Alcon.ca

PRODUCT MONOGRAPH
VIGAMOX®
Moxifloxacin Hydrochloride Ophthalmic Solution, 0.5% w/v as moxifloxacin PRODUCT MONOGRAPH
VIGAMOX®
Moxifloxacin Hydrochloride Ophthalmic Solution, 0.5% w/v as moxifloxacin ACTIONS AND CLINICAL PHARMACOLOGY
Moxifloxacin is a synthetic fluoroquinolone antibacterial agent active in vitro against a broad spectrum of Gram-positive and Gram-negative ocular pathogens, atypical microorganisms and The antibacterial action of moxifloxacin results from inhibition of 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 (see Pharmacokinetics/Pharmacodynamics: Following topical ocular administration of VIGAMOX®
(moxifloxacin hydrochloride) ophthalmic solution, moxifloxacin was absorbed into the systemic circulation. Plasma concentrations of moxifloxacin were measured in 21 male and female adult subjects who received bilateral topical ocular doses of VIGAMOX® solution every 8 hours for a total of 13 doses. The mean steady-state Cmax and AUC were 2.7 ng/mL and 41.9 nghr/mL, respectively. These systemic exposure values were at least 1,600 and 1,000 times lower than the mean Cmax and AUC reported after therapeutic 400 mg oral doses of moxifloxacin. The plasma half-life of moxifloxacin was estimated to be 13 hours. Moxifloxacin is widely distributed in the body and is excreted in feces or urine either unchanged or as glucuronide or sulfate conjugates. Tear film concentrations were studied in 31 healthy male and female adult volunteers who were administered 1 drop of VIGAMOX® solution to both eyes every 8 hours for a total of 10 doses. Mean tear concentrations at 5 minutes following the first and last topical dose were 46.0 and 55.2g/mL, respectively. Thereafter, they decline rapidly in a biphasic manner with the means ranging approximately 1 to 4 g/mL over the 1 to 8 hour sampling period. Pre-dose morning tear concentrations on Days 2 to 4 averaged over 4 g/mL. Studies conducted in animals indicate penetration into the conjunctiva and ocular tissues with prolonged binding to melanin. INDICATIONS AND USAGE
VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution is indicated for the treatment of patients 1 year of age and older with bacterial conjunctivitis caused by susceptible strains of the Aerobic, Gram-Positive
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae
Streptococcus viridans group
Aerobic, Gram-Negative
Acinetobacter species
Haemophilus influenzae
CONTRAINDICATIONS
VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution is contraindicated in patients with a history of hypersensitivity to moxifloxacin, to other quinolones, or to any of the components in this medication (see PHARMACEUTICAL INFORMATION). WARNINGS
VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution is not for injection into the eye. VIGAMOX® solution should not be injected subconjunctivally, nor should it be introduced directly In patients receiving systemically administered quinolones, 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. Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all oral antibiotics. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson Syndrome), vasculitis, arthralgia, myalgia, serum sickness, allergic pneumonitis, interstitial nephritis, acute renal insufficiency or failure, hepatitis, jaundice, acute hepatic necrosis or failure, anemia including hemolytic and aplastic, thrombocytopenia including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities. PRECAUTIONS
General: 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. In general, patients with signs and symptoms of bacterial conjunctivitis should be advised not to Information for Patients: Avoid contaminating the applicator tip with material from the eye,
Systemically administered quinolones have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of The potential of VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution to produce arthropathy in animals has not been studied. Moxifloxacin and other members of the quinolone class have been shown to cause arthropathy in immature Beagle dogs following oral administration Drug Interactions: Drug-drug interaction studies have not been conducted with VIGAMOX®
solution. Moxifloxacin can be chelated by polyvalent ions such as Mg++, Al+++, Fe++ and Zn++. There is limited information available on the concurrent use of VIGAMOX® solution and other Following oral administration, no clinically significant drug-drug interactions between theophylline, warfarin, digoxin, oral contraceptives or glyburide have been observed with moxifloxacin. Theophylline, digoxin, probenecid, and ranitidine have been shown not to alter the pharmacokinetics of moxifloxacin. 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. Pregnancy: Since there are no adequate and well-controlled studies in pregnant women
