SPARFLOZACIN, 5 MCG, SENSI-DISC

K970385 · Becton Dickinson Microbiology Systems · JTN · Mar 10, 1997 · Microbiology

Device Facts

• Record ID: K970385
• Device Name: SPARFLOZACIN, 5 MCG, SENSI-DISC
• Applicant: Becton Dickinson Microbiology Systems
• Product Code: JTN · Microbiology
• Decision Date: Mar 10, 1997
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1620
• Device Class: Class 2

Intended Use

Antimicrobial Susceptibility Test Discs are used for semi-quantitative in vitro susceptibility testing by standardized agar diffusion test procedures. Sparfloxacin Sensi-Discs® are intended for use in determining the susceptibility to Sparfloxacin of a wide range of bacteria, including Staphylococcus aureus, Streptococcus pneumoniae (penicillin-susceptible strains), Enterobacter cloacae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, and Mycoplasma pneumoniae. Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Rhone Poulenc Rorer Pharmaceuticals, Inc., and received FDA approval under NDA No. 20-677.

Device Story

Device consists of paper discs impregnated with 5 mcg of the antimicrobial agent Sparfloxacin. Used in clinical microbiology laboratories to perform standardized agar diffusion susceptibility testing (Bauer-Kirby method). Discs are placed on Mueller Hinton Agar (or specialized media for specific organisms) inoculated with clinical bacterial isolates. Following incubation, zones of inhibition are measured and compared to established NCCLS interpretive standards to categorize organisms as susceptible, intermediate, or resistant. Results assist clinicians in selecting appropriate antimicrobial therapy for patients with infections caused by susceptible pathogens.

Clinical Evidence

No clinical data provided for the device itself; device performance relies on established standardized agar diffusion methodology (NCCLS M2-A5, M100-S6). Clinical efficacy of the drug Sparfloxacin is supported by referenced studies in the drug's package insert, comparing eradication rates against erythromycin and cefaclor in pneumonia and bronchitis patients.

Technological Characteristics

Paper discs impregnated with 5 mcg Sparfloxacin. Principle: Agar diffusion (Bauer-Kirby). Medium: Mueller Hinton Agar (or supplemented variants). Standardized by NCCLS M2-A5 and M100-S6. Manual application and measurement. No software or electronic components.

Indications for Use

Indicated for in vitro agar diffusion susceptibility testing to determine bacterial susceptibility to Sparfloxacin. Target organisms include aerobic Gram-positive (S. aureus, S. pneumoniae) and Gram-negative (E. cloacae, E. coli, H. influenzae, H. parainfluenzae, K. pneumoniae, M. catarrhalis) bacteria, plus C. pneumoniae and M. pneumoniae.

Regulatory Classification

Identification

An antimicrobial susceptibility test disc is a device that consists of antimicrobic-impregnated paper discs used to measure by a disc-agar diffusion technique or a disc-broth elution technique the in vitro susceptibility of most clinically important bacterial pathogens to antimicrobial agents. In the disc-agar diffusion technique, bacterial susceptibility is ascertained by directly measuring the magnitude of a zone of bacterial inhibition around the disc on an agar surface. The disc-broth elution technique is associated with an automated rapid susceptibility test system and employs a fluid medium in which susceptibility is ascertained by photometrically measuring changes in bacterial growth resulting when antimicrobial material is eluted from the disc into the fluid medium. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

Predicate Devices

• BBL® Sensi-Discs® (e.g., Ofloxacin, 5 mcg, Sensi-Disc®)

Submission Summary (Full Text)

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K970385

Date 1/30/97

# SUMMARY OF SAFETY AND EFFECTIVENESS

SUBMITTED BY:

Virginia C. Weinknecht
Regulatory Affairs Specialist
Becton Dickinson Microbiology Systems
P.O. Box 243
Cockeysville, MD 21030-0243

MAR 10 1997

## NAME OF DEVICE:

Trade Name: Sparfloxacin, 5 mcg, Sensi-Discs
Catalog Numbers 4331707, 4331708

Common Name/Description: Antimicrobial Susceptibility Test Discs

Classification Name: Antimicrobial Susceptibility Test Discs

## PREDICATE DEVICE:

Other BBL® Sensi-Discs® such as Ofloxacin, 5 mcg, Sensi-Disc®

## DEVICE DESCRIPTION:

### INTENDED USE:

Antimicrobial Susceptibility Test Discs are used for semi-quantitative in vitro susceptibility testing by standardized agar diffusion test procedures. Sparfloxacin Sensi-Discs® are intended for use in determining the susceptibility to Sparfloxacin of a wide range of bacteria, including *Staphylococcus aureus*, *Streptococcus pneumoniae* (penicillin-susceptible strains), *Enterobacter cloacae*, *Haemophilus influenzae*, *Haemophilus parainfluenzae*, *Klebsiella pneumoniae*, *Moraxella catarrhalis*, *Chlamydia pneumoniae*, and *Mycoplasma pneumoniae*. Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Rhone Poulenc Rorer Pharmaceuticals, Inc., and received FDA approval under NDA No. 20-677.

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# INDICATIONS FOR USE:

Use of BBL® Sparfloxacin Sensi-Discs® for *in vitro* agar diffusion susceptibility testing is indicated when there is a need to determine the susceptibility of bacteria to Sparfloxacin. Sparfloxacin has been shown to be active against most strains of microorganisms listed below, both *in vitro* and in clinical infections, as described in the Rhone Poulenc Rorer Pharmaceuticals, Inc., package insert for this antimicrobic.

