Ofloxacin is a fluoroquinolone anti-infective agent.1, 2, 3, 5, 8, 26, 27, 29, 105, 127
Bacterial Ophthalmic Infections
Ofloxacin 0.3% ophthalmic solution is used for the topical treatment of bacterial conjunctivitis caused by susceptible Staphylococcus aureus , S. epidermidis , Streptococcus pneumoniae , Haemophilus influenzae , Enterobacter cloacae , Proteus mirabilis , or Pseudomonas aeruginosa .1, 127
Although mild, acute bacterial conjunctivitis often resolves spontaneously without anti-infective treatment,135, 136, 137, 141 topical ophthalmic anti-infectives may shorten the time to resolution and reduce severity and risk of complications.135, 136, 137, 141 Treatment of acute bacterial conjunctivitis generally is empiric and use of a broad-spectrum topical ophthalmic antibacterial usually is recommended;135, 136, 141 however, indiscriminate use of topical anti-infectives should be avoided.135, 141 In vitro staining and/or cultures of conjunctival material may be indicated in the management of recurrent, severe, or chronic purulent conjunctivitis or when acute conjunctivitis does not respond to initial empiric topical treatment.135, 136, 141
Results from several controlled studies indicate that ofloxacin 0.3% ophthalmic solution is more effective than placebo (vehicle)1 and as effective as gentamicin 0.3%81 or tobramycin 0.3% ophthalmic solution80 in the treatment of acute bacterial conjunctivitis caused by various gram-positive and/or -negative bacteria. In these studies, which generally included patients with acute conjunctivitis as well as some with blepharoconjunctivitis or blepharitis, efficacy was established in terms of reduction or eradication of bacterial conjunctival pathogens and improvement in ocular manifestations (e.g., discharge, chemosis, hyperemia, lid edema/erythema, burning/pain, foreign body sensation, corneal edema).80, 81 Topical application of ofloxacin 0.3% ophthalmic solution to the eye for 7-10 days was effective in reducing or eradicating all conjunctival pathogens in 78-85% of patients with bacterial conjunctivitis, blepharoconjunctivitis, or blepharitis and produced clinical improvement in virtually all patients.80, 81
In a randomized, double-masked, multicenter study that included 63 patients with conjunctivitis and positive conjunctival cultures, clinical improvement was reported after 2 days in 86% of those treated with ofloxacin 0.3% ophthalmic solution and in 72% of those treated with placebo.1 The microbiologic eradication rate after 2 days of treatment with ofloxacin or placebo was 65 or 25%, respectively.1
Ofloxacin 0.3% ophthalmic solution is used for the topical treatment of bacterial keratitis (corneal ulcers) caused by susceptible S. aureus , S. epidermidis , S. pneumoniae , Ps. aeruginosa , Serratia marcescens , or Propionibacterium acnes .1, 91, 93, 94, 95, 127 Ofloxacin ophthalmic solution is designated an orphan drug by FDA for the treatment of bacterial corneal ulcers.11
Because many forms of bacterial keratitis are associated with subsequent loss of vision as the result of corneal scarring or topographic irregularities and because untreated or severe bacterial keratitis may result in perforation of the cornea with the potential for endophthalmitis and possible loss of the eye, optimal management involves rapid evaluation and diagnosis, timely initiation of treatment, and appropriate follow-up.138 Treatment of community-acquired bacterial keratitis generally is empiric and use of a broad-spectrum topical ophthalmic antibacterial usually is recommended.138 Subconjunctival therapy with an appropriate anti-infective may be necessary if scleral spread or perforation is imminent.138 In vitro staining and/or cultures are indicated in the management of keratitis involving corneal infiltrates that are central, large, and extending to the middle to deep stroma or when keratitis is chronic or unresponsive to treatment with a broad-spectrum topical anti-infective.138