VIGAMOX® solution should only be used during pregnancy if the potential benefit justifies the VIGAMOX® solution has not been studied in pregnant animals. Oral and IV studies in pregnant animals indicated that moxifloxacin is not teratogenic. Decreased fetal birth weights and slightly delayed fetal skeletal development were observed in rats and rabbits following oral and intravenous administration of moxifloxacin, respectively. An increased incidence of smaller fetuses was observed in monkeys following oral dosing (see TOXICOLOGY). When 14C-moxifloxacin was administered orally to pregnant rats, radioactivity penetrated the placenta and was absorbed to a moderate extent by the fetus. The ratio for AUC (0-24 h) for fetal plasma to maternal plasma was As with other members of the quinolone class, moxifloxacin has caused arthropathy in immature Beagle dogs following oral administration. The significance of these findings to humans is Nursing Mothers: Moxifloxacin is excreted in the breast milk of rats following oral and
intravenous administration. Because of the potential for unknown effects from moxifloxacin in infants being nursed by mothers taking VIGAMOX® solution, a decision should be made to either discontinue nursing or discontinue the administration of VIGAMOX® solution, taking into account the importance of VIGAMOX® solution therapy to the mother and the possible risk to the infant Pediatric Use: The safety and efficacy of VIGAMOX® solution in patients less than one year of
The effect of VIGAMOX® solution on weight bearing joints has not been assessed. Oral administration of some quinolones, including moxifloxacin, has been shown to cause arthropathy in Geriatric Use: No overall differences in safety and effectiveness have been observed between
ADVERSE REACTIONS
In clinical trials involving 1068 subjects/patients, VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution was administered twice-daily for three days, three-times-daily for four to fourteen days and eight-times-daily for fourteen days. During treatment with VIGAMOX® solution, 6.6% (71 out of 1068) subjects/patients experienced treatment-related adverse drug reactions and of these only two (0.2%) discontinued study participation. No serious ophthalmic or systemic adverse reactions related to VIGAMOX® solution were reported. Clinical Trial Adverse Drug Reactions
The most frequently reported treatment-related adverse drug reactions were transient eye irritation (3.9%) (burning and/or stinging) and eye pruritus (1.1%). Treatment-related adverse drug reactions that occurred at an incidence of 0.1% to less than 1.0% Eye disorders: ocular hyperaemia, keratoconjunctivitis sicca, abnormal sensation in eye, ocular discomfort, corneal epithelium defect, conjunctivitis, conjunctival haemorrhage, visual acuity General disorders and administration site conditions: sensation of foreign body. Investigations: corneal staining, alanine aminotransferase increased. Nervous system disorders: dysgeusia, headache. Respiratory, thoracic, and mediastinal disorders: pharyngolaryngeal pain. Post-Market Adverse Drug Reactions
All adverse drug reactions with VIGAMOX® solution based on post-marketing reports (from more than 1.1 million units sold) have been reported at an incidence of less than 0.01%. The most frequently reported adverse reactions with VIGAMOX® solution based on post-marketing reports Eye disorders: endophthalmitis, eye irritation, corneal infiltrates, anterior chamber cells, corneal Immune system disorders: hypersensitivity NOS. Skin and subcutaneous disorders: erythema. SYMPTOMS AND TREATMENT OF OVERDOSE
No information is available on overdose of VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution in humans. A topical overdose of VIGAMOX® solution may be flushed from the eye(s) In an oral (gavage) monkey study, doses of moxifloxacin hydrochloride up to 15 mg/kg/day did not produce any toxicity. This dose is at least 10 times higher than the accidental ingestion of the contents of a 3 mL bottle of VIGAMOX® solution by a 10 kg child. DOSAGE AND ADMINISTRATION
The recommended dosage regimen for patients one year of age and older is one drop in the affected PHARMACEUTICAL INFORMATION
1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H- pyrrolol [3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid, monohydrochloride. Moxifloxacin differs from other quinolones in that it has a methoxy function at the 8 position, and an S,S- configured diazabicyclononyl ring moiety at the 7-position. Moxifloxacin hydrochloride is a slightly yellow to yellow crystalline powder. Moxifloxacin differs from other quinolones in that it has a methoxy function at the 8-position, and an S,S configurated diazabicyclononyl ring moiety at Composition: Each mL of VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution
contains 5.45 mg moxifloxacin hydrochloride equivalent to 5 mg moxifloxacin base. Contains:
Active: Moxifloxacin 0.5% (5,000 g/mL); Preservative: None. Product is self-preserved.