- Aerobic Gram-Positive Microorganisms
- *Staphylococcus aureus*
- *Streptococcus pneumoniae* (penicillin-susceptible strains)
- Aerobic Gram-Negative Microorganisms
- *Enterobacter cloacae*
- *Escherichia coli*
- *Haemophilus influenzae*
- *Haemophilus parainfluenzae*
- *Klebsiella pneumoniae*
- *Moraxella catarrhalis*
- Other Microorganisms
- *Chlamydia pneumoniae*
- *Mycoplasma pneumoniae*

# PRODUCT DESCRIPTION:

Sparfloxacin Susceptibility Test Discs are prepared by impregnating high quality paper with accurately determined amounts of Sparfloxacin supplied by the manufacturer, Rhone Poulenc Rorer Pharmaceuticals, Inc., Collegeville, Pennsylvania. Each Sparfloxacin disc is clearly marked on both sides with the agent and content. Sparfloxacin discs are furnished in cartridges of 50 discs each. Sparfloxacin cartridges are packed as either a single cartridge in a single box, or in a package containing ten cartridges.

Agar diffusion methods employing dried filter paper discs impregnated with specific concentrations of antimicrobial agents were developed in the 1940’s. In order to eliminate or minimize variability in the testing, Bauer et al. developed a standardized procedure in which Mueller Hinton Agar was selected as the test medium.

Various regulatory agencies and standards-writing organizations subsequently published standardized reference procedures based on the Bauer-Kirby method. Among the earliest and most widely accepted of these standardized procedures were those published by the U.S. Food and Drug Administration

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(FDA) and the World Health Organization (WHO). The procedure was adopted as a consensus standard by the National Committee for Clinical Laboratory Standards (NCCLS) and is periodically updated. The latest NCCLS documents are M2-A5 (12/93) and M100-S6 (12/95).

Discs containing a wide variety of antimicrobial agents are applied to the surface of Mueller Hinton Agar plates [or Haemophilus Test Medium Agar for H. influenzae or Mueller Hinton Agar with 5% Sheep Blood for S. pneumoniae] inoculated with pure cultures of clinical isolates. Following incubation, the plates are examined and the zones of inhibition surrounding the discs are measured and compared with established zone size ranges for individual antimicrobial agents in order to determine the agent(s) most suitable for use in antimicrobial therapy. The determination as to whether the organism in question is susceptible (S), intermediate (I), or resistant (R) to an antimicrobial agent is made by comparing zone sizes to those found in the respective organism tables of National Committee for Clinical Laboratory Standards (NCCLS) Document M2-A5 ("Performance Standards for Antimicrobial Disk Susceptibility tests - Fifth Edition, Approved Standard", 12/93) and of NCCLS Document M100-S6 ("Performance Standards for Antimicrobial Susceptibility Testing", Sixth Informational Supplement, 12/95).

PERFORMANCE DATA:

See attached Rhone Poulenc Rorer Pharmaceuticals, Inc., product insert section on Susceptibility Tests - Diffusion Techniques for Zagam® (Sparfloxacin).

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# ZAGAM®
(sparfloxacin) Tablets

## DESCRIPTION

Zagam® (sparfloxacin) tablets contain sparfloxacin, a synthetic broad-spectrum antimicrobial agent for oral administration. Sparfloxacin, an aminodithiotropiumetate, is 0.4-mono-1-cyclopropyl-7-aza-3,6-dimethyl-1-piperazinyl-6,8-dithio-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, its empirical formula is C₁₈H₁₈N₂O₃ and it has the following chemical structure:


Sparfloxacin has a molecular weight of 292.41, it occurs as a yellow crystalline powder. It is sparingly soluble in glacial acetic acid or chloroform, very slightly soluble in ethanol (95%), and practically insoluble in water and ether. It dissolves in dilute acetic acid or 0.1 N sodium hydroxide.

Zagam is available as a 200-mg round, white film-coated tablet. Each 300-mg tablet contains the following inactive ingredients: methionylsulfite cellulose NT, corn starch NT, L-methionylnaphthalines NT, magnesium stearate NT, and colloidal silicone dioxide NT. The film-coating contains: methythiothiocypophthaline USP, polyethylene glycol 6000, and titanium dioxide USP.

## CLINICAL PHARMACOLOGY

Absorption: Sparfloxacin is well absorbed following oral administration with an absolute oral bioavailability of 82%. The mean maximum plasma sparfloxacin concentration following a single 400-mg oral dose was approximately 1.3 (±0.2) μg/mL. The area under the curve (mean AUC₀₋ₜₐ₋ₓ) following a single 400-mg oral dose was approximately 24 (±8.9) μg/mL.

Staphyciate plasma concentration was achieved on the first day by giving a loading dose that was double the daily dose. Mean t₀ SDI pharmacokinetic parameters observed for the 24-hour dosing interval with the recommended dosing regimen are shown below:

| Dosing Regimen
emerged | Peak
Cmax (μg/mL) | Trough
C₁₀ (μg/mL) | AUC₀₋ₜₐₓ
t₀ μg/mL |
| --- | --- | --- | --- |
| 400 mg loading dose (day 1) | 1.3 (±0.2) | 0.6 (±0.1) | 20.8 (±2.1) |
| 200 mg q24 hours (staphyciate) | 1.1 (±0.1) | 0.5 (±0.1) | 18.7 (±2.0) |

Maximum plasma concentrations for the initial oral 400-mg loading dose were typically achieved between 2 to 6 hours following administration with a mean value of approximately 4 hours. Maximum plasma concentrations for a 200-mg dose were also achieved between 2 to 6 hours after administration with a mean of about 4 hours.

Oral absorption of sparfloxacin is unaffected by administration with milk or food, including high fat meals. Concurrent administration of enteric containing magnesium hydroxide and aluminum hydroxide reduces the oral bioavailability of sparfloxacin by as much as 50%. (See PRECAUTIONS, Information for Patients, and Drug Interactions.)

Distribution: Upon reaching general circulation, sparfloxacin distributes well into the body, as reflected by the large mean staphyciate volume of distribution (Vdₐ) of 3.9 (±0.8) L/kg. Sparfloxacin exhibits low plasma protein binding in serum at about 40%.

