emerge as [18:<18 years. Patients received sequential intravenous/oral AVELOX or comparator (intravenous ertapenem followed by oral amoxicillin/clavulanate) for 5 to 14 days (mean duration was 9 days with a range of 1 to 24 days). The overall adverse reaction profile in pediatric patients was comparable to that of adult patients. The most frequently occurring adverse reactions in pediatric patients treated with AVELOX were QT prolongation 9.3% (28/301), vomiting, 6.6% (20/301) diarrhea 3.7% (11/301), arthralgia 3.0% (9/301), and phlebitis 2.7% (8/301) (see Table 5). Discontinuation of study drug due to an adverse reaction was reported in 5.3% (16/301) of AVELOX-treated patients versus 1.3% (2/150) of comparator-treated patients. The adverse reaction profile of AVELOX or comparator was similar across all age groups studied. Musculoskeletal adverse reactions were monitored and followed up to 5 years after the end of study treatment. The rates of musculoskeletal adverse reactions were 4.3% (13/301) in the AVELOX-treated group versus 3.3% (5/150) in the comparator-treated group. The majority of musculoskeletal adverse reactions were reported between 12 and 53 weeks after start of study treatment with complete resolution at the end of the study [see Warnings and Precautions (5.9) and Nonclinical Toxicology (13.2)]. Table 5: Table 5 Incidence (%) of Selected Adverse Reactions in 2.0% of Pediatric Patients Treated with AVELOX in cIAI Clinical Trial System Organ Class Adverse Reactions AVELOX N = 301 (%) Comparator N = 150 (%) Gastrointestinal disorders Abdominal pain 8 (2.7) 3 (2.0) Diarrhea 11 (3.7) 1 (0.7) Vomiting 20 (6.6) 12 (8.0) General disorders and administration site conditions Pyrexia 6 (2.0) 4 (2.7) Investigations Aspartate aminotransferase increased 2 (0.7) 3 (2.0) Electrocardiogram QT prolonged 28 (9.3) 4 (2.7) Musculoskeletal and connective tissue disorders Arthralgia 9 (3.0) 2 (1.3) Nervous system disorders Headache 6 (2.0) 2 (1.3) Vascular disorders Phlebitis 8 (2.7) 0 (0) Clinical response was assessed at the test-of-cure visit (28 to 42 days after end of treatment). The clinical response rates observed in the modified intent to treat population were 83.9% (208/248) for AVELOX and 95.5% (127/133) for comparator; see Table 6. Table 6: Clinical Response Rates at 28 42 Days After End of Treatment in Pediatric Patients with cIAI Avelox n (%) Comparator n (%) Difference 2 (95% CI) mITT Population 1 N=248 N=133 Cure 208 (83.9) 127 (95.5) -12.2 (-17.9, -6.4) Failure 17 (6.9) 3 (2.3) Indeterminate 21 (8.5) 3 (2.3) Missing 2 (0.8) 0 1 The modified intent-to-treat (mITT) population is defined as all subjects who were treated with at least one dose of study medication and who have at least one pre-treatment causative organism from the intra-abdominal site of infection or from blood cultures. 2 Difference in clinical cure rates (Avelox - Comparator) and 95% confidence intervals, presented as percentages, are based on stratified analysis by age group using Mantel-Haenszel methods. Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as AVELOX. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing AVELOX to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue AVELOX and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning , and Warnings and Precautions ( 5.2 )]. In controlled multiple-dose clinical trials, 23% of patients receiving oral AVELOX were greater than or equal to 65 years of age and 9% were greater than or equal to 75 years of age. The clinical trial data demonstrate that there is no difference in the safety and efficacy of oral AVELOX in patients aged 65 or older compared to younger adults. In trials of intravenous use, 42% of AVELOX patients were greater than or equal to 65 years of age, and 23% were greater than or equal to 75 years of age. The clinical trial data demonstrate that the safety of intravenous AVELOX in patients aged 65 or older was similar to that of comparator-treated patients. In general, elderly patients may be more susceptible to drug-associated effects of the QT interval. Therefore, AVELOX should be avoided in patients taking drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.5 ), and Clinical Pharmacology ( 12.3 )]. Renal Impairment The pharmacokinetic parameters of moxifloxacin are not significantly altered in mild, moderate, severe, or end-stage renal disease. No dosage adjustment is necessary in patients with renal impairment, including those patients requiring hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) [see Dosage and Administration ( 2 ), and Clinical Pharmacology ( 12.3 )]. Hepatic Impairment No dosage adjustment is recommended for mild, moderate, or severe hepatic insufficiency (Child-Pugh Classes A, B, or C). However, due to metabolic disturbances associated with hepatic insufficiency, which may lead to QT prolongation, AVELOX should be used with caution in these patients [see Warnings and Precaution ( 5.6 ) and Clinical Pharmacology, ( 12.3 )]. Overdosage Single oral overdoses up to 2.8 g were not associated with any serious adverse events. In the event of acute overdose, Empty the stomach and maintain adequate hydration. Monitor ECG due to the possibility of QT interval prolongation. Carefully observe the patient and give supportive treatment. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic moxifloxacin exposure. About 3% and 9% of the dose of moxifloxacin, as well as about 2% and 4.5% of its glucuronide metabolite are removed by continuous ambulatory peritoneal dialysis and hemodialysis, respectively. Avelox Injection Description AVELOX (moxifloxacin hydrochloride) is a synthetic antibacterial agent for oral and intravenous administration. Moxifloxacin, a fluoroquinolone, is available as the monohydrochloride salt of 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3 quinoline carboxylic acid. It is a slightly yellow to yellow crystalline substance with a molecular weight of 437.9. Its empirical formula is C 21 H 24 FN 3 O 4 HCl and its chemical structure is as follows: AVELOX Tablets AVELOX Tablets are available as film-coated tablets containing moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol and ferric oxide. Avelox Injection Avelox Injection for intravenous use is available in ready-to-use single-dose 250 mL flexibags as a sterile, preservative free, 0.8% sodium chloride aqueous solution of moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin) with pH ranging from 4.1 to 4.6. The flexibag is not made with natural rubber latex. The appearance of the intravenous solution is yellow. The color does not affect, nor is it indicative of, product stability. The inactive ingredients are sodium chloride, USP, Water for Injection, USP, and may include hydrochloric acid and/or sodium hydroxide for pH adjustment. Avelox Injection contains approximately 34.2 mEq (787 mg) of sodium in 250 mL. Avelox Injection - Clinical Pharmacology Mechanism of Action AVELOX is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12.4 )]. Pharmacodynamics Photosensitivity Potential A study of the skin response to ultraviolet (UVA and UVB) and visible radiation conducted in 32 healthy volunteers (8 per group) demonstrated that AVELOX does not show phototoxicity in comparison to placebo. The minimum erythematous dose (MED) was measured before and after treatment with AVELOX (200 mg or 400 mg once daily), lomefloxacin (400 mg once daily), or placebo. In this study, the MED measured for both doses of AVELOX were not significantly different from placebo, while lomefloxacin significantly lowered the MED [see Warnings and Precautions ( 5.12 )]. Pharmacokinetics Absorption Moxifloxacin, given as an oral tablet, is well absorbed from the gastrointestinal tract. The absolute bioavailability of moxifloxacin is approximately 90 percent. Co-administration with a high fat meal (that is, 500 calories from fat) does not affect the absorption of moxifloxacin. Consumption of 1 cup of yogurt with moxifloxacin does not affect the rate or extent of the systemic absorption (that is, area under the plasma concentration time curve (AUC). Table 7: Mean ( SD) C max and AUC values following single and multiple doses of 400 mg moxifloxacin given orally C max (mg/L) AUC (mg h/L) Half-life (hr) Single Dose Oral