Inactives: sodium chloride, boric acid and purified water. May also contain hydrochloric
VIGAMOX® solution is isotonic and formulated at pH 6.8 with an osmolality of approximately 290 Stability & Storage Recommendations: Store at 4 - 25 C. Discard 28 days after opening.
AVAILABILITY
VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution, 0.5% is supplied as a 3 mL sterile ophthalmic solution in the Alcon DROP-TAINER® dispensing system consisting of a natural low density polyethylene bottle and dispensing plug and white polypropylene closure. Tamper evidence is provided with a shrink band around the closure and neck area of the package. INFORMATION FOR THE CONSUMER -
VIGAMOX® (moxifloxacin hydrochloride) OPHTHALMIC SOLUTION
VIGAMOX® 0.5% solution Moxifloxacin hydrochloride Medicine to treat eye infections. Read all of this information carefully before you start taking/using this medicine.
 Read this leaflet carefully because it contains important information for you.
 If you have further questions, please ask your doctor or your pharmacist.  This medicine has been prescribed for you personally. Never give it to anyone else. It may harm them, even if their symptoms are the same as yours.  Keep this information. You may need to read it again.
VIGAMOX® SOLUTION AND OTHER MEDICINES
Please tell your doctor or pharmacist if you are taking (or recently took) any other medicines.
Remember to mention medicines that you bought without prescription, over-the-counter.
Do not use other eye products with VIGAMOX® solution unless advised by your doctor.
WHAT MEDICATION HAS BEEN PRESCRIBED?
VIGAMOX® solution contains the fluoroquinolone antibiotic, moxifloxacin.
VIGAMOX® solution is an eye drop solution that treats bacterial conjunctivitis (sometimes referred
to as "pink eye"), an infection of the white of the eye, and works by killing the bacteria causing the
infection.
WHAT DOES VIGAMOX® SOLUTION CONTAIN AND HOW IS IT SUPPLIED?
VIGAMOX® solution eye drops contains moxifloxacin 0.5% (as base), sodium chloride, boric acid,
and purified water. Very small amounts of hydrochloric acid or sodium hydroxide are sometimes
added to keep acidity levels (pH levels) normal.
VIGAMOX® solution is a liquid (a solution) supplied in an oval plastic bottle which contains 3 ml
VIGAMOX® solution. VIGAMOX® solution is a clear greenish-yellow solution.
WHEN SHOULD I NOT USE VIGAMOX® SOLUTION?
If you have ever had any unusual or allergic reaction to moxifloxacin or other quinolones or any of
the ingredients detailed in the section entitled "WHAT DOES VIGAMOX® SOLUTION
CONTAIN AND HOW IS IT SUPPLIED?". Do not use VIGAMOX® solution longer than directed
by your doctor. If you get a worsening of your infection, contact your doctor as soon as possible.


ARE THERE SPECIAL CONSIDERATIONS FOR PREGNANT WOMEN AND WOMEN
WHO ARE BREAST FEEDING?
If you are pregnant, suspect you may be pregnant or are breast feeding consult your doctor or
pharmacist before using VIGAMOX® solution.
ARE THERE SPECIAL CONSIDERATIONS FOR CHILDREN?
