Read p851Ð861 text version

Hospital Pharmacy Volume 38, Number 9, pp 851­861 2003 Wolters Kluwer Health, Inc.

FORMULARY DRUG REVIEWS

Gemifloxacin Mesylate

Dennis J. Cada, PharmD, FASHP, FASCP* (Editor), Terri Levien, PharmD, and Danial E. Baker, PharmD, FASCP, FASHP Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late Phase III trials. The monographs are targeted to your Pharmacy and Therapeutics Committee. Subscribers also receive monthly onepage summary monographs on the agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and CD ROM forms and are available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The September 2003 monograph topics are tositumomab, omalizumab, emtricitabine, testosterone buccal system mucoadhesive, and alfuzosin. The DUE is on omalizumab.

*Executive Editor, The Formulary; Drug Information Pharmacist, Drug Information Center, Washington State University Spokane; Director, Drug Information Center and Professor of Pharmacy Practice; College of Pharmacy, Washington State University Spokane, 310 North Riverpoint Boulevard, PO Box 1495, Spokane, WA 99210-1495.

Generic Name: GEMIFLOXACIN MESYLATE Proprietary Name: Factive (GeneSoft Pharmaceuticals) Approval Rating: 1S Therapeutic Class: Fluoroquinolones Similar Drugs: Gatifloxacin, Levofloxacin, Moxifloxacin, Trovafloxacin

nity-acquired pneumonia caused by S. pneumoniae (including penicillin-resistant strains, penicillin MIC greater than or equal to 2 mcg/mL), H. influenzae, M. catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae.1 CLINICAL PHARMACOLOGY Gemifloxacin is a fluoroquinolone antimicrobial with broad-spectrum activity against Gram-positive and Gram-negative organisms. It has a spectrum of activity most similar to moxifloxacin and trovafloxacin. Gemifloxacin has activity against a variety of respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae,

INDICATIONS Gemifloxacin is indicated for the treatment of acute exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis and the treatment of mild-to-moderate commu-

Haemophilus parainfluenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, and Staphylococcus aureus.2 Gemifloxacin also has activity against Staphylococcus epidermidis, Salmonella sp., Shigella sp., Neisseria gonorrhoeae, and some anaerobes (Peptostreptococcus, Porphyromonas, and Fusobacterium sp.).3­7 Table 1 summarizes MIC90 data for gemifloxacin and several other fluoroquinolones against common respiratory pathogens. In a clinical trial, gemifloxacin retained activity (MIC 0.25 mg/L) against one S. pneumoniae isolate demonstrating resistance to ofloxacin (MIC 64 mg/L), ciprofloxacin (MIC greater than 16 mg/L), grepafloxacin (MIC 8 mg/L), levofloxacin (MIC 16 mg/L), and trovafloxacin (MIC 8 mg/L).8 Other in vitro studies have demonstrated gemifloxacin activity with MICs less than 0.5 mg/L against ciprofloxacinand ofloxacin-intermediate and resistant S. pneumoniae.9­12 Gemifloxacin had greater ex vivo bactericidal activity than trovafloxacin against a penicillinand ciprofloxacin-resistant strain of S. pneumoniae.13 Gemifloxacin had greater activity ex vivo in urine than trovafloxacin against Escherichia coli and Staphylococcus saprophyticus.14 Compared with ofloxacin, gemifloxacin had greater urinary bactericidal titers for Gram-positive uropathogens and lower urinary bactericidal titers for Gram-negative

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Table 1. MIC90s of Several Available Fluoroquinolones Against Common Respiratory Pathogens

Organism MSSA MRSA S. pneumoniae No. Isolates 689 69 674 72 347 2632 2020 50 909 550 417 88 Gemi 0.06 0.03 4 8 0.03 0.03 0.03 0.016 0.06 0.03 0.03 0.03 0.03 0.03 0.12 0.25 0.25 1 0.5 0.008 0.03 0.008 0.004 0.008 0.008 1 0.25 0.008 0.015 0.008 0.004 0.015 0.015 16 8 Cipro 1 1 > 16 > 16 2 2 2 1 2 2 2 2 2 4 >4 > 16 64 > 32 0.016 0.06 0.016 0.015 0.015 2 0.5 0.03 0.06 0.03 0.015 0.06 16 8 Gati 0.5 0.5 1 0.015 0.008 0 0.03 0.03 Levo 0.5 0.25 16 > 16 1 1 1 1 1 1 1 1 1 1 2 4 8 > 32 0.016 0.06 0.03 0.015 0.015 2 0.5 0.06 0.06 0.06 0.03 0.06 0.06 16 8 Moxi 0 0.12 0.25 0.25 1 4 0.03 0.03 0.03 0.03 0.06 0.06 Trova 0.06 8 0.12 0.25 0.12 0.25 0.25 0.25 0.5 4 4 0.016 0.016 0.03 0.5 0.016 0.016 0.03 16 Reference 16 17 16 17 9 10 16 17 18 19 20 21 10 10 10 11 16 22 23 9 16 17 18 19 21 16 17 9 16 17 18 19 21 16 17

S. pneumoniae, 411 penicillin resistant S. pneumoniae, 649 macrolide resistant S. pneumoniae, reduced ciprofloxacin or ofloxacin susceptibility H. influenzae 142 179 30 29 28 256 1510 50 859 290 96 1575 149 184 471 50 388 205 95 926 72

