Avelox 400 mg

Most Common Clinical Trial Adverse Drug Reactions (≥1% to <10%)

Over 8600 courses of AVELOX (moxifloxacin hydrochloride tablets) and AVELOX I.V. (moxifloxacin hydrochloride injection) treatment have been evaluated for drug safety during clinical development. Of these, 8050 patients received the 400 mg dose. Most adverse events reported in trials were described as transient in nature, mild to moderate intensity, and required no additional treatment. AVELOX was discontinued due to adverse drug reactions (those judged by the investigators to be possibly or probably related to AVELOX) in 3.1% of patients (206 out of 6734) treated with moxifloxacin hydrochloride tablets and 7.0% of patients (131 out of 1872) treated with intravenous moxifloxacin hydrochloride.

AVELOX is not recommended for children under the age of 18 years (see Warnings and Precautions).

Intravenous administration is recommended when it offers a route of administration advantageous to the patient (e.g., severe infection or the patient cannot tolerate the oral dosage form, at the discretion of the physician).

Community acquired pneumonia in hospitalized patients caused by: C. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, S. aureus, S. pneumoniae (including Multi-drug resistant strains).

Multi-Drug Resistant S. pneumoniae (MDRSP) are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 µg/mL), 2nd generation cephalosporins (e.g., cefuroxime axetil), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Complicated intra-abdominal infections due to polymicrobial and monomicrobial infections caused by: B. fragilis {*Increasing resistance of B. fragilis to fluoroquinolones including moxifloxacin has been reported.}, B. thetaiotaomicron, C. perfringens, E. faecalis (Vancomycin sensitive strains only; many strains are only moderately susceptible), E. coli, P. mirabilis, S. anginosus.

Complicated skin and skin structure infections in hospitalized patients caused by: E. cloacae, E. coli, K. pneumoniae, S. aureus (methicillin-susceptible strains).

Appropriate culture and susceptibility tests should be performed before treatment with AVELOX in order to isolate and identify organisms causing the infection and to determine their susceptibility to moxifloxacin. Therapy with AVELOX may be initiated while awaiting the results of these tests; once results become available, appropriate therapy should be continued. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent, but also on the possible emergence of bacterial resistance. The frequency of acquired resistance may vary geographically and with time for certain species. Local area information on resistance patterns is desirable, particularly when treating severe infections.

Clinical trial data demonstrate that there is no significant difference in the safety of AVELOX in patients aged 65 or older. Dosage adjustments based on age are not necessary (see Action and Clinical Pharmacology).

Respiratory Tract Infections: Acute bacterial sinusitis caused by: H. influenzae, M. catarrhalis, S. pneumoniae.

Acute bacterial exacerbation of chronic bronchitis caused by: H. influenzae, H. parainfluenzae, K. pneumoniae, M. catarrhalis, S. aureus, S. pneumoniae.

Community acquired pneumonia of mild to moderate severity caused by: C. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, S. pneumoniae (including Multi-drug resistant strains).

Multi-Drug Resistant S. pneumoniae (MDRSP) are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 µg/mL), 2nd generation cephalosporins (e.g., cefuroxime axetil), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Each oblong, dull red film-coated tablet, engraved “BAYER” on one side and “M400” on the other, contains: moxifloxacin HCl equivalent to moxifloxacin 400 mg. Nonmedicinal ingredients: cellulose microcrystalline, croscarmellose sodium, hydroxypropyl methyl cellulose, lactose monohydrate, magnesium stearate, polyethylene glycol 4000, red ferric oxide and titanium dioxide. Bottles of 30.

Each premixed, ready-to-use 250 mL minibag contains: moxifloxacin HCl equivalent to 400 mg of moxifloxacin in 0.8% saline, with pH ranging from 4.1 to 4.6. The appearance of the intravenous solution is yellow and is not affected by, or indicative of, product stability. Nonmedicinal ingredients: sodium chloride, USP, and Water for Injection, USP. It may also contain hydrochloric acid and/or sodium hydroxide for pH adjustment. No further dilution of this product is necessary.

As with all parenteral products, the intravenous mixture should be inspected visually for clarity, discoloration, particulate matter, precipitate and leakage prior to administration. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

The pharmacokinetic parameters of AVELOX are not significantly altered by mild, moderate, or severe renal impairment. No dosage adjustment is necessary in patients with renal impairment, including patients on chronic dialysis, i.e., hemodialysis or continuous ambulatory peritoneal dialysis. In clinical studies, as renal function decreased, mean exposure (AUC) to the glucuronide conjugate (M2) increased by a factor of 2.8 (Cl_cr<30 mL/min), 7.5 (hemodialysis) and 13.3 (continuous ambulatory peritoneal dialysis).