VIGAMOX® solution can be used in children as young as one year of age. The dosage instructions
for children are the same as for adults and are described in the section entitled "How do I use
VIGAMOX® solution?"
ARE THERE SPECIAL CONSIDERATIONS FOR PATIENTS OVER 65 YEARS OF AGE?
VIGAMOX® solution can be used safely in patients over 65 years of age.
ARE THERE SPECIAL CONSIDERATIONS FOR PATIENTS WITH KIDNEY OR LIVER
PROBLEMS?
VIGAMOX® solution can be used safely in patients with kidney or liver problems.
CAN I DRIVE WHILE USING VIGAMOX® SOLUTION?
If you experience temporary blurred vision or discomfort after using VIGAMOX® solution you
should wait until these symptoms go away before driving or using machinery.
CAN I WEAR CONTACT LENSES WHILE USING VIGAMOX® SOLUTION?
You should not wear contact lenses if you have any signs or symptoms of an eye infection.
HOW DO I USE VIGAMOX® SOLUTION?
The normal dosage is one drop in the affected eye(s) three times a day (in the morning, in the
afternoon, and at night). Use this much unless your doctor told you to do something different. Only
use VIGAMOX® solution eye drops in both eyes if your doctor told you to. Use VIGAMOX®
solution for seven days or for as long as your doctor told you to.
If you miss a dose of this medicine, use the missed dose as soon as possible and then go back to
your regular dosing schedule. If the drop misses your eye, try again.
To keep the dropper tip and solution clean, be careful not to touch the eyelids or surrounding areas
with the dropper tip of the bottle. Keep the bottle tightly closed when not in use.
Get the bottle of VIGAMOX® solution eye drops and a mirror.
Wash your hands.
Open the bottle being careful not to touch the dropper tip. Hold the bottle, pointing down, between
your thumb and fingers.
Tilt your head back. Pull down your eyelid with a clean finger, until there is a 'pocket' between the
eyelid and your eye. The drop will go in there.
Bring the bottle tip close to the eye. Use the mirror if it helps.
Don't touch your eye or eyelid, surrounding areas or other surfaces with the bottle tip. It could
contaminate the drops.
Gently squeeze the bottle to release one drop of VIGAMOX® solution.
If you take drops in both eyes, repeat the steps for your other eye.
VIGAMOX® solution is for use as an eye drop only.
WHAT DO I DO IF I TAKE TOO MUCH VIGAMOX® SOLUTION?
If you put too much of this medicine in your eye(s), rinse it all out with warm tap water. Don't put
in any more drops until it's time for your next regular dose.
If VIGAMOX® solution is accidentally taken by mouth or injected, contact your doctor or
pharmacist for advice.
WHAT SIDE EFFECTS MIGHT I HAVE WITH VIGAMOX® SOLUTION?
Some people who use VIGAMOX® solution may get side effects. They can be unpleasant, but most
of them soon pass. You can usually keep using the drops, unless the effects are serious. If you're
worried, talk to your doctor or pharmacist.
While using VIGAMOX® eye drops you may experience some or all of the following reactions in
your eye: mild temporary burning or stinging, itching, redness, dryness, sensation of pressure,
discomfort, corneal irritations or changes, broken blood vessels in the white part of the eye,
swelling of the eye or eyelid, temporary reduction of vision, pain or other ocular irritations.
You may also experience reactions in other areas of your body, including: altered, bitter or bad
taste, headache, throat irritation and inflammation, a change in liver enzymes, allergic reaction or
skin redness following administration of the drops.
Other side effects not listed above may also occur in some patients.
If you notice any undesirable effects not mentioned in this information, you should stop using
VIGAMOX® solution and call your doctor or pharmacist immediately and follow his/her advice.
HOW LONG CAN I KEEP, AND HOW LONG SHOULD I STORE, VIGAMOX®
SOLUTION?
Keep these eye drops in a safe place out of the reach and sight of children.
Store between 4ºC and 25ºC.