K. pneumoniae M. catarrhalis

P. aeruginosa

NCCLS breakpoints: 2 mcg/mL (susceptible) and 8 mcg/mL (resistant) levofloxacin; 1 mcg/mL (susceptible) and 4 mcg/mL (resistant) gatifloxacin and moxifloxacin; 1 mcg/mL (susceptible) and 4 mcg/mL (resistant) ciprofloxacin; and 2 mcg/mL (susceptible) and 8 mcg/mL (resistant) trovafloxacin MSSA = methicillin-susceptible Staphylococcus aureus; MRSA = methicillin-resistant Staphylococcus aureus

uropathogens. Ofloxacin-resistant uropathogens should also be regarded as gemifloxacin-resistant.15 Although gemifloxacin has lower MIC90 values than other fluoroquinolones, it also has a much

lower breakpoint. The gemifloxacin breakpoint is less than or equal to 0.25 mcg/mL (susceptible) and greater than or equal to 1 mcg/mL (resistant) for Enterobacteriaceae, less than or equal to 0.12 mcg/mL (susceptible) for H.

influenzae and H. parainfluenzae, and less than or equal to 0.12 mcg/mL (susceptible) and greater than or equal to 0.5 mcg/mL (resistant) for S. pneumoniae.1 Singledisk susceptibility tests should be interpreted by the following crite-

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ria: zone diameter greater than or equal to 20 mm (susceptible) and less than or equal to 15 mm (resistant) for Enterobacteriaceae, greater than or equal to 18 mm (susceptible) for H. influenzae and H. parainfluenzae, and greater than or equal to 23 mm (susceptible) and less than or equal to 19 mm (resistant) for S. pneumoniae.1 PHARMACOKINETICS Peak plasma gemifloxacin concentrations are reached within 0.5 to 2 hours following oral administration.1,24­31 Oral bioavailability with the 320 mg tablets is approximately 71%.1 Administration with food resulted in a slight, clinically unimportant delay in the time-topeak concentration and reduction in peak concentration and area under the curve (AUC).26 Following a 320 mg oral dose, mean peak plasma concentrations ranged from 0.86 mg/L to 2.33 mg/L.24,27­30 In healthy volunteers, the mean trough plasma concentrations were 0.06 to 0.07 mcg/mL following 320 mg once daily.25 Steady-state is achieved by the third day of dosing.1 Plasma protein binding is approximately 60% to 70%.25,26 Concentrations in bronchoalveolar lavage fluid exceed those in the plasma. After 5 days of dosing with gemifloxacin 320 mg daily, mean tissue/plasma ratios were 90.5 for bronchoalveolar macrophages, 1.99 for epithelial lining fluid, and 7.21 for bronchial mucosa.1 Mean penetration into inflammatory blister fluid was 69%, with a peak concentration of 0.74 mg/L reached at 3.4 hours after oral gemifloxacin administration.24 The median tissue/plasma ratio was 0.7 in prostatic secretions and 7.5 in ejaculate following a single 320 mg dose.29 In an animal meningitis model, gemifloxacin had good penetration in the cere-

brospinal fluid (22% to 33%).32 The mean serum elimination half-life is 6 to 8 hours.24,25,27­30 Gemifloxacin undergoes limited hepatic metabolism, with all metabolites accounting for less than 10% of the administered dose.1 Gemifloxacin has not been reported to inhibit or induce any of the clinically important cytochrome P450 isozymes.2,33 Gemifloxacin and its metabolites are excreted in the feces and urine.1 Renal clearance is 150 to 160 mL/min, slightly exceeding glomerular filtration rate (120 mL/min) and suggesting active renal secretion.27,30 The amount excreted unchanged in the urine is 25% to 40% of the administered dose.15,24,25,27,29 The pharmacokinetics of gemifloxacin in the elderly did not differ from those in younger subjects. In healthy elderly volunteers, the gemifloxacin half-life was 8 to 10 hours, renal clearance was 225 mL/min, and 30% to 40% of the dose was excreted in the urine unchanged.31 Gemifloxacin pharmacokinetics have not been studied in pediatric patients.1 In patients with mild-to-moderate hepatic impairment, the gemifloxacin AUC was increased 34% and peak concentrations were increased 25% compared with healthy volunteers. In patients with severe hepatic impairment, the gemifloxacin AUC was increased 45% and the peak concentration was increased 41% compared with healthy volunteers. Gemifloxacin elimination half-life was not affected. Routine dosage adjustments are not recommended in patients with mild-to-severe hepatic impairment.1 In patients with renal impairment, the gemifloxacin AUC was increased 70%. Dosage adjustments are recommended in patients with creatinine clearance 40

mL/min or less.1 Hemodialysis removes approximately 20% to 30% of an oral gemifloxacin dose.1 COMPARATIVE EFFICACY Community-Acquired Pneumonia Gemifloxacin 320 mg once daily was compared with trovafloxacin 200 mg once daily in a randomized, double-blind study enrolling 571 patients with community-acquired pneumonia in the US, Mexico, and Spain. The duration of treatment was 7 days, with extension to 14 days permitted for patients with severe infection, an atypical pathogen, or at the investigator's discretion. Two-thirds of patients were treated for 7 days. The most common pathogens were Mycoplasma pneumoniae and S. pneumoniae. In per-protocol assessment at follow-up (14 to 21 days after completion of therapy), clinical success (sufficient improvement with no further antimicrobial therapy necessary) was reported for 95.8% of patients (228/238) in the gemifloxacin group and 93.6% (218/233) in the trovafloxacin group. In the intent-to-treat population, clinical success at follow-up was 87.6% (254/290) with gemifloxacin and 81.1% (228/281) with trovafloxacin (95% CI 0.5 to 12.4 for the treatment difference). S. pneumoniae eradication was 100% (18/18) with gemifloxacin and 93% (14/15) with trovafloxacin. Gemifloxacin produced eradication or presumed eradication of 94% (116/123) of key initial pathogens; trovafloxacin produced eradication or presumed eradication of 95% (104/109). Seven organisms in the gemifloxacin group and five in the trovafloxacin group persisted or were presumed to persist. Combined clinical and bacteriologic response at follow-up in the intentto-treat population was 84.2% in