Sparfloxacin penetrates well into body fluids and tissues. Results of tissue and body fluid distribution studies demonstrated that oral administration of sparfloxacin produces sustained concentrations and that sparfloxacin concentrations in lower respiratory tract tissues and fluids generally exceed the corresponding plasma concentrations. The concentration of sparfloxacin in respiratory tissues (pulmonary parenchyma, bronchial wall, and bronchial mucosa) at 2 to 6 hours following standard oral dosing was approximately 2 to 6 times greater than the corresponding concentration in plasma. Concentrations in these respiratory tissues increase at up to 24 hours following dosing. Sparfloxacin is also highly concentrated into alveolar macrophages compared to plasma. Tissue or fluid to plasma sparfloxacin concentration ratios for respiratory tissues and fluids are:

| Tissue to Plasma Sparfloxacin Concentration Mean Ratio (%CV)* | | | |
| --- | --- | --- | --- |
| Respiratory tissues and fluids | n** value | Time of Collection Probiotics | |
| | | 2 to 6 hours | 12 to 24 hours |
| alveolar macrophages | 6/5 | 51.8 (88.7%) | 66.1 (47.8%) |
| epithelial lining fluid | 10/10 | 12.2 (26.7%) | 17.8 (35.3%) |
| pulmonary parenchyma | 8/7 | 5.9 (15.0%) | 15.8 (32.0%) |
| bronchial wall | 8/7 | 2.8 (18.0%) | 5.7 (25.0%) |
| bronchial mucosa | 6/5 | 2.7 (11.5%) | 2.1 (11.6%) |

* % CV (percent coefficient of variation)

** For tissues with two values, the first n is for 2 to 6 hours and the second n is for 12 to 24 hours.

Mean pleural effusion to plasma concentration ratios were 0.34 and 0.69 at 4 and 20 hours postdose, respectively.

Metabolism: Sparfloxacin is metabolized by the liver, primarily by phase II glucuronidation, to form a glucuronide conjugate. Its metabolism does not utilize or interfere with cytochrome-mediated oxidation, in particular cytochrome P450.

Excretion: The total body clearance and renal clearance of sparfloxacin were 11.4 (±3.6) and 1.6 (±0.5) L/hr, respectively. Sparfloxacin is excreted in both the feces (50%) and urine (50%). Approximately 10% of an orally administered dose is excreted in the urine as unchanged drug in patients with normal renal function. Following a 400-mg loading dose of sparfloxacin, the mean urine concentration 4 hours postdose was in excess of 12.5 μg/mL, and measurable concentrations of active drug persisted through six days for subjects with normal renal function.

The terminal elimination phase half-life (t₀) of sparfloxacin in plasma generally varies between 16 and 30 hours, with a mean t₀ of approximately 20 hours. The t₀ is independent of the administered dose, suggesting that sparfloxacin elimination kinetics are linear.

## Special Populations

Gartem: The pharmacokinetics of sparfloxacin are not altered in the elderly with normal renal function.

Pediatric: The pharmacokinetics of sparfloxacin in pediatric subjects have not been studied.

Gender: There are no gender differences in the pharmacokinetics of sparfloxacin.

Renal insufficiency: In patients with renal impairment (creatinine clearance ≥50 mL/min), the terminal elimination half-life of sparfloxacin is lengthened. Single or multiple doses of sparfloxacin in patients with varying degrees of renal impairment typically produce plasma concentrations that are twice those observed in subjects with normal renal function. (See PRECAUTIONS: General and DISKAGE AND ADMINISTRATION.)

Hepatic insufficiency: The pharmacokinetics of sparfloxacin are not altered in patients with mild or moderate hepatic impairment without cholestasis.

## MICROBIOLOGY

Sparfloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Sparfloxacin exerts its antibacterial activity by inhibiting DNA gyrase, a bacterial topoisomerase. DNA gyrase is an essential enzyme which controls DNA topology and assists in DNA replication, repair, deactivation, and transcription.

Quinolones differ in chemical structure and mode of action from β-lactam antibiotics. Quinolones may, therefore, be active against bacteria resistant to β-lactam antibiotics.

Adhesive stress-resistance has been observed between sparfloxacin and other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to sparfloxacin.

In vitro tests show that the combination of sparfloxacin and rifampin is antagonistic against Staphylococcus aureus.

Sparfloxacin 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
- Streptococcus pneumoniae (penicillin-susceptible strain)
- Aerobic gram-negative microorganisms
- Enterobacter cloacae
- Haemophilus influenzae
- Haemophilus parainfluenzae
- Klebsiella pneumoniae
- Klebsiella catarrhalis
- Other microorganisms
- Chlamydia pneumoniae
- Mycoplasma pneumoniae

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

Sparfloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 1 μg/mL or less against most (≥80%) strains of the following microorganisms; however, the safety and effectiveness of sparfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

## Aerobic gram-positive microorganisms

### Streptococcus agalactiae

- Streptococcus pneumoniae (penicillin-resistant strain)
- Streptococcus pyogenes
- Viridans group streptococci

### Aerobic gram-negative microorganisms

- Acinetobacter anthracis
- Acinetobacter lwoffii
- Citrobacter diversus
- Enterobacter aerogenes
- Klebsiella oxytoca
- Legionella pneumophila
- Morganella morganii
- Proteus mirabilis
- Proteus vulgaris

## SUBCEPTIDUTY TESTS

Drinking: In vitro and quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method* (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of sparfloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Streptococcus pneumoniae:

| MIC (μg/mL) | Interpretation |
| --- | --- |
| 0.1 | Susceptible (2) |
| 3 | Intermediate (3) |
| 24 | Resistant (6) |

For testing Haemophilus influenzae and Haemophilus parainfluenzae:

| MIC (μg/mL) | Interpretation |
| --- | --- |
| ≤0.25 | Susceptible (5) |

*These interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.