Do not use this medicine after the expiry date (shown as "EXP" on the bottle and on the carton).
This medicine should be thrown away 28 days after opening.
FURTHER INFORMATION
Contact your doctor or pharmacist.

MANUFACTURER
Alcon Canada Inc.
2665 Meadowpine Blvd., Mississauga, Canada L5N 8C7
MICROBIOLOGY
Moxifloxacin has in vitro activity against a wide range of Gram-positive and Gram-negative The antibacterial action of moxifloxacin results from inhibition of 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 presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, a proposed mechanism of Moxifloxacin concentrations at twice the MIC are sufficient to be bactericidal for most strains of Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Concentrations of moxifloxacin somewhat greater than twice the MIC were bactericidal for strains of Escherichia coli while those greater than ten times the MIC were bactericidal for Streptococcus pyogenes. Resistance: The mechanism of resistance of quinolones, including moxifloxacin, is different from
that of macrolides, aminoglycosides, tetracyclines or -lactams. 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 slowly via multiple-step mutations and occurs in vitro at a general frequency of between 1.8 x 10-9 to less than 1 x 10-11 in one strain of Staphylococcus aureus and one strain of Streptococcus pneumoniae. Moxifloxacin has been shown to be active against most strains of the following microorganisms (see Table 1), both in vitro and in clinical infections from the US and India as described in the Table 1: Moxifloxacin In Vitro Activity Against Clinical Isolates
Pathogen
MIC Range
Aerobic, Gram-Positive
Aerobic, Gram-Negative
Acinetobacter species
The following in vitro data (Table 2) are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution in treating ophthalmic infections due to these organisms 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 ophthalmic efficacy has not been established. This list of organisms (Table 2) is provided as guidance only in assessing the potential treatment of conjunctival infections. Moxifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2 g/mL or less (systemic breakpoint susceptibility) against most (greater than or equal to 90%) strains of the Table 2: Susceptibility of Bacterial Conjunctivitis Isolates to Moxifloxacin
Bacterial Species
MIC Range
Aerobic Gram-positive Microorganisms
Bacillus cereus
Aerobic, Gram-negative Microorganisms
Acinetobacter baumannii
Susceptibility Tests: There are currently no NCCLS approved standards for assessing in vitro
susceptibility of conjunctival isolates to topical antibiotics, including moxifloxacin. Standardized systemic susceptibility tests may not be appropriate to predict clinical effectiveness in treating PHARMACOLOGY
Animal Pharmacokinetics:
Ocular tissue concentrations of moxifloxacin were determined in pigmented rabbits following a single bilateral 30 L topical administration of 0.3% ophthalmic solution of moxifloxacin (n=3 rabbits sampled at each time point). Mean maximum concentrations (Cmax) in cornea and aqueous humor were 12.5  3.8 g/g and 1.78  0.39 g/mL, respectively, and were achieved within 30 minutes after dosing. In iris-ciliary body, a moxifloxacin Cmax of 10.4  5.6 g/g was observed at 1 hour and declined slowly relative to other tissues, presumably due to binding to melanin pigment, which is characteristic of fluoroquinolones. The accumulation in ocular tissues of moxifloxacin after multiple dosing has not been studied. Maximum plasma concentrations were low (approximately 0.01 g/mL) and declined rapidly. The distribution of radiolabeled moxifloxacin was also studied in pigmented rabbits after a single unilateral 30 L dose of a 0.3% 14C-moxifloxacin solution (n=4 rabbits sampled at each time point). Mean Cmax values in cornea, conjunctiva, aqueous humor and iris-ciliary body were 10.6  2.8 g/g, 2.54  0.40 g/g, 1.36  0.33 g/mL and 7.54  3.34 g/g, respectively. Maximum concentrations and half-lives in ocular tissues are summarized in Table 3. Table 3: Maximum Concentrations and Half-Lives of Radiolabeled Moxifloxacin in Ocular