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the gemifloxacin group and 80.4% in the trovafloxacin group. Adverse effects were similar in the two groups.8 In a randomized, open-label study, gemifloxacin was compared with IV ceftriaxone/oral cefuroxime in 341 patients with community-acquired pneumonia. Patients from 69 centers in 15 countries (primarily the US, Poland, Canada, Germany, and Italy) were randomized to therapy with either oral gemifloxacin 320 mg once daily for 7 to 14 days or IV ceftriaxone 2 g once daily for 1 to 7 days followed by oral cefuroxime 500 mg twice daily for 1 to 13 days (for a total of up to 14 days). A macrolide was administered concomitantly to 38% of patients in the cephalosporin-treatment group. The most frequently isolated pathogens were S. pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and H. influenzae. Among clinically evaluable patients, the clinical success rate at follow-up (21 to 28 days after completion of therapy) was 92.2% (107/116) for gemifloxacin and 93.4% (113/121) for ceftriaxone/cefuroxime. Bacteriologic success at follow-up in the bacteriologically evaluable patients was 90.6% (58/64) with gemifloxacin and 87.3% (55/63) for ceftriaxone/cefuroxime. Adverse events were similar in the two treatment groups.34 Gemifloxacin labeling also contains information from three additional studies evaluating gemifloxacin in community-acquired pneumonia. Gemifloxacin 320 mg once daily for 7 days was compared with amoxicillin/clavulanate potassium 500 mg/125 mg three times daily for 10 days in 228 patients. Clinical response at follow-up was achieved in 88.7% of patients in the gemifloxacin group and 87.6%

of patients in the amoxicillin/clavulanate potassium group. In two uncontrolled studies evaluating gemifloxacin 320 mg once daily for 7 days, clinical response was achieved in 91.7% (154/168) and 89.8% (132/147).1 Gemifloxacin was also evaluated in an international open-label study enrolling 216 patients with community-acquired pneumonia and 261 patients with acute exacerbation of chronic bronchitis. Patients were enrolled from centers in Central and South America, Asia, and Europe and received gemifloxacin 320 mg once daily for 7 days. The most frequently isolated pathogens were H. influenzae, S. pneumoniae, C. pneumoniae, S. aureus, and K. pneumoniae. Clinical success at follow-up (21 to 28 days after completion of therapy) in the intent-to-treat population was 83.1% for patients with acute exacerbation of chronic bronchitis and 82.9% for patients with community-acquired pneumonia. At follow-up, bacteriologic success in the patients with pretreatment bacteriologic information available was 77.9% (60/77) in the community-acquired pneumonia population and 91.2% (52/57) in the acute exacerbation of chronic bronchitis population. Treatment was deemed successful in 100% (8/8) of patients with acute exacerbation of chronic bronchitis due to S. pneumoniae and 66% (12/18) with community-acquired pneumonia due to S. pneumoniae. Overall presumed eradication of all pathogens in the bacteriologic intent-to-treat population was 93.7%.35 Acute Exacerbation of Chronic Bronchitis Gemifloxacin was compared with clarithromycin in a doubleblind, double-dummy study con-

ducted in 93 centers in Europe and North America and enrolling 712 patients with acute exacerbation of chronic bronchitis. Patients received gemifloxacin 320 mg once daily for 5 days (351 patients) or clarithromycin 500 mg twice daily for 7 days (361 patients). Clinical success at follow-up (study days 13 to 24) was 85.4% in the gemifloxacin group and 84.6% in the clarithromycin group in the perprotocol population and 79.5% for gemifloxacin and 78.2% for clarithromycin in the intent-to-treat population. Peak flow improved to a similar extent in the two groups (from 56% to 62.6% in the gemifloxacin group and from 54.3% to 59.8% in the clarithromycin group from baseline to follow-up at study days 13 to 24). H. influenzae was the most frequently isolated pathogen. Bacteriologic success was 86.7% in the gemifloxacin group and 73.1% for clarithromycin at follow-up (study days 13 to 24) in the perprotocol patient population. At follow-up at study days 25 to 38, bacteriologic success was statistically greater in the gemifloxacin group than the clarithromycin group in this population (81.8% vs 62%; treatment difference 19.8%; 95% CI 2.2 to 37.5), but not in the intent-to-treat population (71.9% vs 56.1%; treatment difference 15.9%; 95% CI ­0.8 to 32.6). The median time to eradication of H. influenzae was 1 day in the gemifloxacin group and 2 days in the clarithromycin group (P = 0.02). The most common adverse effects were diarrhea and nausea in the gemifloxacin group and diarrhea and taste perversion in the clarithromycin group.36 A long-term phase of this study including 438 patients from the US and Canada (214 receiving gemifloxacin and 224 receiving clar-

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ceftriaxone/cefuroxime (treatment difference = 10.5, 95% CI 0.7 to 20.4). The median time to discharge was 9 days in the gemifloxacin group compared with 11 days in the ceftriaxone/cefuroxime group (P = 0.04). Bacteriologic success for the bacteriologic intent-to-treat population was 81.3% for gemifloxacin and 82.4% for ceftriaxone/ cefuroxime at the end of therapy. Corresponding values at follow-up were 62.5% for gemifloxacin and 60.8% for ceftriaxone/cefuroxime. Diarrhea occurred more frequently in the gemifloxacin group (8.1% vs 0.7%) and largely accounted for the overall increased incidence of adverse effects potentially related to gemifloxacin (11% vs 5.9%).40 SINUSITIS A 5-day course of gemifloxacin therapy was compared with a 7day course of gemifloxacin in a double-blind study conducted in Europe and Canada enrolling 421 patients with acute bacterial sinusitis. Patients were enrolled if symptoms fit eligibility requirements; however, radiological confirmation of the diagnosis was required within 72 hours of randomization. Patients were randomized to therapy with gemifloxacin 320 mg once daily for either 5 days (218 patients) or 7 days (203 patients). Therapy for 5 days was as effective as therapy for 7 days. Clinical response at follow-up (study days 18 to 25) in the per-protocol population was 87.3% in the 5-day group and 86.9% in the 7-day group. In the intent-to-treat population, clinical success at follow-up was 83.5% in the 5-day group and 84.2% in the 7-day group. Combined clinical and radiologic response in the intent-to-treat population was achieved in 78.9% in the 5-day group and 77.8% in the