Healthy (n = 372) 3.1 1 36.1 9.1 11.5 15.6 a Multiple Dose Oral Healthy young male/female (n = 15) 4.5 0.5 48 2.7 12.7 1.9 Healthy elderly male (n = 8) 3.8 0.3 51.8 6.7 Healthy elderly female (n = 8) 4.6 0.6 54.6 6.7 Healthy young male (n = 8) 3.6 0.5 48.2 9 Healthy young female (n = 9) 4.2 0.5 49.3 9.5 1. Range of means from different studies Table 8: Mean ( SD) C max and AUC values following single and multiple doses of 400 mg moxifloxacin given by 1-hour intravenous infusion C max (mg/L) AUC (mg h/L) Half-life (hour) Single Dose intravenous Healthy young male/female (n = 56) 3.9 0.9 39.3 8.6 8.2 15.4 a Patients (n = 118) Male (n = 64) 4.4 3.7 Female (n = 54) 4.5 2> < 65 years (n = 58) 4.6 4.2 65 years (n = 60) 4.3 1.3 Multiple Dose intravenous Healthy young male (n = 8) 4.2 0.8 38 4.7 14.8 2.2 Healthy elderly (n =12; 8 male, 4 female) 6.1 1.3 48.2 0.9 10.1 1.6 Patients b (n = 107) Male (n = 58) 4.2 2.6 Female (n = 49) 4.6 1.5 <65 years (n = 52) 4.1 1.4 65 years (n = 55) 4.7 2.7 1. Range of means from different studies 2. Expected C max (concentration obtained around the time of the end of the infusion) Plasma concentrations increase proportionately with dose up to the highest dose tested (1200 mg single oral dose). The mean ( SD) elimination half-life from plasma is 12 1.3 hours; steady-state is achieved after at least three days with a 400 mg once daily regimen. Mean Steady-State Plasma Concentrations of Moxifloxacin Obtained With Once Daily Dosing of 400 mg Either Orally (n=10) or by Intravenous Infusion (n=12) Distribution Moxifloxacin is approximately 30 50% bound to serum proteins, independent of drug concentration. The volume of distribution of moxifloxacin ranges from 1.7 to 2.7 L/kg. Moxifloxacin is widely distributed throughout the body, with tissue concentrations often exceeding plasma concentrations. Moxifloxacin has been detected in the saliva, nasal and bronchial secretions, mucosa of the sinuses, skin blister fluid, subcutaneous tissue, skeletal muscle, and abdominal tissues and fluids following oral or intravenous administration of 400 mg. Moxifloxacin concentrations measured post-dose in various tissues and fluids following a 400 mg oral or intravenous dose are summarized in Table 9. The rates of elimination of moxifloxacin from tissues generally parallel the elimination from plasma. Table 9: Moxifloxacin Concentrations (mean SD) in Tissues and the Corresponding Plasma Concentrations After a Single 400 mg Oral or Intravenous Dose a Tissue or Fluid N Plasma Concentration (mcg/mL) Tissue or Fluid Concentration (mcg/mL or mcg/g) Tissue Plasma Ratio Respiratory Alveolar Macrophages 5 3.3 0.7 61.8 27.3 21.2 10 Bronchial Mucosa 8 3.3 0.7 5.5 1.3 1.7 0.3 Epithelial Lining Fluid 5 3.3 0.7 24.4 14.7 8.7 6.1 Sinus Maxillary Sinus Mucosa 4 3.7 1.1 b 7.6 1.7 2 0.3 Anterior Ethmoid Mucosa 3 3.7 1.1 b 8.8 4.3 2.2 0.6 Nasal Polyps 4 3.7 1.1 b 9.8 4.5 2.6 0.6 Skin, Musculoskeletal Blister Fluid 5 3 0.5 c 2.6 0.9 0.9 0.2 Subcutaneous Tissue 6 2.3 0.4 d 0.9 0.3 e 0.4 0.6 Skeletal Muscle 6 2.3 0.4 d 0.9 0.2 e 0.4 0.1 Intra-Abdominal Abdominal tissue 8 2.9 0.5 7.6 2 2.7 0.8 Abdominal exudate 10 2.3 0.5 3.5 1.2 1.6 0.7 Abscess fluid 6 2.7 0.7 2.3 1.5 0.8 0.4 1. All moxifloxacin concentrations were measured 3 hours after a single 400 mg dose, except the abdominal tissue and exudate concentrations which were measured at 2 hours post-dose and the sinus concentrations which were measured 3 hours post-dose after 5 days of dosing. 2. N = 5 3. N = 7 4. N = 12 5. Reflects only non-protein bound concentrations of drug. Metabolism Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate conjugate (M1) accounts for approximately 38% of the dose, and is eliminated primarily in the feces. Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2), which is excreted exclusively in the urine. Peak plasma concentrations of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are generally less than 10% those of moxifloxacin. In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2. Excretion Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% in feces). A total of 96% 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean ( SD) apparent total body clearance and renal clearance are 12 2 L/hr and 2.6 0.5 L/hr, respectively. Pharmacokinetics in Specific Populations Geriatric Following oral administration of 400 mg moxifloxacin for 10 days in 16 elderly (8 male; 8 female) and 17 young (8 male; 9 female) healthy volunteers, there were no age-related changes in moxifloxacin pharmacokinetics. In 16 healthy male volunteers (8 young; 8 elderly) given a single 200 mg dose of oral moxifloxacin, the extent of systemic exposure (AUC and C max ) was not statistically different between young and elderly males and elimination half-life was unchanged. No dosage adjustment is necessary based on age. In large phase III studies, the concentrations around the time of the end of the infusion in elderly patients following intravenous infusion of 400 mg were similar to those observed in young patients [see Use in Specific Populations ( 8.5 )]. Gender Following oral administration of 400 mg moxifloxacin daily for 10 days to 23 healthy males (19 75 years) and 24 healthy females (19 70 years), the mean AUC and C max were 8% and 16% higher, respectively, in females compared to males. There are no significant differences in moxifloxacin pharmacokinetics between male and female subjects when differences in body weight are taken into consideration. A 400 mg single dose study was conducted in 18 young males and females. The comparison of moxifloxacin pharmacokinetics in this study (9 young females and 9 young males) showed no differences in AUC or C max due to gender. Dosage adjustments based on gender are not necessary. Race Steady-state moxifloxacin pharmacokinetics in male Japanese subjects were similar to those determined in Caucasians, with a mean C max of 4.1 mcg/mL, an AUC 24 of 47 mcg h/mL, and an elimination half-life of 14 hours, following 400 mg p.o. daily. Renal Insufficiency The pharmacokinetic parameters of moxifloxacin are not significantly altered in mild, moderate, severe, or end-stage renal disease. No dosage adjustment is necessary in patients with renal impairment, including those patients requiring hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). In a single oral dose study of 24 patients with varying degrees of renal function from normal to severely impaired, the mean peak concentrations (C max ) of moxifloxacin were reduced by 21% and 28% in the patients with moderate (CL CR 30 and 60 mL/min) and severe (CL CR> <30 mL/min) renal impairment, respectively. The mean systemic exposure (AUC) in these patients was increased by 13%. In the moderate and severe renally impaired patients, the mean AUC for the sulfate conjugate (M1) increased by 1.7-fold (ranging up to 2.8-fold) and mean AUC and C max for the glucuronide conjugate (M2) increased by 2.8-fold (ranging up to 4.8-fold) and 1.4-fold (ranging up to 2.5-fold), respectively [see Use in Specific Populations (8.6)]. The pharmacokinetics of single dose and multiple dose moxifloxacin were studied in patients with CL CR> < 20 mL/min on either hemodialysis or continuous ambulatory peritoneal dialysis (8 HD, 8 CAPD). Following a single 400 mg oral dose, the AUC of moxifloxacin in these HD and CAPD patients did not vary significantly from the AUC generally found in healthy volunteers. C max values of moxifloxacin were reduced by about 45% and 33% in HD and CAPD patients, respectively, compared to healthy, historical controls. The exposure (AUC) to the sulfate conjugate (M1) increased by 1.4- to 1.5-fold in these patients. The mean AUC of the glucuronide conjugate (M2) increased by a factor of 7.5, whereas the mean C max values of the glucuronide conjugate (M2) increased by a factor of 2.5 to 3, compared to healthy subjects. The sulfate and the glucuronide conjugates of moxifloxacin are not microbiologically active, and the clinical implication of increased exposure to these metabolites in patients with renal disease including those undergoing HD and CAPD has not been studied. Oral administration of 400 mg QD AVELOX for 7 days to patients on HD or CAPD produced mean systemic exposure (AUC ss ) to moxifloxacin similar to