The current absence of data on resistant strains produces defining any categories other than "Susceptible." Strains treating MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

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# (or testing Streptococcus pneumoniae)

| MIC (μg/mL) | Interpretation |
| --- | --- |
| ≤0.5 | Susceptible (S) |

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

The current absence of data on resistant strains provided defining any categories other than "Susceptible." Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobium compound in the blood reaches the concentration usually achievable. A report of "intermediate" indicates that the result should be considered "nontotal" and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies a double clinical applicability in body sites where the drug is physiologically concentrated or it situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small concentrated techniques 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 sparfloxacin powder should provide the following MIC values:

| Microcorrosion | MIC Range (μg/mL) |
| --- | --- |
| Enterococcus faecalis ATCC 29213 | 0.12-0.5 |
| Escherichia coli ATCC 25923 | 0.004-0.015 |
| Haemophilus influenzae ATCC 49247+ | 0.084-0.016 |
| Staphylococcus aureus ATCC 29213 | 0.03-0.12 |
| Streptococcus pneumoniae ATCC 49619+ | 0.12-0.5 |

* This quality control range is applicable to only *H. influenzae* ATCC 49247+ and the 0.12-0.5 for a broth microdilution procedure using Haemophilus Test Medium (HTM).

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

Diffusion techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to microdialysed compounds. One such standardized procedural requires the use of standardized inoculum concentrations. This procedure uses paper discs impregnated with 5-μg sparfloxacin to test the susceptibility of microorganisms to sparfloxacin.

Reports from the laboratory providing results of the standard single-disc susceptibility test with a 5-μg sparfloxacin disc should be interpreted according to the following criteria:

For aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Streptococcus pneumoniae:

| Zone Diameter (mm) | Interpretation |
| --- | --- |
| ≤15 | Susceptible (S) |
| 15-19 | Intermediate (I) |
| ≥15 | Resistant (R) |

Haemophilus influenzae and Haemophilus parainfluenzae should not be tested by diffusion techniques. An MIC should be determined for these isolates.

| Zone Diameter (mm) | Interpretation |
| --- | --- |
| ≤15 | Susceptible (S) |

* These zone diameter standards for Streptococcus pneumoniae apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO₂.

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

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

As with standard 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-μg sparfloxacin disc should provide the following zone diameters in these laboratory quality control strains:

| Microcorrosion | Zone Diameter (mm) |
| --- | --- |
| Escherichia coli ATCC 25923 | 20-30 |
| Staphylococcus aureus ATCC 25923 | 27-33 |
| Streptococcus pneumoniae ATCC 49619+ | 21-37 |

* These quality control limits apply to tests conducted with *S. pneumoniae* ATCC 49619 using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO₂.

# INDICATIONS AND USAGE

Sugars (spalfloxacin) is indicated for the treatment of adults (≥ 18 years of age) with the following infections caused by susceptible strains of the designated microorganisms:

- Community-acquired pneumonia caused by *Chlamydia pneumoniae*, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Rhodobacter pneumoniae, or Streptococcus pneumoniae.
- Acute bacterial exacerbations of chronic bronchitis caused by *Chlamydia pneumoniae*, Enterobacter cloacae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, or Streptococcus pneumoniae.

Appropriate culture and susceptibility tests should be performed before treatment or order to isolate and identify organisms causing the infection and to determine their susceptibility to sparfloxacin. Therapy with sparfloxacin may be initiated before results of these tests are shown; only results should be available, appropriate therapy should be selected. Culture and susceptibility testing performed periodically during therapy will provide information on the continued susceptibility of the pathogen to the antimicrobial agent and also on the possible emergence of bacterial resistance.

# CONTRAINDICATIONS

Sparfloxacin is contraindicated for individuals with a history of hypersensitivity or photosensitivity reactions.

Torsade de pointes has been reported in patients receiving sparfloxacin concomitantly with disconcerted and antiobliquone. Consequence, sparfloxacin is contraindicated for individuals receiving these drugs as well as other GC, prolonging antiarrhythmic drugs recorded to cause tortaicin, such as class Ia antiarrhythmic agents (e.g., quinidine, procainamide), class Ib antiarrhythmic agents (e.g., sotalol), and bepridil. Sparfloxacin is contraindicated in patients with known GC, prolongation of in patients being treated concomitantly with medications known to produce an increase in the GC, normal endorhythmic life profiles (e.g., terfenadine). (See WARNINGS and PRECAUTIONS.)

It is essential to avoid exposure to the sun, bright natural light, and UV rays throughout the entire duration of treatment and for 5 days after treatment is stopped. Sparfloxacin is contraindicated in patients whose life-time or employment will not permit compliance with required safety precautions concerning photosensitivity. (See WARNINGS and PRECAUTIONS.)

# WARNINGS

**WIDERATE TO SEVERE PHOTOTOXIC REACTIONS HAVE OCCURRED IN PATIENTS EXPOSED TO DIRECT OR INDIRECT SUNLIGHT OR TO SATIROAL EXTRANOLYT LIQUIDS. THESE SAMPLE DURING OR FOLLOWING TREATMENT THESE REACTIONS HAVE ALSO OCCURRED IN PATIENTS EXPOSED TO SHADED OR DIFFUSE LIGHT. INCLUDING EXPOSURE THROUGH GLASS OR DURING CLOUDY AREA, THROUGH INGESTION OF THESE DUSTS OR DISCONTINUE SPARFLOXACIN THERAPY AT THE FIRST SIGNS OR SYMPTOMS OF A PHOTOTOXICITY REACTION SUCH AS A SENSATION OF SKIN BURNING, REDNESS, SWELLING, BUSTERS, RASH, ITCNING, OR DERMATITIS.**

The overall incidence of drug related phototoxicity in the 1985 patients who received sparfloxacin during clinical trials with recommended dosage was 7.9% (n=126). Phototoxicity ranged from mild 4.1% (n=83) to moderate 3.2% (n=52) to severe 0.6% (n=9). In the same period, the treatment of normal daily activity. The frequency of phototoxicity reactions characterized by blister formation was 0.8% (n=13) of which 2 were severe. The discontinuation rate due to phototoxicity independent of drug relationship was 1.1% (n=17).