7-day group. Diarrhea, nausea, and rash were the most common adverse effects. Rash occurred in 1.4% of patients in the 5-day group and 5.9% of patients in the 7-day group.41 Gemifloxacin and cefuroxime axetil were compared in the treatment of acute bacterial sinusitis in a double-blind study enrolling 675 patients. Patients were randomized to therapy with gemifloxacin 320 mg once daily for 7 days (338 patients) or cefuroxime axetil 250 mg twice daily for 10 days (337 patients). Clinical success in the per-protocol population at followup (days 17 to 28) was 87.7% (249/284) with gemifloxacin and 88.9% (263/296) with cefuroxime axetil. Bacteriologic success at follow-up was 93.5% with gemifloxacin and 93.6% with cefuroxime axetil.42 CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS Gemifloxacin is contraindicated in patients with a history of hypersensitivity to gemifloxacin, other fluoroquinolones, or any of the product ingredients.1 Gemifloxacin may cause QT prolongation in some patients; the maximal change in QTc interval occurs approximately 5 to 10 hours after oral administration of gemifloxacin. Gemifloxacin was associated with a mean QT prolongation of less than 5 milliseconds.2 Higher doses of gemifloxacin show a doserelated impact on QT prolongation. The maximum prolongation change in the QTc with a dose of 480 mg was 5.5 msec and 640 mg produced a 16 msec change.2 Gemifloxacin should not be used in patients with a history of QTc prolongation, patients with uncorrected electrolyte disorders (hypokalemia or hypomagnesemia), and patients receiving class

IA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic agents. Gemifloxacin should be used with caution in conjunction with other agents known to prolong the QTc interval, and in patients with ongoing proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia. The recommended dose should not be exceeded, particularly in patients with renal or hepatic impairment. No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with gemifloxacin treatment in over 6775 patients, including 653 patients concurrently receiving agents known to prolong the QTc interval and five patients with hypokalemia.1,34,43 Rash occurred in 2.8% of patients treated with gemifloxacin in clinical trials, although the incidence in individual trials ranged from 1% to 32%.1,2. Gemifloxacin therapy should be discontinued in patients who develop a rash while on treatment.1 An increased incidence of rash has been observed in patients younger than 40 years of age, female patients, and postmenopausal females taking hormone therapy.1,2 The incidence of rash correlates with longer duration of therapy.41 Prolonging the duration of therapy beyond 7 days results in an increased rash incidence in all patient groups except men over the age of 40 years.1 Twothirds of the patients who developed a rash did so after 7 days of therapy, usually 8 to 10 days after starting therapy. Rash resolved within 7 days in 60% of cases and within 14 days in 80% of cases.1,2 The most frequently reported rash findings include macules, papules, and pruritus. Mucus membrane involvement has also been observed.2 The manufacturer has

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ithromycin) evaluated the proportion of patients who remained free of recurrence requiring additional antimicrobial therapy after resolution of the initial episode. Patients returned for follow-up for up to 26 weeks after study entry. More gemifloxacin-treated patients remained free of recurrence at week 26 (71% vs 58.5%, treatment difference 12.5%; 95% CI 2.46 to 22.59; P = 0.016). Fewer patients in the gemifloxacin group were hospitalized due to respiratory tract infectionrelated illness during the 26-week assessment (2.3% vs 6.3%; treatment difference ­4%; 95% CI ­7.67 to ­0.15; P = 0.059). Extrapolating this information, 25 patients would need to be treated with gemifloxacin rather than clarithromycin to prevent one additional hospitalization.36 Overall, gemifloxacin-treated patients spent 0.2 days hospitalized for respiratory tract infection-related illness over the 26-week study compared with 0.37 days per clarithromycintreated patient (46% reduction in hospital days per patient). The mean cost per patient per hospitalization was also reduced in the gemifloxacin group ($138 vs $258). The number of outpatient visits did not differ between groups. Overall, the total mean respiratory tract infection-related direct medical cost per patient was $302 in the gemifloxacin group and $429 in the clarithromycin group, with the difference in hospitalization costs accounting for 95% of the difference. When lost productivity costs (work and usual activities) were included, the total mean cost per patient was $1468 for gemifloxacin and $1797 for clarithromycin.37 Gemifloxacin was also compared with trovafloxacin in a double-blind, double-dummy Euro-

pean study enrolling 617 patients with acute exacerbation of chronic bronchitis. Patients were randomized to therapy with gemifloxacin 320 mg once daily for 5 days (303 patients) or trovafloxacin 200 mg once daily for 5 days (314 patients). Clinical success at followup (days 12 to 19) in the per-protocol population was 91.5% for gemifloxacin and 87.6% for trovafloxacin. In the intent-to-treat population, clinical success at follow-up was 89.4% for gemifloxacin and 83.1% for trovafloxacin (treatment difference 6.3%; 95% CI 0.9 to 11.7). The most commonly isolated pathogens were H. influenzae, M, catarrhalis, H. parainfluenzae, S. pneumoniae, and S. aureus. Bacteriologic per-protocol success was 86.8% with gemifloxacin and 82.4% with trovafloxacin. In these 112 bacteriologically evaluable patients, clinical success was 83% with gemifloxacin and 82% with trovafloxacin. More patients in the trovafloxacin group withdrew from the study (9.9% vs 5%, P = 0.02). Adverse effects occurred more frequently in the trovafloxacin group.38 Another study compared gemifloxacin 320 mg once daily for 5 days with levofloxacin 500 mg once daily for 7 days in 300 patients. Clinical success at followup in the per-protocol group was 88.2% with gemifloxacin and 85.1% with levofloxacin.1 Gemifloxacin was also compared with amoxicillin/clavulanic acid in a double-blind, doubledummy study enrolling 600 patients with acute exacerbation of chronic bronchitis. Patients were randomized to therapy with gemifloxacin 320 mg once daily for 5 days (304 patients) or amoxicillin/clavulanate 500/125 mg three times daily for 7 days (296

