OFLOXACIN (ofloxacin 200 mg) Dailymed

Warning

SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones, including ofloxacin,  have been associated with  disabling and potentially irreversible serious adverse reactions that have occurred together, including:     • Tendinitis and tendon rupture     • Peripheral neuropathy     • Central nervous system effects (see WARNINGS). Discontinue ofloxacin immediately and avoid the use of fluoroquinolones, including ofloxacin, in patients who experience any of these serious adverse reactions (see WARNINGS).      • Fluoroquinolones, including ofloxacin, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid ofloxacin in patients with a known history of myasthenia gravis (See WARNINGS). •Because fluoroquinolones, including ofloxacin, have been associated with serious adverse reactions (see WARNINGS), reserve ofloxacin for use in patients who have no alternative treatment options for the following indications:        o Acute exacerbation of chronic bronchitis        o Uncomplicated cystitis (see INDICATIONS and USAGE)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ofloxacin tablets and other antibacterial drugs, ofloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Description

Ofloxacin tablets are a synthetic broad-spectrum antimicrobial agent for oral administration. Chemically, ofloxacin, USP, a fluorinated carboxyquinolone, is the racemate, (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. The chemical structure is:

C₁₈H₂₀FN₃O₄                           M.W. 361.4

Ofloxacin, USP is an off-white to pale yellow crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine. The relative solubility characteristics of ofloxacin USP at room temperature, as defined by USP nomenclature, indicate that ofloxacin, USP is considered to be soluble in aqueous solutions with pH between 2 and 5. It is sparingly to slightly soluble in aqueous solutions with pH 7 (solubility falls to 4 mg/mL) and freely soluble in aqueous solutions with pH above 9. Ofloxacin USP has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Fe⁺³> Al⁺³> Cu ⁺²> Ni ⁺²> Pb⁺²> Zn⁺²> Mg⁺²> Ca ⁺²> Ba ⁺²

Ofloxacin tablets, USP contain the following inactive ingredients: lactose monohydrate, pregelatinized maize starch, hydroxy propyl methyl cellulose, talc,  magnesium stearate, polyethylene glycol, sodium starch glycolate, and titanium dioxide. Additionally, the 200 mg and 400 mg tablets contain iron oxide yellow.

The imprinting ink for 200 mg, 300 mg and 400 mg strength contains FD&C blue #1, isopropyl alcohol, Nbutyl alcohol, propylene glycol, shellac and titanium dioxide.

Clinical Pharmacology

Following oral administration, the bioavailability of ofloxacin in the tablet formulation is approximately 98%. Maximum serum concentrations are achieved one to two hours after an oral dose. Absorption of ofloxacin after single or multiple doses of 200 to 400 mg is predictable, and the amount of drug absorbed increases proportionately with the dose. Ofloxacin has biphasic elimination. Following multiple oral doses at steady-state administration, the half-lives are approximately 4 to 5 hours and 20 to 25 hours. However, the longer half-life represents less than 5% of the total AUC. Accumulation at steady-state can be estimated using a half-life of 9 hours. The total clearance and volume of distribution are approximately similar after single or multiple doses. Elimination is mainly by renal excretion. The following are mean peak serum concentrations in healthy 70 to 80 kg male volunteers after single oral doses of 200, 300, or 400 mg of ofloxacin or after multiple oral doses of 400 mg. 

Oral Dose	Serum Concentration  2 Hours After Admin. (mcg/mL)	Area Under the Curve  (AUC( 0 to ∞) )(mcg•h/mL)
200 mg single dose	1.5	14.1
300 mg single dose	2.4	21.2
400 mg single dose	2.9	31.4
400 mg steady-state	4.6	61.0

Steady-state concentrations were attained after four oral doses, and the area under the curve (AUC) was approximately 40% higher than the AUC after single doses. Therefore, after multiple-dose administration of 200 mg and 300 mg doses, peak serum levels of 2.2 mcg/mL and 3.6 mcg/mL, respectively, are predicted at steady-state.

In vitro, approximately 32% of the drug in plasma is protein bound.