As with some other types of phototoxicity, there is the potential for exacerbation of the reaction on re-exposure to sunlight or artificial ultraviolet light prior to complete recovery from the reaction. In a few cases, recovery from phototoxicity reactions was prolonged for several weeks. In rare cases, reactions have returned up to several weeks after stopping sparfloxacin therapy.

**EXPOSURE TO DIRECT OR INDIRECT SUNLIGHT OR TO SATIROAL EXTRANOLYT LIQUIDS. EXPOSED OR SUNBLOOED SHOULD BE AVOIDED WHILE TAKING SPARFLOXACIN AND FOR FIVE DAYS FOLLOWING THERAPY. SPARFLOXACIN THERAPY SHOULD BE DISCONTINUED IMMEDIATELY AT THE FIRST SIGNS OR SYMPTOMS OF PHOTOTOXICITY.**

These phototoxic reactions have occurred with and without the use of sun-screens or sunblocks and have been associated with a single dose of sparfloxacin. However, a study in healthy volunteers has demonstrated that some symptoms produce, specifically those same in bloating UVR spectrum wavelengths (those containing the active ingredients: ectoproline or Pefacil® 1780), sun moderate the photoperoxidizing effect of sparfloxacin; however, many liver-the-counter sunitaneous do not provide adequate UVR protection.

Increases in the GC, phthalate or been obtained through exposure treated with sparfloxacin. After a single loading dose of 400 mg, a mean increase in GC, interval of 11 msec (2.9%) is seen; at steady-state the mean increase is 7 msec (1.8%). The magnitude of the GC, effect dose not increase with repeated administration, and the GC, returns to baseline within 48 hours of the last dose. In clinical trials involving 1480 patients with a baseline GC measurement, the mean prolongation at steady-state was 10 msec (2.5%); 0.7% of patients had a GC, interval greater than 800 msec; however, no arrhythmic effects were seen.

**THE SAFETY AND EFFECTIVENESS OF SPARFLOXACIN IN CHLORIDE, ADD-LESCENTS (UNDER THE AGE OF 18 YEARS), PROMANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.** (See PRECAUTIONS - Pregnancy, Nursing Mothers; and Pediatric Use.)

Sparfloxacin has been shown to cause arthropathy in immature dogs when given in oral doses of 25 mg/kg/day (approximately 1.8 times the highest human dose on a mg/ml basis) for seven consecutive days. Examination of the weight-bearing points of the body revealed small vessels lesions of the cartilage. Other sunnylones also produce sessions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.

Convulsions and toxic psychoses have been reported in patients receiving quinolones, including sparfloxacin. Quinolones may also cause increased intracranial pressure and central nervous system stimulation which may lead to tremors, restlessness/agitation, anxiety/nervousness, lightheadedness, confusion, hallucinations, perilesion, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving sparfloxacin, the drug should be discontinued and appropriate measures included: 1-2 with other quinolones; sparfloxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., serum or/oral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). Cases of seizure associated with hypoglycemia have been reported. (See PRECAUTIONS: General Information for Patients, Drug Interactions and ADVERSE REACTIONS.)

Serious and occasionally fatal hypersensitivity (including anaphylatoxic or anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolones. Some (e)ubiquitous and/or severe (c) and (d)ular collapse, hypersensitivity, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, and/or itching. Only a few patients had a history of previous hypersensitivity reactions. If an allergic reaction to sparfloxacin occurs, the drug should be discontinued immediately. Serious acute hypersensitivity reactions may require immediate treatment with epinephrine, and other resuscitative measures including oxygen, intravenous fluids, antihistamines, corticosteroids, present amines, and airway management, including intubation, as clinically indicated.

Serious and sometimes fatal events, some due to hypersensitivity, and some

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due to uncertain etiology; have been reported rarely in patients receiving therapy with quinolones. These events may be severe and generally occur following the administration of multiple doses. Clinics may have a positive role in more of the following: fever, rash or severe dermatologic reactions (e.g.,sular 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 hemolysis and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or thrombologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity and supportive measures instituted. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including sparfloxacin, and may range to severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a down produced by Clostridium difficile is an primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.

Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported with sparfloxacin and other quinolones. Sparfloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendons or tendon rupture has been confidently excluded. Tendon rupture can occur at any time during or after the first sparfloxacin.

# PRECAUTIONS

General. Adequate hydration of patients receiving sparfloxacin should be maintained to prevent the formation of a highly concentrated urine.

Administer sparfloxacin with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of sparfloxacin may be required. Adjustment of the dosage regimen is necessary for patients with impaired renal function (maximum clearance 450 mL/min. (See GUNSUM, PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Avoid the concomitant prescription of medications known to prolong the QT, interval, e.g., erythromycin, terfenadine, estentisine, clozapine, pentamidine, triazolidine, and azotoprofen.

Avoid exposure to direct or indirect sunlight (including through glass, while using sunscreen) and surmicots, reflected sunlight, e.g., during the day, and to discontinue the drug at the first sign of a skin rash or other allergic reaction.

- to stop fluids liberally.

Drug Interactions

Diastolic Sparfloxacin has no effect on the pharmacokinetics of digoxin.