that generally seen in healthy volunteers. Steady-state C max values were about 22% lower in HD patients but were comparable between CAPD patients and healthy volunteers. Both HD and CAPD removed only small amounts of moxifloxacin from the body (approximately 9% by HD, and 3% by CAPD). HD and CAPD also removed about 4% and 2% of the glucuronide metabolite (M2), respectively. Hepatic Insufficiency No dosage adjustment is recommended for mild, moderate, or severe hepatic insufficiency (Child-Pugh Classes A, B, or C). However, due to metabolic disturbances associated with hepatic insufficiency, which may lead to QT prolongation, AVELOX should be used with caution in these patients [see Warnings and Precautions ( 5.6 ) and Use in Specific Populations ( 8.7 )]. In 400 mg single oral dose studies in 6 patients with mild (Child-Pugh Class A) and 10 patients with moderate (Child-Pugh Class B) hepatic insufficiency, moxifloxacin mean systemic exposure (AUC) was 78% and 102%, respectively, of 18 healthy controls and mean peak concentration (C max ) was 79% and 84% of controls. The mean AUC of the sulfate conjugate of moxifloxacin (M1) increased by 3.9-fold (ranging up to 5.9-fold) and 5.7-fold (ranging up to 8-fold) in the mild and moderate groups, respectively. The mean C max of M1 increased by approximately 3-fold in both groups (ranging up to 4.7- and 3.9-fold). The mean AUC of the glucuronide conjugate of moxifloxacin (M2) increased by 1.5-fold (ranging up to 2.5-fold) in both groups. The mean C max of M2 increased by 1.6- and 1.3-fold (ranging up to 2.7- and 2.1-fold), respectively. The clinical significance of increased exposure to the sulfate and glucuronide conjugates has not been studied. In a subset of patients participating in a clinical trial, the plasma concentrations of moxifloxacin and metabolites determined approximately at the moxifloxacin T max following the first intravenous or oral AVELOX dose in the Child-Pugh Class C patients (n=10) were similar to those in the Child-Pugh Class A/B patients (n=5), and also similar to those observed in healthy volunteer studies. Drug-Drug Interactions The following drug interactions were studied in healthy volunteers or patients. Antacids and iron significantly reduced bioavailability of moxifloxacin, as observed with other fluoroquinolones [see Drug Interactions ( 7.1 )]. Calcium, digoxin, itraconazole, morphine, probenecid, ranitidine, theophylline, cyclosporine and warfarin did not significantly affect the pharmacokinetics of moxifloxacin. These results and the data from in vitro studies suggest that moxifloxacin is unlikely to significantly alter the metabolic clearance of drugs metabolized by CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2 enzymes. Moxifloxacin had no clinically significant effect on the pharmacokinetics of atenolol, digoxin, glyburide, itraconazole, oral contraceptives, theophylline, cyclosporine and warfarin. However, fluoroquinolones, including AVELOX, have been reported to enhance the anticoagulant effects of warfarin or its derivatives in the patient population [see Drug Interactions ( 7.2 )]. Antacids When moxifloxacin (single 400 mg tablet dose) was administered two hours before, concomitantly, or 4 hours after an aluminum/magnesium-containing antacid (900 mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 12 healthy volunteers there was a 26%, 60% and 23% reduction in the mean AUC of moxifloxacin, respectively. Moxifloxacin should be taken at least 4 hours before or 8 hours after antacids containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc, or didanosine buffered tablets for oral suspension or the pediatric powder for oral solution [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.1 )]. Atenolol In a crossover study involving 24 healthy volunteers (12 male; 12 female), the mean atenolol AUC following a single oral dose of 50 mg atenolol with placebo was similar to that observed when atenolol was given concomitantly with a single 400 mg oral dose of moxifloxacin. The mean C max of single dose atenolol decreased by about 10% following co-administration with a single dose of