Tissues from Pigmented Rabbits
Cmax (g equivalents/g)  SD
t½ (hours)
Tear film concentrations of moxifloxacin were measured in pigmented rabbits (n=3) after single unilateral administration of 30 L of a 0.3% moxifloxacin ophthalmic solution. The mean concentration of moxifloxacin was 366  214 g/mL at the first sampling point of 1 minute after dosing. The levels then declined rapidly such that by 5 minutes after dosing the concentrations were approximately 20 g/mL. The concentrations in the tear film were 1.73  1.50 g/mL at 6 hours post-dosing. Tear concentration data are summarised in Table 4. Table 4: Tear Concentrations of Moxifloxacin Following Administration of a 0.3%
Moxifloxacin Solution to Pigmented Rabbits
Time After Dose (minutes)
Mean Concentration  SD
Sample Size
(g/mL)
* 1of 3 samples below quantitation limit of the assay. These samples were assigned a value of one half the limit of quantitation for calculation of the mean (1 g/mL/2 = 0.5 g/mL). Human Pharmacokinetics: Plasma concentrations were studied in 21 healthy male and female
subjects who were administered VIGAMOX® (moxifloxacin hydrochloride) ophthalmic solution to both eyes every 8 hours for a total of 13 doses. The results showed measurable plasma concentrations of moxifloxacin (0.75 ng/mL) in 16 of 21 subjects at 4-hours following the first dose, and in all subjects following the last dose. Figure 1 shows the mean moxifloxacin plasma The mean steady-state estimates for Cmax and AUC were 2.7 ng/mL and 41.9 nghr/mL, respectively. The steady-state parameter estimates for Cmax and AUC were at least 1,600 and 1,000 fold lower than mean Cmax and AUC values reported after therapeutic 400 mg oral doses of moxifloxacin. The steady-state plasma half-life of moxifloxacin was estimated to be 13 hours. Subgroup analysis by race (Caucasian, Asian) showed no meaningful differences in the mean steady-state pharmacokinetic parameters of moxifloxacin. Gender differences in the steady-state Cmax and AUC were seen; however, when adjusted for body weight, the differences were minimized Tear film concentrations of moxifloxacin were studied in 31 healthy male and female adult volunteers who were administered 1 drop of VIGAMOX® solution to both eyes every 8 hours for a Mean tear concentrations at 5 minutes following the first and last topical dose were 46.0 and 55.2g/mL, respectively. Thereafter, mean tear concentrations rapidly declined in a biphasic manner with means ranging from approximately 1 to 4 g/mL over the 1 to 8 hour sampling period. Pre-dose morning tear concentrations on Days 2 to 4 averaged over 4 g/mL, demonstrating that concentrations are above the MICs for most of the common organisms in conjunctivitis over the 24- Elimination and Metabolism: Moxifloxacin is widely distributed in the body tissues and approximately 50% is bound to serum proteins. Animal studies indicate some penetration into conjunctiva and ocular tissues with prolonged binding to melanin. Approximately 45% of an oral dose is excreted as unchanged drug, and most of the rest as glucuronide and sulfate conjugates in feces and urine. The cytochrome P450 enzyme system is not involved in metabolizing the drug. Drug-Drug Interactions: Specific drug-drug pharmacokinetic interaction studies were not conducted with VIGAMOX® solution. Given the low systemic exposure observed for moxifloxacin after topical ocular administration of VIGAMOX® solution, clinically relevant drug-drug interactions through protein binding, renal elimination or hepatic metabolism are unlikely following topical ocular administration. Moxifloxacin can be chelated by polyvalent ions such as Mg++, Al+++, In vitro studies with cytochrome P450 isozymes have shown 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 enzymes. The pharmacokinetics of