ProQuin^® XR
(ciprofloxacin hydrochloride)
Extended-Release Tablets, 500 mg

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ProQuin XR and other antibacterial drugs. ProQuin XR should be used only to treat uncomplicated urinary tract infections that are strongly suspected to be caused by bacteria.

ProQuin XR (ciprofloxacin hydrochloride) extended-release tablets contain ciprofloxacin hydrochloride, a synthetic broad-spectrum fluoroquinolone antimicrobial agent for oral administration.

Ciprofloxacin hydrochloride is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride. The molecular weight of the monohydrate is 385.82. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:

ProQuin XR is available as 500 mg (ciprofloxacin equivalent) tablets. ProQuin XR tablets are blue film-coated and oval-shaped. The inactive ingredients are povidone, magnesium stearate, polyethylene oxide, and film coating (Opadry^® Blue).

When ProQuin XR is administered with food, approximately 87% of ciprofloxacin is gradually released from the tablet over a 6-hour period. When administered following a meal maximum plasma ciprofloxacin concentrations are attained approximately 4.5-7 hours after dosing with ProQuin XR tablets. ProQuin XR should be administered with a main meal of the day, preferably the evening meal; if ProQuin XR is given while fasting, the bioavailability will be lowered substantially. Administration of ProQuin XR with a standardized meal (1000 calories, 50% fat) increased the C_max and AUC_0‑24h by approximately 120% and 170%, respectively, compared to administration under fasting conditions; the mean T_max was prolonged from 2.3 hours to 4.5 hours. The following table presents the pharmacokinetic parameters obtained at steady state for ProQuin XR 500 mg qd versus CIPRO 250 mg bid.

The in vitro binding of ciprofloxacin to plasma proteins over a concentration rangingfrom 0.9 to 30 micromolar is 9.9% to 36.6%, which is not likely to cause clinically significant protein binding interactions with other drugs.

Four metabolites of ciprofloxacin have been identified in human urine and feces. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The metabolites are desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4), which account for approximately 11% of the total dose.

The plasma elimination half-life of ciprofloxacin in healthy volunteers following a ProQuin XR 500 mg dose was approximately 4.5 hours. Following a 500 mg oral dose of ProQuin XR, 29.6% was excreted in the urine over 24 hours as unchanged drug for both formulations.

Following administration of a single 500 mg dose of ProQuin XR, approximately 41% of the oral dose was excreted into the urine over 96 hours as unchanged drug and metabolites. The urinary excretion of ciprofloxacin was virtually complete within 24 hours after dosing. Urinary excretion is a main route of elimination of ciprofloxacin and its urinary concentrations relative to the MICs of the bacterial species may be important to understanding the efficacy of ciprofloxacin for the treatment of urinary tract infections. The mean urinary ciprofloxacin concentration after dosing with ProQuin XR 500 mg qd and CIPRO 250 mg bid are shown in the following table:

The renal clearance of ciprofloxacin following administration of ProQuin XR, which is approximately 304 - 383 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination.

Approximately 43% of the oral dose of ProQuin XR is recovered from the feces as unchanged drug and metabolites within 7 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms. The bactericidal action of ciprofloxacin results from inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases) which are required for bacterial DNA replication, transcription, repair and recombination. The mechanism of action of quinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Resistance to ciprofloxacin in vitro develops slowly (multiple step mutation). Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between <10^-9 to 1x10^-6.

Ciprofloxacin is less active when tested at acidic pH. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the MIC by more than a factor of 2.

Ciprofloxacin has been shown to be active against most strains of the following organisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-negative microorganisms

    Escherichia coli

    Klebsiella pneumoniae

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

Ciprofloxacin exhibits in vitro MICs of 1 mcg/mL or less against most (>90%) strains of the following microorganisms; however, the safety and effectiveness of ProQuin XR in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative microorganisms

    Proteus mirabilis

Interpretive criteria for urinary isolates have not been established for ProQuin XR. Interpretive criteria established based on systemic drug levels may not be appropriate for uncomplicated urinary tract infections.

ProQuin XR is indicated only for the treatment of uncomplicated urinary tract infections (acute cystitis) caused by susceptible strains of the designated microorganisms uled below. ProQuin XR is not interchangeable with other ciprofloxacin extended-release or immediate release oral formulations. See DOSAGE AND ADMINISTRATION for specific recommendations.

Uncomplicated urinary tract infections (acute cystitis) caused by Escherichia coli and Klebsiella pneumoniae.