Methylxanthines: Sparfloxacin does not increase plasma meclofenate concentrations. Since there is no interaction with threophytine, interaction with other methylxanthines such as caffeine is unlikely.

Hipofen: Sparfloxacin does not increase the anti-coagulant effect of warfarin.

Cimetidine: Cimetidine does not affect the pharmacokinetics of sparfloxacin.

Aniacids and Sucralfate: Aluminum and magnesium anions are not present in patients exposed to direct sunlight while receiving drugs in this case. Excessive exposure to sunlight should be avoided. In clinical trials with sparfloxacin, phototoxicity was observed in approximately 7% of patients. Therapy should be discontinued if phototoxicity (e.g., a skin eruption) occurs.

As with other quinolones, sparfloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epileptics) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). (See WARNINGS and Drug Interactions.)

# Information for Patients:

Patients should be advised:

- to avoid exposure to direct or indirect sunlight (including through glass, while using sunscreen) and surmicots, reflected sunlight, e.g., during the day, and to discontinue the drug at the first sign of a skin rash or other allergic reaction;
- to stop fluids liberally.

Drug Interactions

Diastolic Sparfloxacin has no effect on the pharmacokinetics of digoxin.

Methylxanthines: Sparfloxacin does not increase plasma meclofenate concentrations. Since there is no interaction with theophylline, interaction with other methylxanthines such as caffeine is unlikely.

Hipofen: Sparfloxacin does not increase the anti-coagulant effect of warfarin.

Cimetidine: Cimetidine does not affect the pharmacokinetics of sparfloxacin.

Aniacids and Sucralfate: Aluminum and magnesium anions are not present in patients exposed to direct sunlight while receiving drugs in this case. Excessive exposure to sunlight should be avoided. In clinical trials with sparfloxacin, phototoxicity was observed in approximately 7% of patients. Therapy should be discontinued if phototoxicity (e.g., a skin eruption) occurs.

As with other quinolones, sparfloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epileptics) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). (See WARNINGS and Drug Interactions.)

# Drug Laboratory Test Interactions:

Sparfloxacin therapy may produce false-negative culture results for Mycobacterium tuberculosis by suppression of mycobacterial growth.

Carcinogenesis: Mutagenesis, Impairment of Fertility

Carcinogenesis: Sparfloxacin may not carcinogenic in mice or rats when administered for 154 weeks at daily oral doses 3.5 - 5.2 times greater than the maximum human dose (400 mg), respectively, based upon mg/ml. These doses corresponded to plasma concentrations approximately equal to those and 2.2 times greater than (rat) maximum human plasma concentrations.

Mutagenesis: Sparfloxacin was not mutagenic in Salmonella typhimurium TA98, TA100, TA110, TA120, TA130, or Escherichia coli strain, ESBL-2, nor in Chinese hamster lung cells. Sparfloxacin and other quinolones have been shown to be mutagenic in Salmonella typhimurium strain TA102 and to induce DNA repair in Escherichia coli, perhaps due to their inhibitory effect on bacterial DNA gyrase. Sparfloxacin induced chromosomal aberrations in Chinese hamster lung cells in vitro and in vivo by ropinirole (or ropinirole) in the mouse. No increase in chromosomal aberrations or microtubule in bone marrow cells was observed after sparfloxacin was administered orally to mice.

Impairment of Fertility: Sparfloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses up to 15.4 times the maximum human dose (400 mg) based upon mg/ml (equivalent to approximately 12 times the maximum human plasma concentration).

Pregnancy: Teratogenic effects Pregnancy Category C

Reproduction studies performed in rats, rabbits, and monkeys at oral doses 6.2, 4.4, and 3.6 times higher than the maximum human dose, respectively, based upon mg/ml corresponding to plasma concentrations 4.5- and 8.5-fold higher than in humans in the monkey and rat, respectively (dd not reveal any evidence of teratogenic effects. At these doses, sparfloxacin was clearly mutagenic toxic to the rabbit and monkey with evidence of slight maternal toxicity observed in rats). When administered to pregnant rats at day 4, maternal toxicity was observed. No increase in chromosomal aberrations or microtubule in bone marrow cells was observed after sparfloxacin was administered orally to mice.

Hypothetical: Sparfloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses up to 15.4 times the maximum human dose (400 mg) based upon mg/ml (equivalent to approximately 12 times the maximum human plasma concentration).

# Laboratory: Teratogenic effects Pregnancy Category C

Reproduction studies performed in rats, rabbits, and monkeys at oral doses 6.2, 4.4, and 3.6 times higher than the maximum human dose, respectively, based upon mg/ml corresponding to plasma concentrations 4.5- and 8.5-fold higher than in humans in the monkey and rat, respectively (dd not reveal any evidence of teratogenic effects. At these doses, sparfloxacin was clearly mutagenic toxic to the rabbit and monkey with evidence of slight maternal toxicity observed in rats). When administered to pregnant rats at day 4, maternal toxicity was observed. No increase in chromosomal aberrations or microtubule in bone marrow cells was observed after sparfloxacin was administered orally to mice.

Hypothetical: Sparfloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses up to 15.4 times the maximum human dose (400 mg) based upon mg/ml (equivalent to approximately 12 times the maximum human plasma concentration).

# Laboratory: Teratogenic effects Pregnancy Category C

Reproduction studies performed in rats, rabbits, and monkeys at oral doses 6.2, 4.4, and 3.6 times higher than the maximum human dose, respectively, based upon mg/ml corresponding to plasma concentrations 4.5- and 8.5-fold higher than in humans in the monkey and rat, respectively (dd not reveal any evidence of teratogenic effects. At these doses, sparfloxacin was clearly mutagenic toxic to the rabbit and monkey with evidence of slight maternal toxicity observed in rats). When administered to pregnant rats at day 4, maternal toxicity was observed. No increase in chromosomal aberrations or microtubule in bone marrow cells was observed after sparfloxacin was administered orally to mice.