Results from a randomized, double-masked, multicenter study in 140 patients with corneal ulcers and positive cultures indicate that ofloxacin 0.3% ophthalmic solution is as effective as a topical regimen consisting of tobramycin 1.5% solution and cefazolin 10% solution (prepared extemporaneously; not commercially available in the US).1, 91, 95 In this study, clinical cure (i.e., complete reepithelialization and no progression of the infiltrate on 2 consecutive visits) was attained in 82% of patients treated with ofloxacin 0.3% ophthalmic solution and in 80% of those treated with the topical regimen of tobramycin and cefazolin.1, 91, 95 While nonprogression of infiltrate usually occurred about 3 days after initiating therapy with either regimen,91 the median time to clinical cure was 11 or 10 days in patients treated with topical ofloxacin or concomitant therapy with topical tobramycin and topical cefazolin, respectively.1, 91 In this study, success of ofloxacin therapy did not depend on the patient's age, initial size of the epithelial defect, depth of stromal infiltrate, or presence of anterior chamber inflammation.91
Ofloxacin 0.3% otic solution is used for the topical treatment of otitis externa caused by susceptible S. aureus , Escherichia coli , or Ps. aeruginosa .105, 106 Results of comparative studies in adults and children with otitis externa indicate that ofloxacin otic solution is as effective as fixed-combination neomycin, polymyxin B, and hydrocortisone otic solution based on clinical and microbiologic response.106
Diffuse, uncomplicated acute otitis externa in otherwise healthy patients usually should be treated initially with topical therapy (e.g., otic anti-infective or antiseptic with or without an otic corticosteroid).139, 143 Topical therapy should be supplemented with systemic anti-infective therapy if the patient has a medical condition that could impair host defenses (e.g., diabetes mellitus, human immunodeficiency virus [HIV] infection) or if the infection has spread into the pinna or skin of the neck or face, or into deeper tissues such as occurs with malignant otitis externa.139 Malignant otitis externa is an invasive, potentially life-threatening infection, especially in immunocompromised patients, and requires prompt diagnosis and long-term treatment with systemic anti-infectives.110, 111, 139
Ofloxacin 0.3% otic solution is used topically for the treatment of acute otitis media caused by susceptible S. aureus , S. pneumoniae , H. influenzae , Moraxella catarrhalis , or Ps. aeruginosa in patients with tympanostomy tubes.105
Chronic Suppurative Otitis Media
Ofloxacin 0.3% otic solution is used topically for the treatment of chronic suppurative otitis media (CSOM) caused by susceptible S. aureus , P. mirabilis , or Ps. aeruginosa in patients with perforated tympanic membranes.105, 107 Because commercially available ofloxacin otic solution is sterile ,105 unlike the fixed-combination ciprofloxacin hydrochloride and hydrocortisone otic suspension (which is nonsterile),120 ofloxacin otic solution can be used for the treatment of otic infections even when the tympanic membrane is perforated.105
In an open label study in patients with chronic suppurative otitis media and a chronically perforated tympanic membrane in the infected ear(s), treatment with ofloxacin 0.3% otic solution resulted in complete resolution of otorrhea 7-10 days after completion of therapy in 91% of patients and microbiologic response in 100% of evaluable patients.107
Ofloxacin is applied topically to the eye as a 0.3% ophthalmic solution.1, 127
Ofloxacin ophthalmic solution is for topical ophthalmic use only ;1, 127 the ophthalmic solution should not be injected subconjunctivally or directly into the anterior chamber of the eye.1, 127
Care should be taken to avoid contaminating the applicator tip with material from the eye, fingers, or other source.1, 127
Ofloxacin is instilled topically into the ear canal as a 0.3% otic solution.105
Ofloxacin otic solution is for topical otic use only ;105 the otic solution is not for ophthalmic use or injection.105
To avoid dizziness that may result from instilling a cold preparation into the ear canal, the container of otic solution should be warmed in the hands for 1-2 minutes before use.105
The patient should lie with the affected ear upward.105 The appropriate amount of otic solution should be instilled into the ear;105 this position should be maintained for 5 minutes to facilitate penetration of the solution into the ear canal.105 When treating acute otitis media or chronic suppurative otitis media, the tragus of the ear should be pumped 4 times by pushing inward to facilitate penetration of the solution into the middle ear.105 The procedure should be repeated for the opposite ear if necessary.105
