CIPROFLOXACIN- ciprofloxacin hydrochloride solution/ drops 
Unit Dose Services

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Ciprofloxacin Ophthalmic Solution

DESCRIPTION

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 H FN O •HCl•H O and its chemical structure is as follows: 1718332

Ciprofloxacin Structural Formula

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: ciprofloxacin HCl 3.5 mg equivalent to 3 mg base. benzalkonium chloride 0.006%. acetic acid, edetate disodium 0.05%, mannitol 4.6%, purified water, sodium acetate, hydrochloric acid and/or sodium hydroxide may be used to adjust pH. The pH is approximately 4.5 and the osmolality is approximately 300 mOsm. Active:Preservative:Inactive:

CLINICAL PHARMACOLOGY

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 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. in vitro

Ciprofloxacin has been shown to be active against most strains of the following organisms both and in clinical infections. (See section). in vitroINDICATIONS AND USAGE

Gram-Positive

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

(Viridans Group) Streptococcus

Gram-Negative

Haemophilus influenzae

Pseudomonas aeruginosa

Serratia marcescens

Ciprofloxacin has been shown to be active against most strains of the following organisms, however, in vitrothe clinical significance of these data is unknown:

Gram-Positive

(Many strains are only moderately susceptible) Enterococcus faecalis

Staphylococcus haemolyticus

Staphylococcus hominis

Staphylococcus saprophyticus

Streptococcus pyogenes

Gram-Negative

Acinetobacter calcoaceticus subsp. anitratus

Aeromonas caviae

Aeromonas hydrophila

Brucella melitensis

Campylobacter coli

Campylobacter jejuni

Citrobacter diversus

Citrobacter freundii

Edwardsiella tarda

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus ducreyi

Haemophilus parainfluenzae

Klebsiella pneumoniae

Klebsiella oxytoca

Legionella pneumophila

Moraxella (Branhamella) catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Neisseria meningitidis

Pasteurella multocida

Proteus mirabilis

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Salmonella enteritidis

Salmonella typhi

Shigella sonneii

Shigella flexneri

Vibrio cholerae

Vibrio parahaemolyticus

Vibrio vulnificus

Yersinia enterocolitica

Other Organisms

(only moderately susceptible) and (only moderately susceptible). Chlamydia trachomatisMycobacterium tuberculosis

Most strains of and some strains of are resistant to ciprofloxacin as are most anaerobic bacteria, including and Pseudomonas cepaciaPseudomonas maltophiliaBacteroides fragilisClostridium 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 usually develops slowly (multiple-step mutation). in vitro

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.

Clinical Studies

Following therapy with Ciprofloxacin Ophthalmic Solution, 76% of the patients with corneal ulcers and positive bacterial cultures were clinically cured and complete re-epithelialization occurred in about 92% of the ulcers.

In 3 and 7 day multicenter clinical trials, 52% of the patients with conjunctivitis and positive conjunctival cultures were clinically cured and 70-80% had all causative pathogens eradicated by the end of treatment.

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

(Viridans Group)* Streptococcus

Conjunctivitis:

Haemophilus influenzae

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

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

CONTRAINDICATIONS

A history of hypersensitivity to ciprofloxacin or any other component of the medication is a contraindication to its use. A history of hypersensitivity to other quinolones may also contraindicate the use of ciprofloxacin.

WARNINGS

NOT FOR INJECTION INTO THE EYE.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

Remove contact lenses before using.

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 to 8 days (seven within the first 24-72 hours), in five patients, resolution was noted in 10-13 days. In nine patients, exact resolution days were unavailable; however, at follow-up examinations, 18-44 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 mutagenicity tests have been conducted with ciprofloxacin and the test results are listed below: in vitro

 
Microsome Test (Negative) Salmonella/
 
DNA Repair Assay (Negative) E. coli
 
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
 
Chinese Hamster V Cell HGPRT Test (Negative) 79
 
Syrian Hamster Embryo Cell Transformation Assay (Negative)
 
Point Mutation Assay (Negative) Saccharomyces cerevisiae
 
Mitotic Crossover and Gene Conversion Assay (Negative) Saccharomyces cerevisiae
 
Rat Hepatocyte DNA Repair Assay (Positive)

Thus, two of the eight tests were positive, but the results of the following three test systems gave negative results: in vivo

 
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. Pregnancy Category C:

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

Safety and effectiveness in pediatric patients below the age of 1 year have not been established. 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.

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 ). 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. PRECAUTIONS

OVERDOSAGE

A topical overdose of Ciprofloxacin Ophthalmic Solution may be flushed from the eye(s) with warm tap water.

DOSAGE AND ADMINISTRATION

Corneal Ulcers

The recommended dosage regimen for the treatment of 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. corneal ulcers

Bacterial Conjunctivitis

The recommended dosage regimen for the treatment of 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. bacterial conjunctivitis

HOW SUPPLIED

NDC:50436-5130-1 in a BOTTLE of 5 SOLUTION/ DROPSS

STORAGE

Store at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature]. Protect from light.

ANIMAL PHARMACOLOGY

Ciprofloxacin and related drugs have been shown to cause arthropathy in immature animals of most species tested following oral administration. However, a one-month topical ocular study using immature Beagle dogs did not demonstrate any articular lesions.

Rx Only

Manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

Rev. 282:02 1/09 MG #18143

CIPROFLOXACIN SOLUTION/ DROPS

Label Image
CIPROFLOXACIN 
ciprofloxacin solution/ drops
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:50436-5130(NDC:50383-282)
Route of AdministrationOPHTHALMIC, TOPICALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
CIPROFLOXACIN HYDROCHLORIDE (CIPROFLOXACIN) CIPROFLOXACIN3 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
BENZALKONIUM CHLORIDE 
ACETIC ACID 
EDETATE DISODIUM 
MANNITOL 
WATER 
SODIUM ACETATE 
HYDROCHLORIC ACID 
SODIUM HYDROXIDE 
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:50436-5130-15 mL in 1 BOTTLE
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07667301/21/2005
Labeler - Unit Dose Services (831995316)
Registrant - Unit Dose Services (831995316)
Establishment
NameAddressID/FEIBusiness Operations
Unit Dose Services831995316REPACK(50436-5130)

Revised: 2/2012
Document Id: 2d4eaeee-b9b6-4943-a8fe-b5c02b96e06d
Set id: 91db1198-1570-4dc4-897d-8ab207163d69
Version: 2
Effective Time: 20120229
 
Unit Dose Services