moxifloxacin. Calcium Twelve healthy volunteers were administered concomitant moxifloxacin (single 400 mg dose) and calcium (single dose of 500 mg Ca ++ dietary supplement) followed by an additional two doses of calcium 12 and 24 hours after moxifloxacin administration. Calcium had no significant effect on the mean AUC of moxifloxacin. The mean C max was slightly reduced and the time to maximum plasma concentration was prolonged when moxifloxacin was given with calcium compared to when moxifloxacin was given alone (2.5 hours versus 0.9 hours). These differences are not considered to be clinically significant. Digoxin No significant effect of moxifloxacin (400 mg once daily for two days) on digoxin (0.6 mg as a single dose) AUC was detected in a study involving 12 healthy volunteers. The mean digoxin C max increased by about 50% during the distribution phase of digoxin. This transient increase in digoxin C max is not viewed to be clinically significant. Moxifloxacin pharmacokinetics were similar in the presence or absence of digoxin. No dosage adjustment for moxifloxacin or digoxin is required when these drugs are administered concomitantly. Glyburide In diabetics, glyburide (2.5 mg once daily for two weeks pretreatment and for five days concurrently) mean AUC and C max were 12% and 21% lower, respectively, when taken with moxifloxacin (400 mg once daily for five days) in comparison to placebo. Nonetheless, blood glucose levels were decreased slightly in patients taking glyburide and moxifloxacin in comparison to those taking glyburide alone, suggesting no interference by moxifloxacin on the activity of glyburide. These interaction results are not viewed as clinically significant. Iron When moxifloxacin tablets were administered concomitantly with iron (ferrous sulfate 100 mg once daily for two days), the mean AUC and C max of moxifloxacin was reduced by 39% and 59%, respectively. Moxifloxacin should only be taken more than 4 hours before or 8 hours after iron products [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.1 )]. Itraconazole In a study involving 11 healthy volunteers, there was no significant effect of itraconazole (200 mg once daily for 9 days), a potent inhibitor of cytochrome P4503A4, on the pharmacokinetics of moxifloxacin (a single 400 mg dose given on the 7 th day of itraconazole dosing). In addition, moxifloxacin was shown not to affect the pharmacokinetics of itraconazole. Morphine No significant effect of morphine sulfate (a single 10 mg intramuscular dose) on the mean AUC and C max of moxifloxacin (400 mg single dose) was observed in a study of 20 healthy male and female volunteers. Oral Contraceptives A placebo-controlled study in 29 healthy female subjects showed that moxifloxacin 400 mg daily for 7 days did not interfere with the hormonal suppression of oral contraception with 0.15 mg levonorgestrel/0.03 mg ethinylestradiol (as measured by serum progesterone, FSH, estradiol, and LH), or with the pharmacokinetics of the administered contraceptive agents. Probenecid Probenecid (500 mg twice daily for two days) did not alter the renal clearance and total amount of moxifloxacin (400 mg single dose) excreted renally in a study of 12 healthy volunteers. Ranitidine No significant effect of ranitidine (150 mg twice daily for three days as pretreatment) on the pharmacokinetics of moxifloxacin (400 mg single dose) was detected in a study involving 10 healthy volunteers. Theophylline No significant effect of moxifloxacin (200 mg every twelve hours for 3 days) on the pharmacokinetics of theophylline (400 mg every twelve hours for 3 days) was detected in a study involving 12 healthy volunteers. In addition, theophylline was not shown to affect the pharmacokinetics of moxifloxacin. The effect of co-administration of 400 mg once daily of moxifloxacin with theophylline has not been studied. Warfarin No significant effect of moxifloxacin (400 mg once daily for eight days) on the pharmacokinetics of R- and S-warfarin (25 mg single dose of warfarin sodium on the fifth day) was detected in a study involving 24 healthy volunteers. No significant change in prothrombin