patients). Clinical success at follow-up (days 14 to 21) in the per-protocol group was 93.6% for gemifloxacin and 93.2% for amoxicillin/clavulanate. The most frequently isolated pathogens were M. catarrhalis, H. influenzae, S. pneumoniae, and S. aureus. Bacteriologic success at follow-up in the per-protocol bacteriologically evaluable population was 90.9% for gemifloxacin and 79.5% for amoxicillin/clavulanate (difference not significant; 95% CI ­3.3 to 26). Adverse events occurred with similar frequency in the two groups, although diarrhea occurred more commonly with amoxicillin/clavulanate (10.5% vs 2.3%, P < 0.01).39 In another study, open-label gemifloxacin was compared with sequential IV ceftriaxone followed by oral cefuroxime in an open-label study enrolling 274 adult hospitalized patients with acute exacerbation of chronic bronchitis. Patients were randomized to therapy with oral gemifloxacin 320 mg once daily for 5 days or IV ceftriaxone 1 g once daily for a maximum of 3 days followed by oral cefuroxime axetil 500 mg twice daily for a maximum of 7 days. Patients received a mean of 4.8 days of gemifloxacin compared with 7.8 days of ceftriaxone/cefuroxime. The median time to switch from ceftriaxone to cefuroxime was 3 days. The most frequently isolated pathogens were H. influenzae, S. pneumoniae, and M. catarrhalis. Clinical success at follow-up (days 21 to 28) in the per-protocol group was 86.8% (105/121) for gemifloxacin and 81.3% (91/112) for ceftriaxone/cefuroxime (treatment difference = 5.5, 95% CI ­3.9 to 14.9). Clinical success in the intent-to-treat cohort was 82.6% (114/138) for gemifloxacin and 72.1% (98/136) for

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agreed to conduct a comparative study of gemifloxacin (5000 patients) and an active control (2500 patients) with at least 10% of patients of African origin, 10% of Asian origin, and 10% of Hispanic origin to gain additional safety information, particularly with regard to rash.44 Elevations in liver enzymes occurred with similar frequency in gemifloxacin-treated and comparator-treated (ciprofloxacin, levofloxacin, clarithromycin/cefuroxime axetil, amoxicillin/clavulanate potassium, and ofloxacin) patients. The incidence was increased in patients receiving gemifloxacin doses of 480 mg per day or greater. Liver enzyme elevations were not associated with clinical symptoms. Liver enzyme elevations resolved following discontinuation of therapy. Doses in excess of 320 mg per day are not recommended.1,2,8,34,35 Other warnings and precautions are similar to the other fluoroquinolones, including use in children, adolescents, pregnant women, and lactating women; hypersensitivity reactions; tendon and cartilage effects; central nervous system effects; antibiotic-associated colitis; and photosensitivity reactions.1 ADVERSE REACTIONS The most commonly observed adverse events during gemifloxacin therapy have included diarrhea, rash, nausea, headache, abdominal pain, vomiting, and dizziness.1,2,8,34,35,36,38,39,41,45 In healthy volunteers, gemifloxacin 320 mg once daily for 7 days produced mild phototoxicity, similar to that observed with ciprofloxacin 500 mg twice daily for 7 days.46 In clinical trials, photosensitivity reactions were reported in 0.039% of patients.1

DRUG INTERACTIONS Administration of gemifloxacin 10 minutes before an aluminum and magnesium antacid (Maalox) resulted in an 85% reduction in the gemifloxacin AUC. Administration of gemifloxacin 3 hours after the antacid resulted in a 15% reduction in the AUC, which is unlikely to be clinically important. Administration of gemifloxacin 2 hours before the antacid did not result in clinically important changes in the gemifloxacin AUC (increased 3%). Similar results were observed with ferrous sulfate. Gemifloxacin should be administered at least 2 hours before or 3 hours after aluminum and magnesium antacids, ferrous sulfate, multivitamin products containing zinc or other metal cations, or Videx (didanosine) chewable/ buffered tablets and pediatric powder to minimize absorption interactions.1,2,47 When sucralfate was administered 3 hours prior to gemifloxacin, the gemifloxacin AUC was reduced 53% and peak concentration was reduced 69%. When sucralfate was given 2 hours after gemifloxacin, gemifloxacin bioavailability was not affected. Gemifloxacin needs to be given 2 hours before sucralfate to avoid any impact on absorption.1 In contrast, simultaneous administration with calcium carbonate only reduced the gemifloxacin AUC by 21% and the peak concentration by 17%. Administration of calcium carbonate 2 hours before or 2 hours after gemifloxacin had no effect on gemifloxacin exposure.48 Concomitant administration of gemifloxacin with omeprazole or cimetidine resulted in slight (approximately 10%), clinically unimportant increases in gemifloxacin peak concentration and AUC.1,28