The sulfate and glucuronide conjugates are not microbiologically active, and the clinical implication of increased exposure to these metabolites in patients with renal impairment has not been studied (see Action and Clinical Pharmacology and Dosage and Administration).

From the results of animal studies, there is no evidence to suggest that AVELOX is carcinogenic or mutagenic.

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

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. difficile is one primary cause of “antibiotic-associated colitis”.

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

Twenty-five patients from the moxifloxacin hydrochloride clinical datapool (7284 patients) had an episode of atrial fibrillation. In 4 of these patients the relationship between the event and moxifloxacin hydrochloride therapy was assessed as possible, though in each case it could also be explained by pre-existing cardiac disease. There was one episode of atrial fibrillation observed in patients who received a comparator agent (3994 patients).

In controlled multiple-dose clinical trials with oral moxifloxacin, 23% of patients who received moxifloxacin were ≥65 years of age and 9% were ≥75 years of age. In intravenous multiple-dose trials, 45% of the patients who received intravenous moxifloxacin were ≥65 years of age, and 24% were ≥75 years of age. The clinical trial data demonstrate that there is no significant difference in the safety of moxifloxacin in patients aged 65 or older compared to younger adults (see Action and Clinical Pharmacology and Dosage and Administration).

In the pool of 248 moxifloxacin-treated and 243 comparator-treated elderly (≥65 years) patients enrolled in the two pivotal intravenous trials of community acquired pneumonia, the following ECG abnormalities were reported in moxifloxacin vs. comparator patients: QT prolongation (4 vs. 1), ventricular tachycardia (3 vs. 0), tachycardia (2 vs. 1), atrial fibrillation (1 vs. 0), supraventricular tachycardia (1 vs. 0), ventricular extrasystoles (1 vs. 0), and arrhythmia (0 vs. 1). A majority of these patients completed a full-course of therapy.

Adequate and well-controlled studies have not been performed in pregnant women. The extent of exposure in pregnancy is very limited. AVELOX should not be used in pregnant women unless the potential benefits outweigh the potential risk to the fetus.

Moxifloxacin was not teratogenic when administered to pregnant rats during organogenesis at oral doses as high as 500 mg/kg/day or 0.24 times the maximum recommended human dose based on systemic exposure (AUC), but decreased fetal body weights and slightly delayed fetal skeletal development (indicative of fetotoxicity) were observed. Intravenous administration of 80 mg/kg to pregnant rats resulted in maternal toxicity and a marginal effect on fetal and placental weights and the appearance of the placenta. There was no evidence of teratogenicity at intravenous doses as high as 80 mg/kg/day. Intravenous administration of 20 mg/kg/day (approximately equal to the maximum recommended human oral dose based upon systemic exposure) to pregnant rabbits resulted in maternal toxicity, decreased fetal body weights and delayed fetal skeletal ossification. There was no evidence of teratogenicity when pregnant Cynomolgus monkeys were given oral doses as high as 100 mg/kg/day (12.5 times the maximum recommended human dose based upon systemic exposure). An increased incidence of smaller fetuses was observed at 100 mg/kg/day. In an oral pre- and postnatal development study conducted in rats, effects observed at 500 mg/kg/day included slight increases in duration of pregnancy and prenatal loss, reduced pup birth weight and decreased neonatal survival. Treatment-related maternal mortality occurred during gestation at 500 mg/kg/day in this study.

In 400 mg single dose studies in 6 patients with mild (Child Pugh Class A) and 10 patients with moderate (Child Pugh Class B) hepatic insufficiency, oral 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 clinical significance of increased exposure to the sulfate and glucuronide conjugates has not been studied. No dosage adjustment is recommended for patients with mild or moderate hepatic insufficiency (Child Pugh Classes A and B). Due to limited clinical data, the use of moxifloxacin is not recommended for patients with severe hepatic insufficiency (Child Pugh Class C) (see Action and Clinical Pharmacology and Dosage and Administration).

The safety and efficacy of AVELOX (moxifloxacin hydrochloride) in children, pregnant women and nursing women have not been established.

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy, including AVELOX.

There have been occasional reports of fatal hypersensitivity and/or anaphylactic reactions observed with quinolone therapy. These reactions may occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching and other serious skin reactions.