The single dose and steady-state plasma profiles of ofloxacin injection were comparable in extent of exposure (AUC) to those of ofloxacin tablets when the injectable and tablet formulations of ofloxacin were administered in equal doses (mg/mg) to the same group of subjects. The mean steady-state AUC_{(0 to 12)} attained after the intravenous administration of 400 mg over 60 min was 43.5 mcg•h/mL; the mean steady-state AUC_{(0 to 12)} attained after the oral administration of 400 mg was 41.2 mcg•h/mL (two one-sided t-test, 90% confidence interval was 103 to 109). (see following chart).

   Between 0 and 6 h following the administration of a single 200 mg oral dose of ofloxacin to 12 healthy volunteers, the average urine ofloxacin concentration was approximately 220 mcg/mL. Between 12 and 24 hours after administration, the average urine ofloxacin level was approximately 34 mcg/mL.Following oral administration of recommended therapeutic doses, ofloxacin has been detected in buler fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum. The mean concentration of ofloxacin in each of these various body fluids and tissues after one or more doses was 0.8 to 1.5 times the concurrent plasma level. Inadequate data are presently available on the distribution or levels of ofloxacin in the cerebrospinal fluid or brain tissue.Ofloxacin has a pyridobenzoxazine ring that appears to decrease the extent of parent compound metabolism. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Studies indicate that less than 5% of an administered dose is recovered in the urine as the desmethyl or N-oxide metabolites. Four to eight percent of an ofloxacin dose is excreted in the feces. This indicates a small degree of biliary excretion of ofloxacin.The administration of ofloxacin tablets with food does not affect the C_max and AUC_∞ of the drug, but T_max is prolonged.Clearance of ofloxacin is reduced in patients with impaired renal function (creatinine clearance rate < 50 mL/min), and dosage adjustment is necessary. (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION ).Following oral administration to healthy elderly subjects (65 to 81 years of age), maximum plasma concentrations are usually achieved one to two hours after single and multiple twice-daily doses, indicating that the rate of oral absorption is unaffected by age or gender. Mean peak plasma concentrations in elderly subjects were 9 to 21% higher than those observed in younger subjects. Gender differences in the pharmacokinetic properties of elderly subjects have been observed. Peak plasma concentrations were 114% and 54% higher in elderly females compared to elderly males following single and multiple twice-daily doses. [This interpretation was based on study results collected from two separate studies.] Plasma concentrations increase dose-dependently with the increase in doses after single oral dose and at steady state. No differences were observed in the volume of distribution values between elderly and younger subjects. As in younger subjects, elimination is mainly by renal excretion as unchanged drug in elderly subjects, although less drug is recovered from renal excretion in elderly subjects. Consistent with younger subjects, less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites in the elderly. A longer plasma half-life of approximately 6.4 to 7.4 hours was observed in elderly subjects, compared with 4 to 5 hours for young subjects. Slower elimination of ofloxacin is observed in elderly subjects as compared with younger subjects which may be attributable to the reduced renal function and renal clearance observed in the elderly subjects. Because ofloxacin is known to be substantially excreted by the kidney, and elderly patients are more likely to have decreased renal function, dosage adjustment is necessary for elderly patients with impaired renal function as recommended for all patients. (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION ).

MICROBIOLOGY

Ofloxacin is a quinolone antimicrobial agent. The mechanism of action of ofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.

Ofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Fluoroquinolones, including ofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.

Resistance to ofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10^-9 to 10^-11). Although cross-resistance has been observed between ofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to ofloxacin.

Ofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the  INDICATIONS AND USAGE section:

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus (methicillin-susceptible strains)

Streptococcus pneumoniae (penicillin-susceptible strains)

Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms

Citrobacter (diversus) koseri

Enterobacter aerogenes

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae 

Neisseria gonorrhoeae 

Proteus mirabilis 

Pseudomonas aeruginosa

 As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ofloxacin.

Other Microorganisms

Chlamydia trachomatis

 The following in vitro data are available, but their clinical significance is unknown.