Coadministration with probenecid results in a decrease in the renal clearance of gemifloxacin. Administration with cimetidine results in slight changes in the pharmacokinetic parameters of gemifloxacin.2 In drug interaction studies, gemifloxacin did not alter the pharmacokinetics or pharmacodynamics of theophylline, digoxin, warfarin, or oral contraceptives.1,33,49,50 DOSING Gemifloxacin may be administered with or without food.1,26 The recommended dose is 320 mg once daily for 7 days in the treatment of community-acquired pneumonia and for 5 days in the treatment of acute exacerbation of chronic bronchitis.1 In patients with creatinine clearance less than 40 mL/min and patients requiring routine hemodialysis or continuous ambulatory peritoneal dialysis, the dose should be reduced to 160 mg (1/2 tablet) once daily.1 PRODUCT AVAILABILITY Gemifloxacin received FDA approval in April 2003.44 It is available as 320 mg scored tablets.1 A New Drug Application for gemifloxacin was originally filed in 1999 by SmithKline Beecham. In 2000, the FDA issued a nonapprovable letter. Additional studies were conducted in response to the FDA safety concerns regarding rash and hepatic safety. Following the merger of SmithKline Beecham and Glaxo Wellcome, GlaxoSmithKline returned all commercial rights to gemifloxacin back to its Korean manufacturer. GeneSoft Pharmaceuticals subsequently acquired the North American and European rights to gemifloxacin and sought approval.51

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CONCLUSION Gemifloxacin is a fluoroquinolone antibiotic with a broad spectrum of activity. It is effective in the treatment of communityacquired pneumonia and acute exacerbation of chronic bronchitis. It appears to offer no advantages over the other available fluoroquinolone antibiotics in the treatment of these types of infections and may be associated with a higher incidence of rash reactions. In vitro tests show that gemifloxacin generally has a lower MIC against various organisms; whether these lower MICs in the in vitro studies against S. pneumoniae and the other organisms translate into a clinical advantage remains to be proven. REFERENCES

1. Factive [package literature]. Genesoft Pharmaceuticals; April 3, 2003. 2. Food and Drug Administration. FDA Briefing Package: New Drug Application (NDA) 21-158 Factive (gemifloxacin). Anti-Infective Drugs Advisory Committee. March 4, 2003. www.fda.gov. Accessed March 3, 2003. 3. Fernandez-Roblas R, et al. In vitro activity of gemifloxacin (SB-265805) compared with 14 other antimicrobials against intestinal pathogens. J Antimicrob Chemother. 2000;46:1023­7. 4. Berron S, et al. In vitro susceptibilities of 400 Spanish isolates of Neisseria gonorrhoeae to gemifloxacin and 11 other antimicrobial agents. Antimicrob Agents Chemother. 2000;44:2543­4. 5. Goldstein EJC, et al. In vitro activity of gemifloxacin (SB 265805) against anaerobes. Antimicrob Agents Chemother. 1999;43:2231­5. 6. Goldstein EJC, et al. In vitro activity of gemifloxacin compared to seven other oral antimicrobial agents against aerobic and anaerobic pathogens isolated from antral sinus puncture specimens from patients with sinusitis. Diagn Micro Infect Dis. 2002;42:113­8. 7. Kleinkauf N, et al. Comparative in vitro activities of gemifloxacin, other quinolones, and nonquinolone antimi-

crobials against obligately anaerobic bacteria. Antimicrob Agents Chemother. 2001;45:1896­9. 8. File TM Jr, et al. Efficacy and safety of gemifloxacin in the treatment of community-acquired pneumonia: A randomized, double-blind comparison with trovafloxacin. J Antimicrob Chemother. 2001;48:67­74. 9. Rittenhouse S, et al. In vitro antibacterial activity of gemifloxacin and comparator compounds against common respiratory pathogens. J Antimicrob Chemother. 2000;45(suppl S1):23­7. 10.Hoban DJ, et al. A comparative in vitro surveillance study of gemifloxacin activities against 2632 recent Streptococcus pneumoniae isolates from across Europe, North America, and South America. Antimicrob Agents Chemother. 2000;44:3008­11. 11.Perez-Trallero E, et al. Activities of six different quinolones against clinical respiratory isolates of Streptococcus pneumoniae with reduced susceptibility to ciprofloxacin in Spain. Antimicrob Agents Chemother. 2002;46:2665­7. 12.Fuentes F, et al. In vitro susceptibility to gemifloxacin and trovafloxacin of Streptococcus pneumoniae strains exhibiting decreased susceptibility to ciprofloxacin. Eur J Clin Microbiol Infect Dis. 2000;19:137­9. 13.Prieto J, et al. Influence of diminished susceptibility of Streptococcus pneumoniae to ciprofloxacin on the serum bactericidal activity of gemifloxacin and trovafloxacin after a single dose in healthy volunteers. Int J Antimicrob Agents. 2001;18:231­8. 14.Garcia-Calvo G, et al. Antibacterial properties of gemifloxacin and trovafloxacin in urine ex vivo: Phase I study. Antimicrob Agents Chemother. 2001;45:1876­8. 15.Naber CK, et al. Urinary excretion and bactericidal activities of gemifloxacin and ofloxacin after a single oral dose in healthy volunteers. Antimicrob Agents Chemother. 2001;45:3524­30. 16.Hoban DJ, et al. Comparative in vitro activity of gemifloxacin and fluoroquinolones against recent European clinical isolates from a global surveillance study. Eur J Clin Microbiol Infect Dis. 2001;20:814­9. 17.McCloskey L, et al. In vitro activity of gemifloxacin against a broad range of