THE SAFETY AND EFFICACY OF PROQUIN XR IN TREATING PYELONEPHRITIS, COMPLICATED URINARY TRACT INFECTIONS, AND INFECTIONS OTHER THAN UNCOMPLICATED URINARY TRACT INFECTIONS HAVE NOT BEEN DEMONSTRATED. Alternative therapy should be considered for patients who remain symptomatic or develop fever and back pain while on treatment with ProQuin XR.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ProQuin XR and other antibacterial drugs, ProQuin XR should only be used to treat uncomplicated urinary tract infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and sensitivity information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

ProQuin XR is contraindicated in persons with a history of hypersensitivity to ciprofloxacin or any member of the quinolone class of antimicrobial agents, or any of the product components.

THE SAFETY AND EFFECTIVENESS OF PROQUIN XR IN PEDIATRIC PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS:Pediatric Use, Pregnancy, and Nursing Mothers subsections.)

Ciprofloxacin, as with other members of the quinolone class, causes arthropathy and/or chondroplasia in immature dogs. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. The relevance of these findings to the clinical use of ciprofloxacin is unknown. (See ANIMAL PHARMACOLOGY)

Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.

Quinolones, including ciprofloxacin, may also cause CNS events, including nervousness, agitation, insomnia, anxiety, nightmares, or paranoia. (See WARNINGS)

Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while being treated with some members of the quinolones class of drugs. Excessive sunlight should be avoided. Therapy with ciprofloxacin should be discontinued if phototoxicity occurs.

Prescribing ProQuin XR in the absence of a strongly suspected bacterial infection is unlikely to benefit the patient and increases the risk of the development of drug-resistant bacteria.

Patients should be advised:

• that antibacterial drugs, including ProQuin XR, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ProQuin XR is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ProQuin XR or other antibacterial drugs in the future.
• that ProQuin XR should only be used to treat uncomplicated urinary tract infections (also known as bladder infections). The safety and efficacy of ProQuin XR to treat other urinary tract or non-urinary tract infections have not been studied.
• that ProQuin XR should be taken with a main meal of the day, preferably the evening meal. The patient should not take more than one ProQuin XR tablet per day, even if the patient misses a dose
• that ProQuin XR tablets should be taken whole and never split, crushed, or chewed.
• that concomitant administration of ProQuin XR with aluminum or magnesium-containing antacids, sucralfate, VIDEX^®(didanosine) chewable buffered tablets or pediatric powder, metal cations such as iron and calcium, and multivitamin preparations containing zinc should be avoided. ProQuin XR should be administered at least 4 hours before or 2 hours after these products. (See CLINICAL PHARMACOLOGY: Drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS: Drug Interactions)
• that ProQuin XR should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone, since the absorption of ciprofloxacin may be significantly reduced. However, ProQuin XR may be taken with a meal that contains these products. (See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions)
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue ProQuin XR at the first sign of a skin rash or other allergic reaction and contact their physician.
• to avoid excessive sunlight or artificial ultraviolet (UV) light while receiving ProQuin XR and to discontinue therapy if phototoxicity occurs.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, patients should discontinue treatment and contact their physician.
• that if they experience pain, inflammation, or rupture of a tendon to discontinue treatment, to inform their physician, and to rest and refrain from exercise.
• to contact their doctor if they do not feel better or if they develop fever and back pain while or after taking ProQuin XR.
• that ProQuin XR may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.
• that ProQuin XR may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is a history of this condition.

Rodent carcinogenicity studies were not required. Two in in vitro mutagenicity tests were conducted with ciprofloxacin:

• Bacterial Reverse Mutation Assay; negative for mutagenicity in the presence and absence of an S-9 metabolic activation system.
• Chinese Hamster Ovary (CHO) Chromosomal Aberration Assay; positive for inducing chromosomal aberrations.

In addition to the in vitro genotoxicity assays, an in vivo rat micronucleus study with ciprofloxacin was negative.

Fertility studies performed with male and female rats at oral doses of ciprofloxacin up to 600 mg/kg/day (approximately 10-fold the recommended 500 mg therapeutic dose based upon body surface area) revealed no evidence of impairment.

Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue ciprofloxacin taking into account the importance of the drug to the mother.

The safety and effectiveness of ProQuin XR in pediatric patients and adolescents less than 18 years of age have not been established. Quinolones, including ciprofloxacin, cause arthropathy in juvenile animals. (See WARNINGS)

Clinical experience with ProQuin XR did not include sufficient number of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Reported clinical experience with other formulations of ciprofloxacin has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is substantially excreted by the kidney and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. (See CLINICAL PHARMACOLOGY and DOSAGE and ADMINISTRATION)

Two clinical trials enrolled 1,095 patients, of whom 547 patients received ProQuin XR 500 mg once daily and 538 patients received CIPRO 250 mg twice daily for 3 days. The patients were followed for approximately 5 weeks after the end of study drug dosing. Most adverse events reported were described as mild to moderate in severity and required no treatment. ProQuin XR was discontinued due to adverse reactions thought to be drug-related in 0.5% of patients.