Ofloxacin exhibitsin vitro minimum inhibitory concentrations (MIC values) of 2 mcg/mL or less against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of ofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms

Staphylococcus epidermidis(methicillin-susceptible strains)

Staphylococcus saprophyticus

Streptococcus pneumoniae (penicillin-resistant strains)

Aerobic Gram-Negative Microorganisms

Acinetobacter calcoaceticus 

Bordetella pertussis 

Citrobacter freundii 

Enterobacter cloacae 

Haemophilus ducreyi 

Klebsiella oxytoca 

Moraxella catarrhalis 

Morganella morganii 

Proteus vulgaris 

Providencia rettgeri

Providencia stuartii

Serratia marcescens

Anaerobic Microorganisms

Clostridium perfringes

Other Microorganisms

Chlamydia pneumoniae

Gardnerella vaginalis

Legionella pneumophila

Mycoplasma hominis

Mycoplasma pneumoniae

Ureaplasma urealyticum

Ofloxacin is not active against Treponema pallidum (see WARNINGS ).

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC values). These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method^1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ofloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa:

MIC (mcg/mL)	Interpretation
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

For testing Haemophilus influenzae:^a

MIC (mcg/mL)	Interpretation
≤ 2	Susceptible (S)

^a This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae using HaemophilusTest Medium.^1,3

The current absence of data on resistant strains precludes defining any results other than “Susceptible.” Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.For testing Neisseria gonorrhoeae:^b

MIC (mcg/mL)	Interpretation
< 0.25	Susceptible (S)
0.5 to 1	Intermediate (I)
> 2	Resistant (R)

^b These interpretive standards are applicable only to agar dilution tests using GC agar base and 1% defined growth supplement incubated in 5% CO₂. For testing Streptococcus pneumoniae and Streptococcus pyogenes:^c

MIC (mcg/mL)	Interpretation
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

^c These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ofloxacin powder should provide the following MIC values:

Microorganism		MIC Range (mcg/mL)
Escherichia coli	ATCC 25922	0.015 to 0.12
Haemophilus influenzae	ATCC 49247d	0.016 to 0.06
Neisseria gonorrhoeae	ATCC 49226e	0.004 to 0.016
Pseudomonas aeruginosa	ATCC 27853	1 to 8
Staphylococcus aureus	ATCC 29213	0.12 to 1
Streptococcus pneumoniae	ATCC 49619f	1 to 4

^d This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using Haemophilus Test Medium (HTM).<sup>1,3

e</sup> This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using GC agar base with 1% defined growth supplement incubated in 5% CO₂.

^f This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.

DIffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg ofloxacin to test the susceptibility of microorganisms to ofloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg ofloxacin disk should be interpreted according to the following criteria:

For testing Enterobacteriaceae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa:

Zone Diameter (mm)	Interpretation
≥ 16	Susceptible (S)
13 to 15	Intermediate (I)
≤ 12	Resistant (R)

For testing Haemophilus influenzae:^g

Zone Diameter (mm)	Interpretation
≥ 16	Susceptible (S)

  ^g This zone diameter standard is applicable only to disk diffusion tests with Haemophilus influenzae using Haemophilus Test Medium (HTM)² incubated in 5% CO₂.

The current absence of data on resistant strains precludes defining any results other than “Susceptible.” Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Neisseria gonorrhoeae: ^h

Zone Diameter (mm)	Interpretation
≥ 31	Susceptible (S)
25 to 30	Intermediate (I)
≤ 24	Resistant (R)

^h These zone diameter standards are applicable only to disk diffusion tests using GC agar base and 1% defined growth supplement incubated in 5% CO₂.

For testing Streptococcus pneumoniaeand Streptococcus pyogenes: ⁱ

Zone Diameter (mm)	Interpretation
≥ 16	Susceptible (S)
13 to 15	Intermediate (I)
≤ 12	Resistant (R)

ⁱ These zone diameter standards are applicable only to disk diffusion tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO₂.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ofloxacin. 

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 mcg ofloxacin disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism		Zone Diameter (mm)
Escherichia coli	ATCC 25922	29 to 33
Haemophilus influenzae	ATCC 49247j	31 to 40
Neisseria gonorrhoeae	ATCC 49226k	43 to 51
Pseudomonas aeruginosa	ATCC 27853	17 to 21
Staphylococcus aureus	ATCC 25923	24 to 28
Streptococcus pneumoniae	ATCC 49619l	16 to 21

<sup>j This quality control range is applicable only to H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)2 incubated in 5% CO₂.

k This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by a disk diffusion procedure using GC agar base with 1% defined growth supplement incubated in 5% CO₂.

l This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO₂.</sup>