recent clinical isolates from the USA. J Antimicrob Chemother. 2000;45(suppl S1):13­21. 18.Deshpande LM, et al. Antimicrobial activity of advanced-spectrum fluoroquinolones tested against more than 2000 contemporary bacterial isolates of species causing community-acquired respiratory tract infections in the United States (1999). Diagn Micro Infect Dis. 2000;37:139­42. 19.Koeth LM, et al. Comparative in vitro activity of gemifloxacin to other fluoroquinolones and nonquinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999­2000. Int J Antimicrob Agents. 2002;19:33­7. 20.Hoban DJ, et al. Comparative in vitro activity of gemifloxacin, ciprofloxacin, levofloxacin and ofloxacin in a North American surveillance study. Diagn Micro Infect Dis. 2001;40:51­7. 21.Boswell FJ, et al. Comparison of the in vitro activities of several new fluoroquinolones against respiratory pathogens and their abilities to select fluoroquinolone resistance. J Antimicrob Chemother. 2002;50:495­502. 22.King A, et al. Comparative in vitro activity of gemifloxacin. J Antimicrob Chemother. 2000;45(suppl S1):1­12. 23.Davies TA, et al. Antipneumococcal activities of gemifloxacin compared to those of nine other agents. Antimicrob Agents Chemother. 2000;44:304­10. 24.Gee T, et al. Pharmacokinetics and tissue penetration of gemifloxacin following a single oral dose. J Antimicrob Chemother. 2001;47:431­4. 25.Allen A, et al. Multiple-dose pharmacokinetics and tolerability of gemifloxacin administered orally to healthy volunteers. Antimicrob Agents Chemother. 2001;45:540­5. 26.Allen A, et al. The effect of food on the bioavailability of oral gemifloxacin in healthy volunteers. Int J Antimicrob Agents. 2000;16:45­50. 27.Allen A, et al. Pharmacokinetics and tolerability of gemifloxacin (SB-265805) after administration of single oral doses to healthy volunteers. Antimicrob Agents Chemother. 2000;44:1604­8. 28.Allen A, et al. Effect of omeprazole on the pharmacokinetics of oral gemi-

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floxacin in healthy volunteers. Chemotherapy. 1999;45:496­503. 29.Naber KG, et al. Pharmacokinetics and penetration of gemifloxacin versus ofloxacin into prostate secretion and ejaculate after single oral dosing in volunteers [abstract]. 37th Infectious Disease Society America Annual Meeting; November 18­21, 1999; Philadelphia. 30.Davy M, et al. Pharmacokinetics and tolerability of gemifloxacin in healthy Japanese and Caucasian volunteers [abstract 2264]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17­20, 2000; Toronto. 31.Pay V, et al. Multiple-dose pharmacokinetics and tolerability of gemifloxacin following once-daily repeat oral 320 mg doses to healthy elderly volunteers [abstract 2265]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17­20, 2000; Toronto. 32.Cottagnoud P, et al. Gemifloxacin is efficacious against penicillin-resistant and quinolone-resistant pneumococci in experimental meningitis. Antimicrob Agents Chemother. 2002;46:1607­9. 33.Davy M, et al. Lack of effect of gemifloxacin on the steady-state pharmacokinetics of theophylline in healthy volunteers. Chemotherapy. 1999;45:478­84. 34.Lode H, et al. Oral gemifloxacin versus sequential therapy with intravenous ceftriaxone/oral cefuroxime with or without a macrolide in the treatment of community-acquired pneumonia: A randomized, open-label, multicenter study of clinical efficacy and tolerability. Clin Ther. 2002;11:1915­36. 35.Ball P, et al. Efficacy and safety of gemifloxacin 320 mg once-daily for 7 days in the treatment of adult lower res-

piratory tract infections. Int J Antimicrob Agents. 2001;18:19­27. 36.Wilson R, et al. A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther. 2002;24:639­52. 37.Halpern MT, et al. Cost-effectiveness of gemifloxacin: Results from the GLOBE study. Am J Health Syst Pharm. 2002;59:1357­65. 38.Ball P, et al. Efficacy of gemifloxacin in acute exacerbations of chronic bronchitis: A randomized, double-blind comparison with trovafloxacin. J Chemother. 2001;13:288­98. 39.File T, et al. Gemifloxacin versus amoxicillin/clavulanate in the treatment of acute exacerbations of chronic bronchitis. J Chemother. 2000;12:314­25. 40.Wilson R, et al. Oral gemifloxacin once daily for 5 days compared with sequential therapy with IV ceftriaxone/ oral cefuroxime (maximum 10 days) in the treatment of hospitalized patients with acute exacerbations of chronic bronchitis. Respir Med. 2003;97:242­9. 41.Ferguson BJ, et al. Short treatment durations for acute bacterial rhinosinusitis: Five days of gemifloxacin versus 7 days of gemifloxacin. Otolaryngol Head Neck Surg. 2002;127:1­6. 42.Ferguson BJ, et al. Efficacy of once daily gemifloxacin for 7 days compared with cefuroxime axetil twice daily for 10 days in the treatment of acute bacterial sinusitis [abstract 814]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17­20, 2000; Toronto. 43.Bird N, et al. Assessment of the effect of gemifloxacin on QTc interval in healthy volunteers [abstract 821]. 40th

Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17­20, 2000; Toronto. 44.Goldberger MJ. FDA approval letter: NDA21-158. April 4, 2003. www.fda.org. Accessed April 18, 2003. 45.Henkel TJ, et al. Safety of gemifloxacin in patients aged > 65 years with respiratory and urinary tract infections [abstract 813]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17­20, 2000; Toronto. 46.Vousden M, et al. Evaluation of phototoxic potential of gemifloxacin in healthy volunteers compared with ciprofloxacin. Chemotherapy. 1999;45: 512­20. 47.Allen A, et al. Effect of Maalox on the bioavailability of oral gemifloxacin in healthy volunteers. Chemotherapy. 1999;45:504­11. 48.Lode H, et al. Effect of calcium carbonate on the bioavailability of gemifloxacin in healthy volunteers [abstract 2266]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17­20, 2000; Toronto. 49.Vousden M, et al. Lack of pharmaco kinetic interaction between gemifloxacin and digoxin in healthy elderly volunteers. Chemotherapy. 1999;45:485­90. 50.Davy M, et al. Lack of effect of gemifloxacin on the steady-state pharmacodynamics of warfarin in healthy volunteers. Chemotherapy. 1999;45:491­5. 51.Anonymous [press release]. Genesoft acquires North American and European rights to the novel quinolone antibiotic Factive from LG Life Sciences. GeneSoft. October 22, 2002.