The incidence of all adverse events (regardless of relationship to study drug) reported for at least 2% of patients treated with ProQuin XR during the entire 5-week study period was as follows: fungal infection (2.6%), nasopharyngitis (2.6%), headache (2.4%), and micturition urgency (2.0%).

The incidence of adverse events (regardless of relationship to study drug) reported for at least 1% of patients treated with ProQuin XR during study drug treatment and up to 3 days after study drug was headache (1.5%).

The incidence of adverse events, judged by investigators to be at least possibly drug-related, occurring any time during the study in at least 1% of ProQuin XR-treated patients was fungal infection (1.6%).

Additional uncommon events, judged by the investigator to be at least possibly drug-related, occurring at any time during the study in less than 1% of ProQuin XR-treated patients were:

Cardiac Disorders: ventricular bigeminy.

Immune System Disorders: hypersensitivity.

Gastrointestinal Disorders: abdominal pain, nausea, diarrhea, dyspepsia, aggravated irritable bowel syndrome, lower abdominal pain, vomiting.

General Disorders: suprapubic pain, fatigue, pain, rigors, tenderness.

Infections and Infestations: urinary tract infection, fungal vaginosis, bacterial vaginitis, vaginal candidiasis, vaginal infection, vaginitis.

Investigations: blood bilirubin increased, alanine aminotransferase increased, abdominal aortic bruit, aspartate aminotransferase increased, body temperature increased.

Musculoskeletal and Connective Tissue Disorders: joint swelling, muscle spasms, night cramps.

Nervous System Disorders: headache, dizziness, disturbance in attention, paresthesia.

Renal and Urinary Disorders: micturition urgency, dysuria, urinary frequency, abnormal urine odor.

Reproductive System and Breast Disorders: female genital pruritus.

Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.

Skin/Subcutaneous TissueDisorders: rash, pruritus, urticaria.

The following adverse events, some of them life threatening, regardless of incidence or relationship to drug, have been reported during clinical trials and from worldwide post-marketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy, and all indications). Because these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or a causal relationship to drug exposure. The events in alphabetical order are:

Abnormal gait, achiness, acidosis, agitation, agranulocytosis, allergic reactions (ranging from urticaria to anaphylactic reactions), amylase increase, anemia, angina pectoris, angioedema, anosmia, anxiety, arrhythmia, arthralgia, ataxia, atrial flutter, bleeding diathesis, blurred vision, bronchospasm, C. difficile associated diarrhea, candidiasis (cutaneous, oral), candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, cholestatic jaundice, chromatopsia, confusion, convulsion, delirium, depression, diplopia, drowsiness, dysphagia, dyspnea, edema (conjunctivae, face, hands, laryngeal, lips, lower extremities, neck, pulmonary), epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, fever, fixed eruptions, flushing, gastrointestinal bleeding, gout (flare up), grand mal convulsion, gynecomastia, hallucinations, hearing loss, hematuria, hemolytic anemia, hemoptysis, hemorrhagic cystitis, hepatic failure, hepatic necrosis, hepatitis, hiccup, hyperesthesia, hyperpigmentation, hypertension, hypertonia, hypoesthesia, hypotension, ileus, insomnia, interstitial nephritis, intestinal perforation, jaundice, joint stiffness, lethargy, lightheadedness, lipase increase, lymphadenopathy, malaise, manic reaction, marrow depression, migraine, moniliasis (oral, gastrointestinal, vaginal), mouth dryness, myalgia, myasthenia, myasthenia gravis (possible exacerbation), myocardial infarction, myoclonus, nephritis, nightmares, nystagmus, oral ulceration, pain (arm, back, breast, chest, epigastric, eye, extremities, foot, jaw, neck, oral mucosa), palpitation, pancreatitis, pancytopenia, paranoia, paresthesia, peripheral neuropathy, perspiration (increased), petechia, phlebitis, phobia, pleural effusion, polyuria, postural hypotension, prothrombin time prolongation, pseudomembranous colitis (the onset of symptoms may occur during or after antimicrobial treatment), pulmonary embolism, purpura, renal calculi, renal failure, respiratory arrest, respiratory distress, restlessness, serum sickness-like reaction, Stevens-Johnson syndrome, sweating, syncope, tachycardia, taste loss, tendonitis, tendon rupture, tinnitus, torsade de pointes, toxic epidermal necrolysis, toxic psychosis, tremor, twitching, unresponsiveness, urethral bleeding, urinary retention, urination (frequent), vaginal pruritus, vasculitis, ventricular ectopy, vesicles, visual acuity (decreased), visual disturbances (flashing lights, change in color perception, overbrightness of lights), weakness.

The following laboratory adverse events were reported for ProQuin XR-treated patients during clinical trials: anemia, blood bilirubin increased, alanine aminotransferase increased, aspartate aminotransferase increased, platelet count decreased, and hematuria. All events were reported for <1% of ProQuin XR-treated patients, except for hematuria (1.2%).