Care should be taken to avoid contaminating the applicator tip with material from the fingers or other source.105
Bacterial Ophthalmic Infections
For the topical treatment of bacterial conjunctivitis in adults and children 1 year of age and older, 1 or 2 drops of ofloxacin 0.3% ophthalmic solution should be instilled in the affected eye(s) every 2-4 hours on days 1 and 2, then 1 or 2 drops of the ophthalmic solution should be instilled 4 times daily on days 3 through 7.1, 127
The usual duration of topical anti-infective treatment for bacterial conjunctivitis is 5-10 days;135, 136, 141 some experts state that 5-7 days of such treatment usually is adequate for mild bacterial conjunctivitis.135
For the topical treatment of bacterial keratitis (corneal ulcers) in adults and children 1 year of age and older, 1 or 2 drops of ofloxacin 0.3% ophthalmic solution should be instilled in the affected eye(s) every 30 minutes while awake and at approximately 4 and 6 hours after retiring on days 1 and 2.1, 127 On days 3 through 7 or 9, 1 or 2 drops of the ophthalmic solution should be instilled in the affected eye(s) every hour while awake;1, 127 then, 1 or 2 drops of the solution should be instilled 4 times daily until treatment completion.1, 127
Some experts state that the initial regimen should be reevaluated and modified if there is no improvement or stabilization of keratitis within 48 hours after initiation of treatment.138
For the topical treatment of bacterial otitis externa in children 6 months to 13 years of age, 5 drops of ofloxacin 0.3% otic solution (0.25 mL, 0.75 mg of ofloxacin) should be instilled into the canal of the affected ear(s) once daily for 7 days.105
For the topical treatment of bacterial otitis externa in adults and adolescents 13 years of age or older, 10 drops of ofloxacin 0.3% otic solution (0.5 mL, 1.5 mg of ofloxacin) should be instilled into the canal of the affected ear(s) once daily for 7 days.105
The optimal duration of topical therapy for the treatment of acute otitis externa has not been determined, but 7-10 days is usually recommended.139 Some experts state that appropriate treatment of acute otitis externa should result in improvement in symptoms (otalgia, itching, fullness) within 48-72 hours, although resolution of symptoms may take up to 2 weeks.139 The manufacturer states that if there is no improvement in otitis externa after 1 week of treatment, cultures should be used to help guide further treatment.105
For the topical treatment of acute otitis media in pediatric patients 1-12 years of age with tympanostomy tubes, 5 drops of ofloxacin 0.3% otic solution (0.25 mL, 0.75 mg of ofloxacin) should be instilled into the canal of the affected ear(s) twice daily for 10 days.105
Chronic Suppurative Otitis Media
For the topical treatment of chronic suppurative otitis media in adults and pediatric patients 12 years of age or older with perforated tympanic membranes, 10 drops of ofloxacin 0.3% otic solution (0.5 mL, 1.5 mg of ofloxacin) should be instilled into the canal of the affected ear(s) twice daily for 14 days.105
Ofloxacin ophthalmic69, 80, 81, 91 and otic preparations106, 107 generally are well tolerated following topical application.
The most frequent adverse effects following topical application of ofloxacin 0.3% ophthalmic solution in the eye are transient1, 19, 127 ocular burning or discomfort.1, 19, 81, 91, 127 Stinging,1, 81, 127 redness,1, 127 pruritus,1, 19, 80 chemical conjunctivitis/keratitis,1, 91, 95, 127 foreign body sensation,1, 127 blurred vision,1, 127 ocular/periocular/facial edema,1, 127 eye pain,1, 127 photophobia,1, 81, 127 tearing,1, 127 and dryness1, 127 also have been reported.
Hemorrhagic conjunctivitis with palpebral edema has been reported rarely following topical application of ofloxacin ophthalmic solution.69
Since systemic absorption may occur following topical application of ofloxacin to the eye,1, 19, 70, 127 the possibility of adverse systemic effects exists.88, 89
Although a causal relationship to the drug has not been definitely established,80, 88, 89 dizziness1, 80, 127 and nausea1, 127 have been reported rarely following topical application of ofloxacin ophthalmic solution.