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Continuing Education Case Study Quiz

Goal -- The goal of this program is to inform the participant about gemifloxacin. Objectives -- At the completion of this program, the participant will be able to: 1. 3. 4. 5. Describe the pharmacology of gemifloxacin. Apply the information on gemifloxacin to a case study. Discuss the risks associated with the use of gemifloxacin. Be able to discuss the potential benefit of gemifloxacin in the treatment of a patient's condition. 10. The maximum recommended dose of gemifloxacin for GK for an acute exacerbation of chronic bronchitis is: A. 320 mg once daily B. 160 mg once daily C. 320 mg every other day D. 160 mg every other day 11. For GK, gemifloxacin should be dosed: A. Two hours before and 2 hours after her multivitamin B. Two hours before and 3 hours after her multivitamin C. Two hours before and 3 hours after her calcium carbonate D. Anytime 12. GK should take her gemifloxacin: A. On an empty stomach B. With a small snack C. With a full meal D. With or without food 13. The dose of gemifloxacin prescribed for GK: A. Is for an excessive duration B. Was not adjusted for her renal function C. Is the recommended dose D. Was adjusted for her hepatic function 14. GK developed a rash after 7 days on gemifloxacin. What should be done now? A. The gemifloxacin dose should be reduced B. Gemifloxacin should be discontinued C. The prescribed course of therapy should be continued D. She should be switched to an alternative fluoroquinolone 15. Which patient characteristics increased GK's risk of developing a rash while on gemifloxin? A. Female gender B. Being a postmenopausal female and being treated with estrogen therapy C. Long duration of gemifloxin therapy D. All of the above

Key Words -- antimicrobial; Factive; fluoroquinolone; gemifloxacin 1. A FDA approved indication for gemifloxacin is: A. Moderate to severe community-acquired pneumonia B. Acute sinusitis C. Acute exacerbation of chronic bronchitis D. All of the above 2. Gemifloxacin has a spectrum of activity most similar to that of: A. Moxifloxacin B. Ciprofloxacin C. Levofloxacin D. Ofloxacin 3. The mean serum elimination halflife of gemifloxacin is: A. 3 to 4 hours B. 6 to 8 hours C. 10 to 12 hours D. 16 to 18 hours 4. Which statement regarding gemifloxacin elimination is true? A. Gemifloxacin undergoes extensive hepatic metabolism. B. Gemifloxacin undergoes active renal secretion. C. The majority of the dose is excreted unchanged in the urine. D. Gemifloxacin metabolites are not detected in the urine. 5. Gemifloxacin dosage adjustments are necessary in: A. Patients with hepatic impairment B. Patients with renal impairment C. Elderly patients D. Patients on phenytoin 6. Gemifloxacin should be used with caution with which of the following agents? A. Ibuprofen B. Ipratropium C. Ziprasidone D. Fluticasone 7. Gemifloxacin has what effect on cytochrome P450 isozymes? A. Inducer of CYP 2D6 B. Inhibits CYP 2D6 C. Inhibits CYP 1A2 D. No effect 8. The most common adverse effects associated with gemifloxacin include: A. Diarrhea and rash B. Diarrhea and photosensitivity C. Rash and tendon rupture D. Nausea and constipation 9. When necessary, a 160 mg dose is administered as: A. 160 mg tablet B. 4 mL of a 40 mg/mL suspension C. One half of a 320 mg tablet D. Powder papers Case History GK is a 53-year-old female with chronic obstructive pulmonary disease and hypertension. She is 5'4" tall and weighs 155 pounds. Her medication regimen includes lisinopril and hydrochlorothiazide for her hypertension, ipratropium and albuterol for her COPD, estradiol for menopausal vasomotor symptoms, calcium carbonate with vitamin D to prevent osteoporosis, and a multivitamin with minerals. Her most recent blood pressure was 162/85, although she had forgotten to take her daily doses of lisinopril and hydrochlorothiazide that day. Her serum creatinine is 1.9 mg/dL (calculated CrCl = 38 mL/min). CK develops an acute exacerbation of chronic bronchitis and is prescribed a 10 day course of gemifloxacin 160 mg daily.

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Drug Evaluations: Gemifloxacin ACPE #071-999-03-009-H01 (0.15 CEU) Program Expires: September 2006 To receive continuing education credit, complete this form and mail with your $7 processing fee (made payable to WSU College of Pharmacy) to: College of Pharmacy, Continuing Education Dept. Washington State University Spokane 310 North Riverpoint Boulevard PO Box 1495 Spokane, WA 99210-1495 Tel: (509) 358-7732 Print clearly or type. Please allow 4 weeks for processing. Name______________________________________ Address: ___________________________________ ___________________________________________ City: _______________ State: ______ Zip: _____ Note: Your answer sheet will be graded confidentially and you will receive prompt notification of your score. In order to receive continuing education credit for this program, you need a minimum correct response rate of 70%.

PROGRAM EVALUATION Please rate our continuing education offering by responding to the following questions: 1. Were the educational objectives met? completely fairly well not at all 2. The overall quality of the program was: excellent good fair poor 3. Was the content of this article relevant to the practice of pharmacy? excellent good fair poor 4. How long did it take you to complete this continuing education program? _______ hours 5. What other continuing education programs or topics would you like to see? _________________________________________ _________________________________________ _________________________________________

_____________________________________________ _____________________________________________

Answer Key

1. A B 2. A B 3. A B 4. A B 5. A B 6. A B 7. A B 8. A B C D C D C D C D C D C D C D C D 9. A B 10. A B 11. A B 12. A B 13. A B 14. A B 15. A B C D C D C D C D C D C D C D

The Washington State University College of Pharmacy is accredited by the American Council on Pharmaceutical Education (ACPE) as a provider of continuing pharmaceutical education.

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