact Lens Wear: Patients should not wear contact lenses if they
`have signs or symptoms of bacterial conjunctivitis. (5.3)
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`The most frequently reported ocular adverse events were conjunctivitis,
`decreased visual acuity, dry eye, keratitis, ocular discomfort, ocular hyperemia,
`ocular pain, ocular pruritus, subconjunctival hemorrhage, and tearing. These
`events occurred in approximately 1% to 6% of patients. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA­
`1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 6/2020
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`DOSAGE AND ADMINISTRATION
`2
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Hypersensitivity Reactions
`5.2
`Growth of Resistant Organisms With Prolonged Use
`5.3
`Avoidance of Contact Lens Wear
`ADVERSE REACTIONS
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`
`6
`7
`8
`
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3
`Pharmacokinetics
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not
`listed.
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`

`NDA 21598/S-024
`Page 4
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`VIGAMOX® is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains of the following
`
`organisms:
`
`Corynebacterium species*
`
`Micrococcus luteus*
`Staphylococcus aureus
`Staphylococcus epidermidis
`Staphylococcus haemolyticus
`Staphylococcus hominis
`Staphylococcus warneri*
`Streptococcus pneumoniae
`Streptococcus viridans group
`Acinetobacter lwoffii*
`Haemophilus influenza
`Haemophilus parainfluenzae*
`Chlamydia trachomatis
`*Efficacy for this organism was studied in fewer than 10 infections.
`
`DOSAGE AND ADMINISTRATION
`2
`Instill one drop in the affected eye 3 times a day for 7 days. VIGAMOX is for topical ophthalmic use.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Ophthalmic solution containing moxifloxacin 0.5%.
`
`CONTRAINDICATIONS
`4
`VIGAMOX is contraindicated in patients with a history of hypersensitivity to moxifloxacin, to other quinolones, or to any
`of the components in this medication.
`
`WARNINGS AND PRECAUTIONS
`5
`Hypersensitivity Reactions
`5.1
`In patients receiving systemically administered quinolones, including moxifloxacin, serious and occasionally fatal
`hypersensitivity (anaphylactic) reactions have been reported, some following the first dose. 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 moxifloxacin occurs, discontinue use
`of the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway
`management should be administered as clinically indicated.
`5.2
`Growth of Resistant Organisms With Prolonged Use
`As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If
`superinfection 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 Lens Wear
`Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis.
`
`ADVERSE REACTIONS
`6
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
`
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`

`NDA 21598/S-024
`Page 5
`of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates
`observed in practice.
`The most frequently reported ocular adverse events were conjunctivitis, decreased visual acuity, dry eye, keratitis, ocular
`discomfort, ocular hyperemia, ocular pain, ocular pruritus, subconjunctival hemorrhage, and tearing. These events
`occurred in approximately 1%-6% of patients.
`Nonocular adverse events reported at a rate of 1%-4% were fever, increased cough, infection, otitis media, pharyngitis,
`rash, and rhinitis.
`7
`DRUG INTERACTIONS
`Drug-drug interaction studies have not been conducted with VIGAMOX®. In vitro studies indicate that moxifloxacin does
`not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, indicating that moxifloxacin is unlikely to alter the
`pharmacokinetics of drugs metabolized by these cytochrome P450 isozymes.
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`Risk Summary
`There are no adequate and well-controlled studies with VIGAMOX® in pregnant women to inform any drug-associated
`risks.
`Oral administration of moxifloxacin to pregnant rats and monkeys and intravenously to pregnant rabbits during the period
`of organogenesis did not produce adverse maternal or fetal effects at clinically relevant doses. Oral administration of
`moxifloxacin to pregnant rats during late gestation through lactation did not produce adverse maternal, fetal or neonatal
`effects at clinically relevant doses (see Data).
`Data
`Animal Data
`Embryo-fetal studies were conducted in pregnant rats administered with 20, 100, or 500 mg/kg/day moxifloxacin by oral
`gavage on Gestation Days 6 to 17, to target the period of organogenesis. Decreased fetal body weight and delayed skeletal
`development were observed at 500 mg/kg/day [277 times the human area under the curve (AUC) at the recommended
`human ophthalmic dose]. The No-Observed-Adverse-Effect-Level (NOAEL) for developmental toxicity was 100
`mg/kg/day (30 times the human AUC at the recommended human ophthalmic dose).
`Embryo-fetal studies were conducted in pregnant rabbits administered with 2, 6.5, or 20 mg/kg/day moxifloxacin by
`intravenous administration on Gestation Days 6 to 20, to target the period of organogenesis. Abortions, increased
`incidence of fetal malformations, delayed fetal skeletal ossification, and reduced placental and fetal body weights were
`observed at 20 mg/kg/day (1086 times the human AUC at the recommended human ophthalmic dose), a dose that
`produced maternal body weight loss and death. The NOAEL for developmental toxicity was 6.5 mg/kg/day (246 times the
`human AUC at the recommended human ophthalmic dose).
