Ciprofloxacin Hydrochloride

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Ciprofloxacin Hydrochloride Prescribing Information

Ciprofloxacin ophthalmic Solution is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

Corneal Ulcers:

Pseudomonas aeruginosa

Serratia marcescens

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus

(Viridans Group) *

Conjunctivitis:

Haemophilus influenzae

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

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

Corneal Ulcers:

The recommended dosage regimen for the treatment of

corneal ulcers

is two drops into the affected eye every 15 minutes for the first six hours and then two drops into the affected eye every 30 minutes for the remainder of the first day. On the second day, instill two drops in the affected eye hourly. On the third through the fourteenth day, place two drops in the affected eye every four hours. Treatment may be continued after 14 days if corneal re-epithelialization has not occurred.

Bacterial Conjunctivitis:

The recommended dosage regimen for the treatment of

bacterial conjunctivitis

is one or two drops instilled into the conjunctival sac(s) every two hours while awake for two days and one or two drops every four hours while awake for the next five days.

The most frequently reported drug related adverse reaction was local burning or discomfort. In corneal ulcer studies with frequent administration of the drug, white crystalline precipitates were seen in approximately 17% of patients (SEE

PRECAUTIONS:

General:

As with other antibacterial preparations, prolonged use of ciprofloxacin may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity reaction.

In clinical studies of patients with bacterial corneal ulcer, a white crystalline precipitate located in the superficial portion of the corneal defect was observed in 35 (16.6%) of 210 patients. The onset of the precipitate was within 24 hours to 7 days after starting therapy. In one patient, the precipitate was immediately irrigated out upon its appearance. In 17 patients, resolution of the precipitate was seen in 1 to8 days (seven within the first 24 to 72 hours), in five patients, resolution was noted in 10 to 13 days. In nine patients, exact resolution days were unavailable; however, at follow-up examinations, 18 to 44 days after onset of the event, complete resolution of the precipitate was noted. In three patients, outcome information was unavailable. The precipitate did not preclude continued use of ciprofloxacin, nor did it adversely affect the clinical course of the ulcer or visual outcome. (SEE

ADVERSE REACTIONS

Information for patients:

Do not touch dropper tip to any surface, as this may contaminate the solution.

Drug Interactions:

Specific drug interaction studies have not been conducted with ophthalmic ciprofloxacin. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, enhance the effects of the oral anticoagulant, warfarin, and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Eight

in vitro

mutagenicity tests have been conducted with ciprofloxacin and the test results are listed below:

Salmonella

/Microsome Test (Negative)

E. coli

DNA Repair Assay (Negative)

Mouse Lymphoma Cell Forward Mutation Assay (Positive)

Chinese Hamster V79 Cell HGPRT Test (Negative)

Syrian Hamster Embryo Cell Transformation Assay (Negative)

Saccharomyces cerevisiae

Point Mutation Assay (Negative)

Saccharomyces cerevisiae

Mitotic Crossover and Gene Conversion Assay (Negative)

Rat Hepatocyte DNA Repair Assay (Positive)

Thus, two of the eight tests were positive, but the results of the following three

in vivo

test systems gave negative results:

Rat Hepatocyte DNA Repair Assay

Micronucleus Test (Mice)

Dominant Lethal Test (Mice)

Long term carcinogenicity studies in mice and rats have been completed. After daily oral dosing for up to two years, there is no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects in these species.

Pregnancy:

Reproduction studies have been performed in rats and mice at doses up to six times the usual daily human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to ciprofloxacin. In rabbits, as with most antimicrobial agents, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion. No teratogenicity was observed at either dose. After intravenous administration, at doses up to 20 mg/kg, no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. There are no adequate and well controlled studies in pregnant women.

Ciprofloxacin Ophthalmic Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

It is not known whether topically applied ciprofloxacin is excreted in human milk; however, it is known that orally administered ciprofloxacin is excreted in the milk of lactating rats and oral ciprofloxacin has been reported in human breast milk after a single 500 mg dose. Caution should be exercised when Ciprofloxacin Ophthalmic Solution is administered to a nursing mother.

Pediatric Use:

The safety and effectiveness of ciprofloxacin ophthalmic solution 0.3% have been established in all ages. Use of ciprofloxacin is supported by evidence from adequate and well controlled studies of ciprofloxacin in adults, children and neonates

[see Clinical Studies].

Although ciprofloxacin and other quinolones cause arthropathy in immature animals after oral administration, topical ocular administration of ciprofloxacin to immature animals did not cause any arthropathy and there is no evidence that the ophthalmic dosage form has any effect on the weight bearing joints.