Stevens-Johnson syndrome that progressed to toxic epidermal necrosis has been reported in at least one patient receiving topical ofloxacin ophthalmic solution.1, 127
Local reactions at the site of otic instillation have occurred in up to 17% of patients receiving ofloxacin 0.3% otic solution for the treatment of otitis externa;105 such reactions also have occurred in patients in whom the drug was instilled into the ear canal for other indications.105 Earache has been reported in up to 1% of patients receiving the topical otic solution, and tinnitus, transient loss of hearing, otitis externa, otitis media, and otorrhagia also have been reported rarely.105
Since systemic absorption may occur following topical application of ofloxacin to the ear,80, 105, 108 the possibility of adverse systemic effects exists.88
Following otic instillation of ofloxacin 0.3% otic solution, taste perversion105, 107 has been reported in 7% of patients with non-intact tympanic membranes.105 Pruritus105, 106, 107 has occurred in up to 4% of patients receiving ofloxacin otic solution.105 Adverse events reported in about 1% of patients receiving the otic drug include dizziness,105, 106, 107 vertigo,105, 106, 107 paresthesia,105, 107 or rash.105, 106
Dermatitis,105 eczema,105, 106 hypoesthesia,105 dyspepsia,105 diarrhea,105 nausea,105, 107 vomiting,105 dry mouth,105 hot flashes,105 flushing,105 headache,105, 107 fever,105 urticaria,105, 107 abdominal pain,105 dysesthesia,105 hyperkinesia,105 tremor,105 halitosis,105 inflammation,105 pain,105 insomnia,105 fungal infection,105 cough,105 pharyngitis,105 rhinitis,105 sinusitis,105 hypertension,105 and tachycardia105, 107 have been reported rarely in patients receiving ofloxacin otic solution.105
Precautions and Contraindications
Ofloxacin 0.3% ophthalmic solution and ofloxacin 0.3% otic solution are contraindicated in patients with a history of hypersensitivity to ofloxacin, other quinolones, or any ingredient in the formulation.1, 105, 127
Serious and occasionally fatal hypersensitivity reactions have been reported rarely in patients receiving systemic quinolones, including systemic ofloxacin, and these reactions have been reported following the initial systemic dose.1, 105, 127 Patients receiving ofloxacin ophthalmic or otic preparations should be advised that hypersensitivity reactions have been reported with systemic ofloxacin and instructed to immediately discontinue the drug and contact a clinician at the first sign of rash or allergic reaction.1, 105, 127 Serious acute hypersensitivity reactions may require immediate emergency treatment;1, 105, 127 oxygen and airway management should be administered as clinically indicated.1, 105, 127
As with other anti-infectives, prolonged use of ofloxacin may result in overgrowth of nonsusceptible organisms, including fungi.1, 105, 127 If superinfection occurs, the drug should be discontinued and other appropriate therapy instituted.1, 105, 127
Precautions Related to Ophthalmic Administration
When ofloxacin ophthalmic solution is used for the topical treatment of bacterial ophthalmic infections, examination with slit-lamp biomicroscopy and, when appropriate, fluorescein staining should be performed as clinically indicated.1, 127
Precautions Related to Otic Administration
When ofloxacin otic solution is used for the topical treatment of bacterial otic infections, cultures should be obtained to guide further treatment if the infection has not improved after 1 week of therapy.105
If otorrhea persists after completion of topical ofloxacin therapy or if 2 or more episodes of otorrhea occur within 6 months, further evaluation is indicated to exclude underlying conditions such as cholesteatoma, foreign body, or tumor.105
Ofloxacin 0.3% ophthalmic solution: Safety and efficacy have not been established in children younger than 1 year of age.1, 127
Ofloxacin 0.3% otic solution: Safety and efficacy for the treatment of otitis externa with intact tympanic membrane have not been established in children younger than 6 months of age.105 The manufacturer states that, although data are not available regarding use of ofloxacin otic solution in children younger than 6 months of age, there are no known safety concerns or differences in disease process in children in this age group that would preclude use of the otic preparation in children younger than 6 months of age.105
Ofloxacin 0.3% otic solution: Safety and efficacy for the treatment of acute otitis media have not been established in children younger than 1 year of age.105 Safety and efficacy for the treatment of chronic suppurative otitis media have not been established in children younger than 12 years of age.105