Hypothetical: Sparfloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses up to 15.4 times the maximum human dose (400 mg) based upon mg/ml (equivalent to approximately 12 times the maximum human plasma concentration).

# Laboratory: Teratogenic effects Pregnancy Category C

Reproduction studies performed in rats, rabbits, and monkeys at oral doses 6.2, 4.4, and 3.6 times higher than the maximum human dose, respectively, based upon mg/ml corresponding to plasma concentrations 4.5- and 8.5-fold higher than in humans in the monkey and rat, respectively (dd not reveal any evidence of teratogenic effects. At these doses, sparfloxacin was clearly mutagenic toxic to the rabbit and monkey with evidence of slight maternal toxicity observed in rats). When administered to pregnant rats at day 4, maternal toxicity was observed. No increase in chromosomal aberrations or microtubule in bone marrow cells was observed after sparfloxacin was administered orally to mice.

Hypothetical: Sparfloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses up to 15.4 times the maximum human dose (400 mg) based upon mg/ml (equivalent to approximately 12 times the maximum human plasma concentration).

B-6

{6}

CENTRAL NERVOUS SYSTEM: paresthesia, hypesthesia, nervousness, somnolence, abnormal dreams, dry mouth, depression, tremor, anxiety, confusion, hallucinations, hyperesthesia, hyperkinesia, sleep disorder, hypokinesia, nergio, abnormal gait, agitation, lightheadedness, emotional lability, euphoria, abnormal thinking, amnesia, twitching.

RESPRATORY: asthma, epistaxis, pneumonia, rhinitis, pharyngitis, bronchitis, hemoptysis, sinusitis, cough increased, dyspnea, laryngismus, lung disorder, pleural disorder.

SKIN/PYPERSENSITIVITY: rash, maculocessive rash, dry skin, herpes simplex, sweating, urticaria, vesiculobulbous rash, exfoliative dermatitis, acne, alopecia, angioedema, contact dermatitis, fungal dermatitis, turcification, pubular rash, skin discoloration, herpes zoster, petechial rash.

SPECIAL SENSES: ear pain, amblyopia, photophobia, tinnitus, conjunctivitis, diathesis, abnormality of accommodation, blepharitis, ear disorder, eye pain, lacrimation disorder, otitis media.

UROGENITAL: vaginitis, dysuria, breast pain, dysmenorrhea, hematuria, menorrhagia, nocturia, polypnea, urinary tract infection, kidney pain, leukorrhea, menorrhagia, nonintegral disorder.

LABORATORY CHANGES: In the US phase 3 clinical trials, with the recommended dosage, the most frequently considered CTG required changes in laboratory parameters listed as adverse events, regardless of relationship to drug, were: elevated ALT (SGPT) (2.0%), AST (SGOT) (2.3%) and white blood cells (1.7%).

Increases for the following laboratory tests were reported in less than 1% of all patients enrolled in clinical trials: alkaline phosphatase, serum amylase, aPTT, blood urea nitrogen, calcium, creatinine, eosinophils, serum lipase, monocytes, neutrophils, total bilirubin, urine glucose, urine protein, urine red blood cells, and urine white blood cells.

Decreases for the following laboratory tests were reported in less than 1% of all patients enrolled in clinical trials: albumin, creatinine clearance, hematocrit, hemoglobin, lymphocytes, phosphorus, red blood cells, and sodium.

Increases and decreases for the following laboratory tests were reported in less than 1% of all patients in clinical trials: blood glucose, platelets, potassium, and white blood cells.

Postmarketing adverse events: The following are additional adverse events regardless of relationship to drug reported from worldwide postmarketing experience with sparfloxacin or other quinolones: acidosis, acute renal failure, agranulocytosis, albuminuria, anaphylactic shock, angioedema, anaemia, ataxia, bullous eruption, candidiasis, cardiosummitans arrest, cerebral thrombosis, convulsions, crystalluria, diagnosis, dysphagia, obvious feeling, emocism, erythema nodosum, exacerbation of myasthenia gravis, gastralgia, hemolysis anemia, hepatic necrosis, hepatitis, hicknag, hyperpigmentation, interstitial nephritis, interstitial pneumonia, intestinal perforation, jaundice, laryngeal or pulmonary edema, manic reaction, hemoptysis, nystagmus, painful viral mucosa, pancreatitis, phobia, prolongation of postmortem time, pseudomembranous colitis, Gunoba's edema, renal calculi, rhabdomyolysis, sensory disturbance, Stevens-Johnson syndrome, abscesses and carcinoma, teratomas, tender rupture, tremor, thrombocytopenia, thrombocytopenia purpura, blood abnormal hydrolysis, toxic psychosis, urinary retention, uveitis, vaginal candidiasis, vasculitis.

Laboratory changes: elevation of serum triglycerides, serum cholesterol, blood glucose, serum potassium, decrease in WBC counts, RBC counts, hemoglobin level, hematocrit level, thrombocyte counts, elevation in GOT, GPT, ALP, LDH, γ-GTP, total bilirubin.

# OVERDOSAGE

In case of overdoses, the patient should be monitored in a suitable equipped medical facility and advised to avoid sun exposure for five days. ECG monitoring is recommended due to the possible prolongation of the CTG interval. There is no known antidote for sparfloxacin overdoses.

It is not known whether sparfloxacin is dialyzable.

Single doses of sparfloxacin were relatively non-toxic via the oral route of administration in mice, rats, and dogs. No deaths occurred within a 14-day post-treatment observation period at the highest oral doses tested, up to 2000 mg/kg in either rodent species, or up to 600 mg/kg in the dog. Clinical signs observed included inedema in mice and dogs, diarrhea in both rodent species, and vomiting, salivation, and tremors in dogs.