Geriatric Use:

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

). Other reactions occurring in less than 10% of patients included lid margin crusting, crystals/scales, foreign body sensation, itching, conjunctival hyperemia and a bad taste following instillation. Additional events occurring in less than 1% of patients included corneal staining, keratopathy/keratitis, allergic reactions, lid edema, tearing, photophobia, corneal infiltrates, nausea and decreased vision.

To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 866-488-0312 or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch

Ciprofloxacin ophthalmic solution is a synthetic, sterile, multiple dose, antimicrobial for topical ophthalmic use. Ciprofloxacin is a fluoroquinolone antibacterial active against a broad spectrum of gram-positive and gram-negative ocular pathogens. It is available as the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acid. It is a faint to light yellow crystalline powder with a molecular weight of 385.8. Its empirical formula is C
₁₇H
₁₈FN
₃O
₃•HCL•H
₂O and its chemical structure is as follows:

Referenced Image

Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-position.

Each mL of ciprofloxacin ophthalmic solution contains:

Active:

Ciprofloxacin hydrochloride 3.5 mg equivalent to 3mg base.

Preservative:

Benzalkonium chloride 0.006%.

Inactives:

Acetic acid, edetate disodium 0.05%, mannitol 4.6%, Sodium acetate, hydrochloric acid and/or sodium hydroxide (to adjust pH) and water for injection. The pH is between 3.5 to 5.5 and the osmolality is between 290 to 300 mOsms/kg.

Systemic Absorption:

A systemic absorption study was performed in which ciprofloxacin ophthalmic solution was administered in each eye every two hours while awake for two days followed by every four hours while awake for an additional 5 days. The maximum reported plasma concentration of ciprofloxacin was less than 5 ng/mL. The mean concentration was usually less than 2.5 ng/mL.

Microbiology

: Ciprofloxacin has

in vitro

activity against a wide range of gram-negative and gram- positive organisms. The bactericidal action of ciprofloxacin results from interference with the enzyme DNA gyrase which is needed for the synthesis of bacterial DNA.

Ciprofloxacin has been shown to be active against most strains of the following organisms both

in vitro

and in clinical infections (SEE

INDICATIONS AND USAGE:

Ciprofloxacin ophthalmic Solution is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

Corneal Ulcers:

Pseudomonas aeruginosa

Serratia marcescens

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus

(Viridans Group) *

Conjunctivitis:

Haemophilus influenzae

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

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

section):

Gram-Positive:

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus

(Viridans Group)

Gram-Negative:

Haemophilus influenzae

Pseudomonas aeruginosa

Serratia marcescens

Ciprofloxacin has been shown to be active

in vitro

against most strains of the following organisms, however,

the clinical significance of these data is unknown:

Gram-Positive:

Enterococcus faecalis

(Many strains are only moderately susceptible)

Staphylococcus haemolyticus

Staphylococcus hominis

Staphylococcus saprophyticus

Streptococcus pyogenes

Gram-Negative:

Acinetobacter calcoaceticus

Escherichia coli

Proteus mirabilis

subsp. anitratus

Haemophilus ducreyi

Proteus vulgaris

Aeromonas caviae

Haemophilus parainfluenzae

Providencia rettgeri

Aeromonas hydrophila

Kiebsiella pneumoniae

Providencia stuartii

Brucella melitensis

Klebsiella oxytoca

Salmonella enteritidis

Campylobacter coli

Legionella pneumophila

Salmonella typhi

Campylobacter jejuni

Moraxella (Branhamella)

Shigella sonneii

Citrobacter diversus

catarrhalis

Shigella flexneri

Citrobacter freundii

Morganella morganii

Vibrio cholerae

Edwardsiella tarda

Neisseria gonorrhoeae

Vibrio parahaemolyticus

Enterobacter aerogenes

Neisseria meningitidis

Vibrio vulnificus

Enterobacter cloacae

Pasteurella multocida

Yersinia enterocolitica

Other Organisms:

Chlamydia trachomatis

(only moderately susceptible) and

Mycobacterium tuberculosis

(only moderately susceptible).

Most strains of

Pseudomonas cepacia

and some strains of

Pseudomonas maltophilia

are resistant to ciprofloxacin as are most anaerobic bacteria, including

Bacteroides fragilis

and

Clostridium difficile

. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2. Resistance to ciprofloxacin

in vitro

usually develops slowly (multiple-step mutation).

Ciprofloxacin does not cross-react with other antimicrobial agents such as beta-lactams or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin.

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Ciprofloxacin Hydrochloride

Ciprofloxacin Hydrochloride Prescribing Information

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