Quinolones, including ofloxacin, have caused arthropathy in immature animals of various species following oral administration.1, 8, 26, 27, 44, 48, 49, 51, 53, 54, 85, 127 In young beagles, ofloxacin given in an oral dosage of 10 mg/kg daily for 7 days (110 times the maximum daily adult ophthalmic dosage) caused blisters and/or erosions in articular cartilage.1, 48 However, topical administration of ofloxacin ophthalmic solution in the eye(s) of immature animals or ofloxacin 0.3% otic solution in the middle ear of young growing guinea pigs has not been reported to cause arthropathy.1, 105, 127 There is no evidence that the ophthalmic solution has any effect on weight-bearing joints.1, 127 There was no evidence of structural or functional changes in the cochlea and no lesions in the ossicle when ofloxacin 0.3% otic solution was administered to the middle ear in guinea pigs for 30 days.105
No changes in hearing function were observed on audiometric evaluation in a limited number of children treated with ofloxacin otic solution.105
No overall differences in safety and efficacy of ofloxacin 0.3% ophthalmic solution have been observed between geriatric and younger adults.1, 127
Mutagenicity and Carcinogenicity
Ofloxacin was not mutagenic in the Ames microbial bacterial mutagen test or in vitro and in vivo cytogenic assays, including the sister chromatid exchange (Chinese hamster and human cell lines) assay, unscheduled DNA repair assay using human fibroblasts, dominant lethal assay, or mouse micronucleus assay.1, 23, 49, 85, 105 When ofloxacin was tested in the in vitro rat hepatocyte DNA repair assay, mouse lymphoma assay, and Rec-assay for DNA repair, results were positive,1, 23, 48, 49, 52, 85 which may indicate a potential for primary DNA damage.48, 49, 52 However, other more sensitive tests, such as the V-79 mammalian cell assay, have not shown evidence of mutagenicity.49
Studies have not been performed to date to evaluate the carcinogenic potential of ofloxacin.1, 53, 85, 105
Pregnancy, Fertility, and Lactation
There are no adequate and controlled studies to date using ofloxacin 0.3% ophthalmic solution or ofloxacin 0.3% otic solution in pregnant women, and these preparations should be used during pregnancy only when potential benefits justify possible risks to the fetus.1, 105, 127
Reproductive studies in rats and rabbits using oral ofloxacin dosages as high as 810 and 160 mg/kg daily (equivalent to 9000 and 1800 times the maximum recommended daily ophthalmic dosage, respectively) did not reveal evidence of teratogenicity.1, 48, 50, 127 However, embryocidal effects were reported in rats and rabbits receiving such dosages.1, 48, 50, 89, 127 Decreased fetal body weight1 and retardation in the degree of ossification and minor skeletal variations, such as cervical ribs and shortened or absent 13th ribs, were reported in the rats;48, 50 increased fetal mortality was reported in the rabbits.1 Perinatal and postnatal studies in rats given oral ofloxacin dosages up to 360 mg/kg daily (4000 times the maximum recommended daily ophthalmic dosage) revealed a decrease in food intake during gestation and an increase in food and water intake during lactation,50 but did not reveal evidence of adverse effects on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the offspring.1, 50, 127
Studies in male and female rats using oral ofloxacin dosages up to 360 mg/kg daily (4000 times the maximum recommended daily ophthalmic dosage) indicate that the drug does not have an appreciable effect on fertility or reproductive performance.1, 48, 49, 50
It is not known whether ofloxacin is distributed into milk following topical application to the eye or ear; however, ofloxacin is distributed into milk following oral administration.1, 105, 127
Because of the potential for serious adverse effects of ofloxacin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1, 105, 127
Specific drug interaction studies have not been performed using ofloxacin ophthalmic or otic preparations.1, 105, 127 However, since systemic absorption may occur following topical application of ofloxacin to the eye or ear,1, 19, 70, 71, 105, 127 the possibility of drug interactions such as those reported with systemic administration of some quinolone anti-infectives (e.g., interactions with theophylline, caffeine, oral anticoagulants, cyclosporine) should be considered.1, 88, 89, 127
Limited information is available on the acute toxicity of ofloxacin in humans.55, 56, 85 The oral LD50 of ofloxacin is 3.6-5.5 g/kg in mice and rats and exceeds 200 mg/kg in dogs.48 The IV LD50 of the drug is 208-276 mg/kg in mice and rats and exceeds 70 mg/kg in dogs.48
Information is not available regarding overdosage of topical ofloxacin in humans; however, overdosage following oral ingestion of the commercially available ophthalmic solution is unlikely given the limited amount of ofloxacin present in the solution.88