# DOSAGE AND ADMINISTRATION

Zapam (sparfloxacin) can be taken with or without food.

The recommended daily dose of Zapam in patients with normal renal function is two 200-mg tablets taken on the first day as a loading dose. Thereafter, one 200-mg tablet should be taken every 24 hours for a total of 10 days of therapy (11 tablets).

The recommended daily dose of Zapam in patients with renal impairment (creatinine clearance >50 mL/min) is two 200-mg tablets taken on the first day as a loading dose. Thereafter, one 200-mg tablet should be taken every 48 hours for a total of 8 days of therapy (8 tablets).

# CLINICAL STUDIES

## Community-Acquired Pneumonia Studies

In two controlled clinical studies of community-acquired pneumonia conducted in the United States, sparfloxacin was compared to erythromycin and cefaclor. The patient clinical success and pathogen eradication rates for sparfloxacin were equivalent to those of the comparators. In these studies, the following pathogen eradication rates/presumed pathogen eradication rates were obtained:

| Organism | Sparfloxacin | Erythromycin* | Cefaclor |
| --- | --- | --- | --- |
| C. pneumoniae | 15/33 (86.4%) | 3/4 (25%) | 5/5 (100%) |
| H. influenzae | 20/24 (83.3%) | 0 | 25/21 (80.8%) |
| H. parainfluenzae | 61/83 (86.8%) | 4/4 (100%) | 31/41 (75.8%) |
| M. catarrhalis | 7/8 (87.5%) | 4/4 (100%) | 5/6 (83.3%) |
| M. pneumoniae | 36/39 (92.3%) | 15/15 (100%) | 20/24 (83.3%) |
| S. pneumoniae | 30/41 (95.1%) | 15/11 (90%) | 16/17 (54.1%) |

*Pathogen numbers were smaller since many of the strains were intrinsically resistant to erythromycin.

# Safety

The following table lists possibly and probably drug-related adverse events that occurred in these studies at an incidence of 52%:

| Event | Sparfloxacin (n=301) | Erythromycin (n=20) | Cefaclor (n=162) |
| --- | --- | --- | --- |
| Abdominal Pain | 6 (1.5%) | 16 (8.5%) | 3 (1.3%) |
| Postparesthesia Reaction | 16 (4.1%) | 0 | 1 (0.5%) |
| CT Internal Prolonged | 6 (2.1%) | 2 (1.0%) | 1 (0.5%) |
| Sinus Bradycardia | 2 (0.5%) | 6 (2.5%) | 0 |
| Diarrhea | 15 (3.9%) | 23 (15.8%) | 7 (4.3%) |
| Flatulemia | 0 | 5 (2.4%) | 0 |
| Nausea | 11 (2.8%) | 32 (15.3%) | 4 (2.5%) |
| Vomiting | 10 (2.6%) | 15 (7.2%) | 1 (0.5%) |
| Insomnia | 6 (1.6%) | 5 (2.4%) | 0 |

## Acute Bacterial Exacerbations of Chronic Bronchitis Study

In a controlled clinical study of acute bacterial exacerbations of chronic bronchitis conducted in the United States, sparfloxacin was compared to olfloxacin. In this study, the following pathogen eradication rates were obtained:

| Organism | Sparfloxacin | Ofloxacin |
| --- | --- | --- |
| H. parainfluenzae | 10/2/301 (29.4%) | 30/35 (84.7%) |
| H. influenzae | 31/57 (85.5%) | 5/19 (83.3%) |
| C. pneumoniae | 27/45 (83.2%) | 26/40 (80%) |
| M. catarrhalis | 26/38 (84.7%) | 22/34 (87.1%) |
| S. pneumoniae | 30/34 (88.2%) | 20/32 (80.9%) |
| S. aureus | 19/19 (84.2%) | 13/14 (52.9%) |
| K. pneumoniae | 17/17 (100%) | 15/17 (88.2%) |
| S. cloacae | 12/13 (82.3%) | 12/15 (80%) |

# Safety

The following table lists possibly and probably drug-related adverse events that occurred in the study at an incidence of ≥2% for either compound.

| Event | Sparfloxacin (n=295) | Ofloxacin (n=403) |
| --- | --- | --- |
| Headache | 11 (2.8%) | 5 (1.5%) |
| Postparesthesia Reaction | 25 (7.2%) | 3 (0.7%) |
| Diarrhea | 6 (1.5%) | 3 (0.7%) |
| Dyspepsia | 11 (2.8%) | 16 (3.5%) |
| Nausea | 16 (4.7%) | 25 (7.2%) |
| Dizziness | 12 (3.0%) | 10 (2.5%) |
| Insomnia | 4 (1.0%) | 46 (11.4%) |
| Taste Penetration | 10 (2.6%) | 10 (2.5%) |

# HOW SUPPLIED

| Emergent Size | NGC 6075 | Description | Markings |
| --- | --- | --- | --- |
| 200 mg | Bulder Face of 11 | 8410-11 (round, white table) | RPR 201 |
| | Bulder of 53 | 8410-53 | |

Store at Controlled Room Temperature 20 to 25°C (68 to 77°F).

Cardiovascular federal law prohibits dispensing without a prescription.

Keep out of the reach of children.

# ANIMAL PHARMACOLOGY

Sparfloxacin and other quinolones have been shown to cause arthropathy in juvenile animals of most species tested. (See WARNINGS).

Sparfloxacin had no convulsive activity in mice when administered alone or in combination with the nonsteroidal anti-inflammatory agents setoprofen, or naproxen.

# References

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Third Edition, Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December, 1993.

2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests—Fifth Edition, Approved Standard NCCLS Document M3-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.

RACINE-POLLENE RISER PHARMACEUTICALS INC.
COLLEBOTTLE, PA 19429 USA
R14000
Rev. 11/95