The following adverse laboratory changes, in alphabetical order, regardless of incidence or relationship to drug, have been reported in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and all indications):

Decreases in blood glucose, BUN, hematocrit, hemoglobin, leukocyte counts, platelet counts, prothrombin time, serum albumin, serum potassium, total serum protein, uric acid.

Increases in alkaline phosphatase, ALT (SGPT), AST (SGOT), atypical lymphocyte counts, blood glucose, blood monocytes, BUN, cholesterol, eosinophils counts, LDH, platelet counts, prothrombin time, sedimentation rate, serum amylase, serum bilirubin, serum calcium, serum cholesterol, serum creatinine phosphokinase, serum creatinine, serum gamma-glutamyl transpeptidase (GGT), serum potassium, serum theophylline (in patients receiving theophylline concomitantly), serum triglycerides, uric acid.

Others: albuminuria, change in serum phenytoin, crystalluria, cylindruria, immature WBCs, leukocytosis, methemaglobinemia, pancytopenia.

In the event of an acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or peritoneal dialysis. Serious adverse effects were not observed in rats receiving single oral doses of ciprofloxacin as high as 2,000 mg/kg.

ProQuin XR and other oral formulations of ciprofloxacin are not interchangeable. ProQuin XR should be administered orally once daily for 3 days with a main meal of the day, preferably the evening meal. ProQuin XR should be administered at least 4 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, VIDEX^®(didanosine) chewable/buffered tablets or pediatric powder, metal cations such as iron, and multivitamin preparations containing zinc.

ProQuin XR tablets should be taken whole and never split, crushed, or chewed.

Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternate pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. No dosage adjustment is required for patient with uUTI and mild to moderate renal impairment. The efficacy of ProQuin XR has not been studied in patients with severe renal impairment. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS: Geriatric Use)

No dosage adjustment is required with ProQuin XR in patients with stable chronic cirrhosis. However, the pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency have not been fully elucidated. (See CLINICAL PHARMACOLOGY: Special Populations)

ProQuin XR is available as blue film-coated tablets containing 500 mg ciprofloxacin. The tablet is debossed with “500”on one side and “DMI” on the other side.

Package                                             Strength                                         NDC Code

Buler 3 Pack                                       500 mg                                           15456-001-03

Bottles of 30                                        500 mg                                           15456-001-30

Bottles of 50                                        500 mg                                           15456-001-50

Store ProQuin XR at 25 °C (77 °F); excursion permitted to 15-30 °C (59-86 °F)

There were no indications of gastrointestinal or other toxic effects due to oral administration of ProQuin XR tablets to male and female beagle dogs at doses up to 1000 mg/day for 28 days (approximately 2.6- and 4.9-fold [male and female dogs, respectively] the recommended therapeutic dose based upon AUC measures of systemic exposure).

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

Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with the fluoroquinolone class of drugs. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals. In contrast, crystalluria is rare in man since human urine is typically acidic.

In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effects of quinolones.

Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals. There was no indication of ocular toxicity in the dog study cited above.

ProQuin XR was evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in a randomized, double-blind, controlled trial conducted in the US. This study compared ProQuin XR (500 mg once daily for 3 days) with ciprofloxacin immediate-release tablets (CIPRO 250 mg twice daily for 3 days). Of the 1,037 patients enrolled, 524 were randomly assigned to the ProQuin XR treatment group and 513 were randomly assigned to the control group. A total of 272 (52%) patients in the ProQuin XR group and 251 (49%) in the CIPRO group were evaluable for efficacy and included in the Per-Protocol population. The primary efficacy variable was bacteriologic eradication of the baseline organism(s) with no new infection at the Test-of-Cure (TOC) visit (Day 4 to 11 post-therapy).

The bacteriological eradication and clinical success rates were similar for both treatment groups. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (ProQuin XR minus control group) are given in the following table:

The bacteriological eradication rates for baseline organisms at the TOC visit were 93% (254/272) for ProQuin XR and 90% (225/251) for CIPRO. Of the patients with their baseline organism eradicated, new infections were detected in 42/254 (16.5%) ProQuin XR-treated patients and 32/225 (14.2%) CIPRO-treated patients at the TOC visit. Gram-negative rods were responsible for new infections in 10 ProQuin XR-treated patients and 7 CIPRO-treated patients, and Enterococcus species were isolated in 24 ProQuin XR-treated patients, and 20 CIPRO-treated patients.

• National Committee for Clinical Laboratory Standards. Methods for Dilution

  Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Sixth Edition.

  Approved Standard NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA,

  January, 2003.

• National Committee for Clinical Laboratory Standards. Performance Standards

  for Antimicrobial Disk Susceptibility Tests Eighth Edition. Approved Standard

  NCCLS Document M2-A8, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2003.

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©2005 Depomed, Inc.

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PRO-001b Issued October 2005