`Pregnant cynomolgus monkeys were administered moxifloxacin at doses of 10, 30, or 100 mg/kg/day by intragastric
`intubation between Gestation Days 20 and 50, targeting the period of organogenesis. At the maternal toxic doses of ≥ 30
`mg/kg/day, increased abortion, vomiting, and diarrhea were observed. Smaller fetuses/reduced fetal body weights were
`observed at 100 mg/kg/day (2864 times the human AUC at the recommended human ophthalmic dose). The NOAEL for
`fetal toxicity was 10 mg/kg/day (174 times the human AUC at the recommended human ophthalmic dose).
`In a pre- and postnatal study, rats were administered moxifloxacin by oral gavage at doses of 20, 100, and 500 mg/kg/day
`from Gestation Day 6 until the end of lactation. Maternal death occurred during gestation at 500 mg/kg/day. Slight
`
`increases in the duration of pregnancy, reduced pup birth weight, and decreased prenatal and neonatal survival were
`observed at 500 mg/kg/day (estimated 277 times the human AUC at the recommended human ophthalmic dose). The
`NOAEL for pre- and postnatal development was 100 mg/kg/day (estimated 30 times the human AUC at the recommended
`human ophthalmic dose).
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`NDA 21598/S-024
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`8.2
` Lactation
`
`Risk Summary
`There is no data regarding the presence of VIGAMOX® in human milk, the effects on the breastfed infants, or the effects
`on milk production/excretion to inform risk of VIGAMOX® to an infant during lactation.
`A study in lactating rats has shown transfer of moxifloxacin into milk following oral administration.
`Systemic levels of moxifloxacin following topical ocular administration are low [see Clinical Pharmacology (12.3)], and
`it is not known whether measurable levels of moxifloxacin would be present in maternal milk following topical ocular
`administration.
`The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for
`VIGAMOX and any potential adverse effects on the breastfed child from VIGAMOX®.
`8.4
`Pediatric Use
`The safety and effectiveness of VIGAMOX have been established in all ages. Use of VIGAMOX is supported by
`evidence from adequate and well controlled studies of VIGAMOX in adults, children, and neonates [see Clinical Studies
`(14)].
`There is no evidence that the ophthalmic administration of VIGAMOX has any effect on weight bearing joints, even
`though oral 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
`VIGAMOX (moxifloxacin ophthalmic solution) 0.5% is a sterile solution for topical ophthalmic use. Moxifloxacin
`hydrochloride is an 8-methoxy fluoroquinolone anti-infective, with a diazabicyclononyl ring at the C7 position. The
`chemical name for moxifloxacin hydrochloride is 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)­
`octahydro-6H-pyrrolol[3,4b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid, monohydrochloride. The molecular formula
`for moxifloxacin hydrochloride is C21H24FN3O4•HCl and its molecular weight is 437.9 g/mol. The chemical structure is
`presented below:
`
`Moxifloxacin hydrochloride is a slightly yellow to yellow crystalline powder.
`Each mL of VIGAMOX solution contains 5.45 mg moxifloxacin hydrochloride, equivalent to 5 mg moxifloxacin base.
`VIGAMOX contains Active: Moxifloxacin 0.5% (5 mg/mL); Inactives: Boric acid, purified water, and sodium chloride.
`
`May also contain hydrochloric acid/sodium hydroxide to adjust pH to approximately 6.8.
`VIGAMOX® is an isotonic solution with an osmolality of approximately 290 mOsm/kg.
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Moxifloxacin is a member of the fluoroquinolone class of anti-infective drugs [see Microbiology (12.4)].
`12.3
`Pharmacokinetics
`Plasma concentrations of moxifloxacin were measured in healthy adult male and female subjects who received bilateral
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`NDA 21598/S-024
`Page 7
`topical ocular doses of VIGAMOX® 3 times a day. The mean steady-state Cmax (2.7 ng/mL) and AUC0-∞ (41.9 ng●hr/mL)
`values were 1600 and 1100 times lower than the mean Cmax and AUC reported after therapeutic 400 mg doses of
`moxifloxacin. The plasma half-life of moxifloxacin was estimated to be 13 hours.
`12.4 Microbiology
`The antibacterial action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase
`IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA.
`
`Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial
`
`cell division.
`The mechanism of action for quinolones, including moxifloxacin, is different from that of macrolides, aminoglycosides,
`or tetracyclines. Therefore, moxifloxacin may be active against pathogens that are resistant to these antibiotics and these
`antibiotics may be active against pathogens that are resistant to moxifloxacin. There is no cross-resistance between
`moxifloxacin and the aforementioned classes of antibiotics. Cross-resistance has been observed between systemic
`moxifloxacin and some other quinolones.
`In vitro resistance to moxifloxacin develops via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a
`general frequency of between 1.8 x 10-9 to less than 1 x 10-11 for gram-positive bacteria.
`Moxifloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in
`clinical infections as described in the Indications and Usage section:
`Aerobic Gram-Positive Microorganisms
`Corynebacterium species*
`
`Micrococcus luteus*
`Staphylococcus aureus
`Staphylococcus epidermidis
`Staphylococcus haemolyticus
`Staphylococcus hominis
`Staphylococcus warneri*
`Streptococcus pneumoniae
`Streptococcus viridans group
`Aerobic Gram-Negative Microorganisms
`Acinetobacter lwoffii*
`Haemophilus influenza
`Haemophilus parainfluenzae*
`Other Microorganisms
`Chlamydia trachomatis
`*Efficacy for this organism was studied in fewer than 10 infections.
`The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The
`safety and effectiveness of VIGAMOX in treating ophthalmological infections due to these microorganisms have not been
`established in adequate and well-controlled trials.
`The following organisms are considered susceptible when evaluated using systemic breakpoints. However, a correlation
`between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is
`provided as guidance only in assessing the potential treatment of conjunctival infections. Moxifloxacin exhibits in vitro
`
`minimal inhibitory concentrations (MICs) of 2 microgram/mL or less (systemic susceptible breakpoint) against most
`(greater than or equal to 90%) strains of the following ocular pathogens.
`Aerobic Gram-Positive Microorganisms
`Listeria monocytogenes
`Staphylococcus saprophyticus
`Streptococcus agalactiae
`Streptococcus mitis
`Streptococcus pyogenes
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`NDA 21598/S-024
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`Streptococcus Group C, G, and F
`Aerobic Gram-Negative Microorganisms
`Acinetobacter baumannii
`Acinetobacter calcoaceticus
`Citrobacter freundii
`Citrobacter koseri
`Enterobacter aerogenes
`Enterobacter cloacae
`Escherichia coli
`Klebsiella oxytoca
`Klebsiella pneumoniae
`Moraxella catarrhalis
`Morganella morganii
`Neisseria gonorrhoeae
`Proteus mirabilis
`Proteus vulgaris
`Pseudomonas stutzeri
`Anaerobic Microorganisms
`Clostridium perfringens
`Fusobacterium species
`Prevotella species
`Propionibacterium acnes
`Other Microorganisms
`Chlamydia pneumoniae
`Legionella pneumophila
`Mycobacterium avium
`Mycobacterium marinum
`Mycoplasma pneumoniae
`13
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis
`Long-term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed. However,
`in an accelerated study with initiators and promoters, moxifloxacin was not carcinogenic in rats following up to 38 weeks
`of oral dosing at 500 mg/kg/day (3224 times the highest recommended total daily human ophthalmic dose for a 60 kg
`person, based on body surface area).
`Mutagenesis
`Moxifloxacin was not mutagenic in four bacterial strains used in the Ames Salmonella reversion assay. As with other
`
`quinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the
`inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay.
`An equivocal result was obtained in the same assay when V79 cells were used. Moxifloxacin was clastogenic in the V79
`chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no
`evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.
`Impairment of Fertility
`Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately
`3224 times the highest recommended total daily human ophthalmic dose, based on body surface area. At 500 mg/kg/day
`orally, there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female
`rats.
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`14
`CLINICAL STUDIES
`In two randomized, double-masked, multicenter, controlled clinical trials in which patients were dosed 3 times a day for 4
`days, VIGAMOX® produced clinical cures on Day 5-6 in 66% to 69% of patients treated for bacterial conjunctivitis.
`Microbiological success rates for the eradication of baseline pathogens ranged from 84% to 94%.
`In a randomized, double-masked, multicenter, parallel-group clinical trial of pediatric patients with bacterial conjunctivitis
`between birth and 31 days of age, patients were dosed with VIGAMOX or another anti-infective agent. Clinical outcomes
`for the trial demonstrated a clinical cure rate of 80% at Day 9 and a microbiological eradication success rate of 92% at
`Day 9.
`Please note that microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.
`16
`HOW SUPPLIED/STORAGE AND HANDLING
`VIGAMOX® is supplied as a sterile ophthalmic solution in a dispensing system consisting of a natural low density
`polyethylene bottle and dispensing plug and tan polypropylene closure. Tamper evidence is provided with a shrink band
`around the closure and neck area of the package.
`3 mL in a 4 mL bottle
`NDC 0065-4013-03
`Storage: Store at 2°C to 25°C (36°F to 77°F).
`17
`PATIENT COUNSELING INFORMATION
`Avoid Contamination of the Product
`
`Advise patients not to touch the dropper tip to any surface to avoid contaminating the contents.
`
`Avoid Contact Lens Wear
`Advise patients not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis [see Warnings and
`
`Precautions (5.3)].
`Hypersensitivity Reactions
`Systemically administered quinolones including moxifloxacin have been associated with hypersensitivity reactions, even
`following a single dose. Instruct patients to discontinue use immediately and contact their physician at the first sign of a
`rash or allergic reaction [see Warnings and Precautions (5.1)].
`
`Distributed by:
`Novartis Pharmaceuticals Corporation
`East Hanover, New Jersey 07936
`
`© Novartis
`
`Reference ID: 4618288
`
`