VIGAMOX® solution has not been studied in patients with hepatic or renal impairment. However, the pharmacokinetics of orally administered moxifloxacin has been The pharmacokinetic parameters of oral moxifloxacin are not significantly altered by mild, moderate or severe renal impairment. No dosage adjustment of VIGAMOX® solution is necessary Pharmacokinetic parameters of oral moxifloxacin were not significantly altered in patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B). Studies were not performed in patients with severe hepatic impairment (Child Pugh Class C). Because of the low systemic exposure by the topical route of administration, no dosage adjustment of VIGAMOX® solution is needed in patients with hepatic impairment. Clinical Studies: In two, randomized, double-masked, multicenter, controlled trials in which 547
patients dosed with VIGAMOX® solution 3 times a day for 4 days, VIGAMOX® solution produced clinical cures on day 5 to 6 in 66% to 69% of patients treated for bacterial conjunctivitis. Microbiological success rates for the eradication of the baseline pathogens ranged from 84% to 94% at the test-of-cure visit (day 9). Please note that microbiologic eradication does not always correlate with clinical outcome in anti-infective trials. TOXICOLOGY
Topical Ocular Studies: Ophthalmic solutions of moxifloxacin were evaluated in repeat-dose
topical ocular studies in rabbits (pigmented) and Cynomolgus monkeys (see Table 5). Table 5: Results of Topical Ocular Studies
Species/No. per
Dose/Route
Duration of
Findings
Treatment
Ocular Toxicity Study: A special ocular toxicity study was conducted in dogs following systemic
(oral) administration of moxifloxacin (see Table 6). The daily dosages of moxifloxacin evaluated in this study are significantly higher than the recommended daily dose of VIGAMOX® (moxifloxacin Table 6: Results of Ocular Toxicity Study
Species/No. per
Dose/Route
Duration of
Findings
Treatment
NOEL = 30 mg/kg orally (over 1300
times > the human dose of
VIGAMOX® ophthalmic solution)
Single and Repeat-Dose Oral and IV Studies: Oral and intravenous single-dose studies
conducted with moxifloxacin are summarized in Table 7, and repeat-dose systemic studies that included ocular evaluations are summarized in Table 8. The daily dose levels of moxifloxacin evaluated in these studies are significantly higher than the recommended daily dose of VIGAMOX® Table 7: Single-Dose Systemic Studies
Strain/Sex
No./Group
LD50 mg/kg B.W.(Conf.
Administration Int. for 95%)
Table 8: Repeat-Dose Systemic Studies
Species/No.
Dose/Route
Duration of
Findings
per Group
Treatment
 body wt. gain at 100, 500, 750 mg/kg mg/kg; histopath unremarkable; NOAEL for females 100 mg/kg, 20 mg/kg for males  body wt. gain at 500 mg/kg both sexes; mg/kg males; ocular evaluations (indirect ophthalmoscope and slit-lamp) unremarkable; histopath 500 mg/kg both sexes, thyroid 500 mg/kg males NOAEL females 100 mg/kg, males 20 mg/kg Vacuolization of subcapsular lens cortex cataractogenesis; prolongation of QT interval at 90 mg/kg; histopath chondropathy at 30 and 90 mg/kg Vomiting, salivation, body wt. gain at 90 blistering of articular cartilage at 30 and 90 mg/kg vomiting, body wt. gain at 135 mg/kg; ophthalmoscope) unremarkable; NOAEL 15 mg/kg Mutagenicity: 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 dominant lethal test in mice. Carcinogenicity: 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 following up to 38 weeks of oral dosing at 500 Reproduction and Teratology: Moxifloxacin had no effect on fertility in male and female rats