The effect of ofloxacin on ocular wound healing has not been fully elucidated.17 Results of in vitro studies using rabbit corneal epithelial cell cultures indicate that a 0.3% solution of ofloxacin does not damage epithelial cells (as determined by inhibition of3H-thymidine uptake).20 In addition, while some in vitro data from studies using rabbit corneal epithelial cells indicate that ofloxacin concentrations as low as 50 mcg/mL (0.005%) can delay early corneal epithelialization and prevent complete wound closure, and ofloxacin concentrations of 2 mg/mL (0.2%) can result in additional cell loss and an increase in corneal wound size,17 other studies in rabbits found no evidence of delayed corneal epithelial wound healing.89, 90 Ocular toxicity studies in rabbits suggest that intravitreal injection of 200 mcg of ofloxacin does not result in permanent retinal damage.18
Ofloxacin usually is bactericidal in action.1, 3, 8, 14, 26, 27, 29, 32, 33, 34, 35, 36, 44, 64, 65, 66, 71, 84, 85, 127 Like other fluoroquinolones, ofloxacin inhibits DNA synthesis in susceptible organisms via inhibition of type II DNA topoisomerases (DNA gyrase, topoisomerase IV).1, 3, 4, 5, 8, 9, 27, 30, 33, 44, 64, 65, 85, 127
Ofloxacin is active in vitro against many gram-positive aerobic bacteria, including penicillinase-producing, nonpenicillinase-producing, and some methicillin-resistant staphylococci (also known as oxacillin-resistant staphylococci).3, 8, 21, 22, 25, 26, 27, 44, 64, 65, 66, 67, 68, 72, 84, 85 Ofloxacin is active in vitro against most gram-negative aerobic bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa .3, 8, 21, 22, 25, 26, 27, 44, 64, 65, 66, 67, 68, 72, 84, 85 Like many other fluoroquinolones, ofloxacin is less active against gram-positive than gram-negative bacteria.3, 8, 25, 26 Ofloxacin is inactive against fungi8, 44 and viruses.8
In vitro and in vivo in conjunctival and/or corneal ulcer infections, ofloxacin is active against some gram-positive aerobic bacteria, including Staphylococcus aureus , S. epidermidis , and Streptococcus pneumoniae , and some gram-negative aerobic bacteria, including Haemophilus influenzae , Enterobacter cloacae , Proteus mirabilis , Serratia marcescens , and Pseudomonas aeruginosa .1, 8, 20, 27, 65, 84, 127 The drug also is active in vitro and in vivo in conjunctival and/or corneal ulcers caused by the anaerobe Propionibacterium acnes .1, 127 Limited in vitro data on isolates from ocular tissues and fluids indicate that most susceptible S. aureus , S. epidermidis , and S. pneumoniae are inhibited by ofloxacin concentrations of 2 mcg/mL or less.65 Higher ofloxacin concentrations generally are required to inhibit Ps. aeruginosa .20, 65 In vitro, ofloxacin usually is at least as active as tobramycin or gentamicin against common ocular pathogens, including S. aureus , S. epidermidis , S. pneumoniae, and Ps. aeruginosa .20, 65, 72
In vitro and in vivo in otic infections, ofloxacin is active against S. aureus , S. pneumoniae , Escherichia coli , H. influenzae , Moraxella catarrhalis , P. mirabilis , and P. aeruginosa .105
Resistance to ofloxacin can be produced in vitro in some strains of Staphylococcus aureus , streptococci, Enterobacteriaceae, and Pseudomonas aeruginosa by serial passage in the presence of increasing concentrations of the drug.3, 4, 8, 27, 44 Ofloxacin resistance resulting from spontaneous mutation occurs rarely in vitro (i.e., with a frequency of 10-11 to 10-9).3, 4, 8, 14, 27, 85 Spontaneous mutation occurs in a single step and results in low-level resistance to the drug.8, 27 However, resistant strains of Escherichia coli 47 and Ps. aeruginosa 8, 26, 39, 46, 47 have emerged during systemic therapy with the drug. Spontaneous resistance to quinolones is concentration dependent, generally occurring only when the MIC for the organism exceeds the concentration of the drug at the infection site by several (e.g., 4-8) fold.64 Therefore, the potential for development of resistance to ofloxacin during ophthalmic administration is likely to be less than that associated with systemic administration of the drug because of the comparatively high drug concentrations achieved in anterior (e.g., corneal, conjunctival) ocular tissues with administration of commercially available ofloxacin ophthalmic solution.64
Cross-resistance can occur between ofloxacin and other fluoroquinolones.1, 105, 127
The extent of ocular and systemic absorption of ofloxacin following topical application to the eye has not been fully elucidated; however, serum concentrations achieved following such application to uninflamed eyes are minimal relative to those produced by usual oral doses of the drug.1, 19, 70 Following topical application to the eye of 1 drop of ofloxacin 0.3% ophthalmic solution 4 times daily for 10.5 days in healthy women, drug concentrations measured in tear film within 40 minutes after the final dose ranged from 5.7-31 mcg/g.1, 19 In this study, ofloxacin concentrations in tear film showed considerable interindividual variation but averaged 9.2 mcg/g 4 hours after application of the next to last dose.1, 19, 80