time was observed. However, fluoroquinolones, including AVELOX, have been reported to enhance the anticoagulant effects of warfarin or its derivatives in the patient population [see Adverse Reactions ( 6.2 ) and Drug Interactions ( 7.2 )]. Microbiology Mechanism of Action The bactericidal action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication, transcription, repair, and recombination. Resistance The mechanism of action for fluoroquinolones, including moxifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin. Resistance to fluoroquinolones occurs primarily by a mutation in topoisomerase II (DNA gyrase) or topoisomerase IV genes, decreased outer membrane permeability or drug efflux. In vitro resistance to moxifloxacin develops slowly via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8 x 10 9 to < 1 x 10 11 for Gram-positive bacteria. Cross Resistance Cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to moxifloxacin. There is no known cross-resistance between moxifloxacin and other classes of antimicrobials. Antimicrobial Activity Moxifloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage ( 1 )]. Gram-positive bacteria Enterococcus faecalis Staphylococcus aureus Streptococcus anginosus Streptococcus constellatus Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] **) Streptococcus pyogenes **MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae ), and are isolates resistant to two or more of the following antibiotics: penicillin (MIC) 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. Gram-negative bacteria Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Moraxella catarrhalis Proteus mirabilis Yersinia pestis Anaerobic bacteria Bacteroides fragilis Bacteroides thetaiotaomicron Clostridium perfringens Peptostreptococcus species Other microorganisms Chlamydophila pneumoniae Mycoplasma pneumoniae The following in vitro data are available, but their clinical significance is unknown .At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for moxifloxacin against isolates of similar genus or organism group. However, the efficacy of AVELOX in treating clinical infections due to these bacteria has not beenestablished in adequate and well controlled clinical trials. Gram-positive bacteria Staphylococcus epidermidis Streptococcus agalactiae Streptococcus viridans group Gram-negative bacteria Citrobacter freundii Klebsiella oxytoca Legionella pneumophila Anaerobic bacteria Fusobacterium species Prevotella species Susceptibility Tests Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum 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 and/or agar). 1,2,4 The MIC values should be interpreted according to the criteria in Table 10. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size prove should be determined using a standardized test method. 2,3 This procedure uses paper disks impregnated with 5 mcg moxifloxacin to test the susceptibility of bacteria to moxifloxacin. The disc diffusion interpretive criteria are provided in Table 10. Anaerobic Techniques For anaerobic bacteria, the susceptibility to moxifloxacin can be determined by a standardized test method. 2,5 The MIC values obtained should be interpreted according to the criteria provided in Table 10. Table 10: Susceptibility Test Interpretive Criteria for Moxifloxacin MIC (mcg/mL) Zone Diameter (mm) Species S I R S I R Enterobacteriaceae 2 4 8 19 16 18 15 Enterococcus faecalis 1 2 4 18 15 17 14 Staphylococcus aureus 0.5 1 2 24 21 23 20 Haemophilus influenzae 1 a a 18 a a Haemophilus parainfluenzae 1 a a 18 a a Streptococcus pneumoniae 1 2 4 18 15 17 14 Streptococcus species 1 2 4 18 15 17 14 Anaerobic bacteria 2 4 8 - - - Yersinia pestis 0.25 a a - - - S=susceptible, I=Intermediate, and R=resistant. a) The current absence of data on moxifloxacin-resistant isolates precludes defining any results other than Susceptible . Isolates yielding test results (MIC or zone diameter) other than susceptible, should be submitted to a reference laboratory for additional testing. A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of today
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