at oral doses as high as 500 mg/kg/day, approximately 21,700 times the highest recommended Moxifloxacin was not teratogenic when administered to pregnant rats during organogenesis at oral doses as high as 500 mg/kg/day (approximately 21,700 times the highest recommended total human ophthalmic dose); however, decreased fetal body weights and slightly delayed fetal skeletal development were observed. There was no evidence of teratogenicity when pregnant Cynomolgus monkeys were given oral doses as high as 100 mg/kg/day (approximately 4,300 times the highest recommended total daily human ophthalmic dose). An increased incidence of smaller fetuses was observed at 100 mg/kg/day. In an oral peri/postnatal development study conducted in rats, marginal effects observed at 500 mg/kg/day included extended duration of pregnancy, increased prenatal loss, reduced birth weight and decreased survival index. Maternal In an intravenous rabbit study, moxifloxacin at 20 mg/kg (approximately 860 times the highest recommended total daily human ophthalmic dose) was found to decrease the gestation rate, decrease fetal weights and delay ossification. REFERENCES
Blondeau JM. A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new 'respiratory quinolones'. J Antimicrob Chemother 1999; 43 Suppl B:1-11. Blondeau JM, Felmingham D. In vitro and in vivo activity of moxifloxacin against community respiratory tract pathogens. Clin Drug Invest 1999;18:57-78. Boswell FJ, Andrews JM, Wise R, Dalhoff A. Bactericidal properties of moxifloxacin and post-antibiotic effect. J Antimicrob Chemother 1999;43(Suppl B):43-9. Brueggemann AB, Coffman SL, Rhomberg PR, Huynh HK, Almer L, Nilius A, Flamm R, Doern GV. Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994-1995. Antimicrob Agents Chemother 2002;46:680-8. Dalhoff A, Petersen U, Endermann R. In vitro activity of Bay 12-8039, a new 8-methoxyquinolone. Chemotherapy 1996; 42:410-25. Doern GV, Heilmann KP, Huynh HK, Rhomberg PR, Coffman SL, Brueggemann AB. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother 2001;45:1721-9. Esposito S, Noviello S, Ianniello F. Comparative in vitro activity of older and newer fluoroquinolones against respiratory tract pathogens. Chemotherapy 2000;46:309-314. Jones ME, Sahm DF, Martin N, Scheuring S, Heisig P, Thornsberry C, Kohrer K, Schmitz F-J. Prevalence of gyrA, gyrB, parC, and parE mutations in clinical isolates of Streptococcus pneumoniae with decreased susceptibilities to different fluoroquinolones and originating from worldwide surveillance studies during 1997-1998 respiratory season. Antimicrob Agents Chemother 2000;44(2):462-6. Klepser ME, Ernst EJ, Petzold R, Rhomberg P, Doern GV. Comparative bactericidal activities of ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Streptococcus pneumoniae in a dynamic in vitro model. Antimicrob Agents Chemother 2001;45:673-8. Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002;133:463-6. Pong A, Thomson KS, Moland, ES, Chartrand SA, Sanders CC. Activity of moxifloxacin against pathogens with decreased susceptibility to ciprofloxacin. J Antimicrob Chemother 1999;44(5):621-7. Schedletzky H, Wiedemann B, Heisig P. The effect of moxifloxacin on its target topoisomerases from Escherichia coli and Staphylococcus aureus. J Antimicrob Chemother 1999; 43 Suppl B:31-7. Schmitz FJ, Hofmann B, Hansen B, Scheuring S, Luckefahr M, Klootwijk M, Verhoef J, Fluit A, Heinz HP, Kohrer K, Jones ME. Relationship between ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin and moxifloxacin (BAY 12-8039) MICs and mutations in grlA, grlB, gyrA and gyrB in 116 unrelated clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 1998;41: 41-484. Siefert HM, Domdey-Bette A, Henninger K, Hucke F, Kohlsdorfer C, Stass HH. Pharmaockinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species. J Antimicrob Chemother 1999;43(Suppl B):69-76. Stass H, Kubitza D. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration. J Antimicrob Chemother 1999;43(Suppl B):83-90. Tankovic J, Bachoual R, Ouabdesselam S, Boudjadja A, Soussy C-J. In vitro activity of moxifloxacin against fluoroquinolone-resistant strains of aerobic gram-negative bacilli and Enterococcus faecalis. J Antimicrob Chemother 1999; 43:19-23. Licensed to Alcon, Inc. from Bayer AG 2004, 2012 Novartis

Source: http://www.alcon.ca/pdf/Product_pharma/Product_pharma_vigamox_eng.pdf