Ofloxacin is absorbed through the cornea into aqueous humor following topical application to the eye; absorption is enhanced in the presence of ocular inflammation and/or epithelial defects.71, 73 In rabbits, topical application of 1 drop of a 0.3% solution of ofloxacin every 30 minutes for 12 hours in eyes with intact epithelium produced aqueous humor drug concentrations averaging 1.2 mcg/mL within 1 hour of the final dose; in eyes with ocular epithelial defects, concurrently obtained ofloxacin concentrations in aqueous humor averaged 2.2 mcg/mL.71 Following topical application to the eye of 1 drop of ofloxacin 0.3% every hour for 8 doses daily for 7 days in rabbits, drug concentrations in aqueous humor within 1 hour of the final dose averaged 0.88 mcg/mL.71 On day 7, distribution of the drug in aqueous humor of those rabbits with ocular epithelial defects induced on day 1 generally was similar to that observed in normal eyes, indicating restoration of epithelium and corneal ulcer healing.71
Following topical application to the eye of 2 drops of a 0.3% solution of ofloxacin every 30 minutes beginning 4 hours before surgery in patients undergoing keratoplasty, corneal tissue, aqueous humor, and vitreous humor concentrations at the time of surgery averaged 4.4, 1.3, and 0.4 mcg/mL, respectively.1, 92, 95 Following topical application to the eye of 1 drop of a 0.3% solution of ofloxacin every 20 minutes for 1 hour (4 doses) in patients undergoing keratoplasty, corneal tissue concentration determined in cornea harvested within 1 hour after the last dose of ofloxacin averaged 0.81 mcg/g (range: 0.32-3.73 mcg/g).104
Some systemic absorption of ofloxacin occurs following topical application to the eyes,1, 19, 70, 71, 127 although use of ofloxacin ophthalmic solution has been associated with a low potential for causing systemic effects.19, 88, 89 Ofloxacin was detectable in serum 10 minutes after ocular instillation of 1 drop of a 0.3% solution in healthy women.19 However, following ocular instillation to the eyes of 1 drop of ofloxacin 4 times daily for 10.5 days in these women,1 serum ofloxacin concentrations 10 minutes after the first dose on day 11 averaged only 1.3 ng/mL.19 Peak serum drug concentrations increased from 1.1 ng/mL on day 1 to 1.9 ng/mL on day 11, indicating some systemic accumulation of ofloxacin following multiple doses.1, 19, 70, 127 In contrast, peak serum concentrations following administration of a single 300-mg oral dose of ofloxacin generally average 2.4-4.6 mcg/mL.8, 27, 85
The extent of otic and systemic absorption of ofloxacin following topical application to the ear has not been fully elucidated; however, serum concentrations achieved following such application are minimal relative to those produced by usual oral doses of the drug.105, 108 While topical application of ofloxacin to the ear canal is associated with minimal penetration into the middle ear when the tympanic membrane is intact, penetration is enhanced in the presence of a perforated tympanic membrane.105, 108 Following topical application of ofloxacin 0.3% otic solution in adults with perforated tympanic membranes, drug concentrations in middle ear mucosa showed considerable interindividual variation and ranged from undetectable to 602 mcg/g.105 Following topical application of ofloxacin 0.3% otic solution in patients with perforated tympanic membranes, drug concentrations in otorrhea ranged from 389-2850 mcg/g 30 minutes after the dose.105 However, concentration of ofloxacin in otorrhea may not reflect exposure of the middle ear to the drug.105
Some systemic absorption of ofloxacin occurs following topical application to the ear.105 Following otic administration of a single dose of ofloxacin 0.3% otic solution (10 drops, 0.5 mL, 1.5 mg of ofloxacin) in adults with tympanostomy tubes with or without otorrhea, serum ofloxacin concentrations averaged 4.1 or 5.4 ng/mL, respectively.105 Following topical instillation of ofloxacin 0.3% otic solution in adults with perforated tympanic membranes, a peak serum concentration of 10 ng/mL was reported.105
Distribution of ofloxacin into human ocular tissues and fluids following topical ophthalmic or systemic administration has not been fully characterized to date.88
Ofloxacin is widely distributed into body tissues and fluids following oral administration.8, 27, 40, 41, 42, 85 Current information on the distribution of ofloxacin into ocular tissues and fluids following systemic administration of the drug is based principally on studies in patients with uninflamed and/or uninfected eyes; distribution is likely to be greater in the presence of inflammation or infection because of disruption of the blood-ocular barrier.57, 73, 75, 76, 77 Following oral or IV administration of ofloxacin in patients undergoing cataract extraction, peak drug concentrations in aqueous humor generally have averaged 20-44% of concurrent serum concentrations.8, 57, 75, 76, 77, 78 Limited data suggest that drug concentrations in vitreous humor following systemic administration of other fluoroquinolones (e.g., ciprofloxacin) are similar to those in aqueous humor.77, 79
Ofloxacin is 20-32% bound to serum proteins in vitro.8, 27, 60
Ofloxacin crosses the placenta and is distributed into amniotic fluid in humans following oral administration.8, 27, 58
It is not known whether ofloxacin is distributed into milk following topical ophthalmic or otic administration;1, 105, 127 the drug is distributed into milk following oral administration.1, 8, 27, 58, 61
The metabolic fate and elimination characteristics of ofloxacin following topical application to the eye have not been fully elucidated.19, 87, 88 Following ocular instillation of 1 drop of ofloxacin 0.3% 4 times daily for 12 doses in healthy individuals, the elimination half-life of drug in tear film was approximately 226 minutes.87 In a study in rabbits, the terminal elimination half-life of ofloxacin in tear film following topical application to the eye was approximately 210 minutes.19, 72 In adults with normal renal function, the serum elimination half-life of ofloxacin in the terminal phase averages 4-8 hours.8, 27, 44, 86
Systemically absorbed ofloxacin undergoes limited biotransformation;1, 8, 27, 43, 85, 86 less than 10% of a single systemic dose of ofloxacin is metabolized.8, 27, 43 Ofloxacin and its metabolites are excreted in urine and feces.8, 27, 85 Ofloxacin is excreted principally in urine as unchanged drug;1, 8, 19, 27, 38, 43, 85, 86 less than 5% of a single systemic dose is excreted in urine as metabolites.8, 27, 38, 59, 85 Approximately 4-8% of a systemic dose is excreted in feces.8, 85
Ofloxacin is a fluoroquinolone anti-infective agent.1, 2, 3, 5, 8, 25, 26, 27, 29, 64, 85 Like other commercially available fluoroquinolones, ofloxacin contains a fluorine at position 6 of the quinolone nucleus.1, 2, 3, 5, 25, 26, 27, 28, 29 Like some other fluoroquinolones (e.g., ciprofloxacin, levofloxacin, norfloxacin), ofloxacin contains a piperazinyl group at position 7.5, 26, 29, 64 The piperazinyl group in ofloxacin results in antipseudomonal activity.5, 26, 29, 64 Unlike the group contained in ciprofloxacin and norfloxacin, the piperazinyl group contained in ofloxacin is methylated and this may contribute to a longer serum half-life compared with unsubstituted moieties.5, 25 Ofloxacin also contains an oxazine ring linking the nitrogen at position 1 and the carbon at position 8 of the quinolone nucleus.1, 3 This fused ring results in increased activity against gram-positive and anaerobic bacteria and also contributes to ofloxacin's low degree of metabolism.2, 5 The methyl group at the C3 position in the oxazine ring results in the formation of isoenantiomers; ofloxacin occurs as a racemic mixture of the two isomers.1, 8, 25, 27 The S -(-) isomer is 8-128 times as active against susceptible gram-positive and -negative bacteria as the R -(+) isomer and about 2-8 times as active as racemic ofloxacin.5, 8, 21, 22, 28, 30, 31, 37, 84
Ofloxacin occurs as an off-white to pale yellow, crystalline powder.23, 85 At room temperature, ofloxacin has aqueous solubilities of 3.5-4 mg/mL at pH 7,85, 89 60 mg/mL at pH 2-5, and 303 mg/mL at pH 9.8.85 The pKas of the drug are 5.74 and 7.9.24
Ofloxacin 0.3% ophthalmic solution is an unbuffered, sterile, isotonic solution of the drug in sterile water;1 hydrochloric acid and/or sodium hydroxide may be added to adjust pH to approximately 6.4 (range: 6-6.8).1 The commercially available ophthalmic solution contains 3 mg of ofloxacin per mL, has an osmolality of approximately 300 mOsm/kg, and contains benzalkonium chloride as a preservative.1
Ofloxacin 0.3% otic solution is a sterile solution of the drug in water for injection;105 hydrochloric acid and/or sodium hydroxide may be added to adjust pH to approximately 6.5.105 The commercially available otic solution contains 3 mg of ofloxacin per mL and contains benzalkonium chloride as a preservative.105
Ofloxacin 0.3% ophthalmic solution should be stored at 15-25°C.1, 127
Ofloxacin 0.3% otic solution should be stored at 20-25°C and protected from light.105
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Ophthalmic | Solution | 0.3%* | Ocuflox® | Allergan |
Ofloxacin Ophthalmic Solution | ||||
Otic | Solution | 0.3%* | Ofloxacin Otic Solution |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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