AVELOX should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antibiotics, including moxifloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome), vasculitis, arthralgia, myalgia, serum sickness, allergic pneumonitis, interstitial nephritis, acute renal insufficiency or failure, hepatitis, jaundice, acute hepatic necrosis or failure, anemia including hemolytic and aplastic, thrombocytopenia including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities (see Contraindications and Adverse Reactions).

Ruptures of the shoulder, hand and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. AVELOX should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy with quinolones, including AVELOX, particularly in elderly patients and in those treated concurrently with corticosteroids.

Convulsions, increased intracranial pressure and toxic psychosis have been reported in patients receiving quinolones. Quinolones, including moxifloxacin, may also cause central nervous system stimulation which may lead to abnormal dreams, agitation, anxiety, confusion, depression, dizziness, emotional lability, hallucinations, insomnia, lightheadedness, nervousness, nightmares, paranoia, restlessness and tremors. These reactions may occur after the first dose. If these reactions occur in patients receiving AVELOX, the drug should be discontinued and appropriate measures instituted.

As with all quinolones, AVELOX should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors that predispose to seizures or lower the seizure threshold (see Adverse Reactions).

Phototoxicity has been reported in patients receiving certain quinolones. In keeping with good medical practice, the patient should be advised to avoid excessive sunlight or artificial ultraviolet light (e.g., sunlamps) during treatment with AVELOX and for one day following completion of treatment. If a sunburn-like reaction or skin eruptions occur, the physician should be contacted. A study in human volunteers concluded that AVELOX has no measurable phototoxic potential.

Some members of the fluoroquinolone class of drugs (of which AVELOX is a member) have been shown to produce skin tumours in the Hairless (Skh-1) mouse when concomitantly exposed to daily irradiations of UV-A light for 16 weeks. In this model, in the absence of exposure to UV-A light, mice treated with the fluoroquinolone did not develop skin tumours. The clinical significance of these findings, particularly for short term use, is not known. Photocarcinogenicity studies with AVELOX have not yet been carried out. During treatment with AVELOX and for one day following completion of treatment, exposure to excessive sunlight or artificial ultraviolet light (e.g., sunlamps) should be avoided.

There are no reported laboratory test interactions.

When intravenous therapy is initiated, patients should be appropriately monitored. If signs of cardiac arrhythmia occur during treatment with AVELOX, treatment should be stopped and an ECG should be performed (see Warnings and Precautions, Cardiovascular, QT Interval Prolongation).

The safety and efficacy of AVELOX in pediatric populations less than 18 years of age have not been established. Quinolones, including AVELOX, cause arthropathy and osteochondrosis in juvenile animals of several species. The significance of these findings to humans is unknown.

Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones.

The safety and efficacy of AVELOX (moxifloxacin hydrochloride) in nursing women have not been established.

AVELOX is excreted in the breast milk of rats and may also be excreted in human milk. Because of the potential for unknown effects from moxifloxacin in infants being nursed by mothers taking moxifloxacin, a decision should be made to either discontinue nursing or discontinue the administration of moxifloxacin, taking into account the importance of moxifloxacin therapy to the mother and the possible risk to the infant.

As with other members of the quinolone class, moxifloxacin has caused arthropathy and/or chondrodysplasia in immature dogs. The significance of these findings to humans is unknown (see Action and Clinical Pharmacology).

AVELOX has been shown to prolong the QT interval of the electrocardiogram in some patients. The drug should be avoided in patients with known prolongation of the QT interval, patients with hypokalemia and patients receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents, due to the lack of clinical experience with the drug in these patient populations and the potential risk.

Sotalol, a Class III antiarrhythmic, has been shown to increase the QTc interval when combined with high doses of intravenous AVELOX in dogs.

Pharmacokinetic studies between moxifloxacin hydrochloride and other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics and tricyclic antidepressants have not been performed. An additive effect of AVELOX and these drugs cannot be excluded, therefore AVELOX should be used with caution when given concurrently with these drugs.

The effect of AVELOX on patients with congenital prolongation of the QT interval has not been studied, but it is expected that these individuals may be more susceptible to drug-induced QT prolongation. AVELOX should be used with caution in patients with ongoing proarrhythmic conditions such as clinically significant bradycardia, acute myocardial ischemia, clinically relevant heart failure with reduced left-ventricular ejection fraction or previous history of symptomatic arrhythmias.

The magnitude of QT prolongation may increase with the infusion rate and with increasing plasma concentrations of the drug. Therefore, the recommended duration of infusion (60 minutes) should not be shortened and the recommended dose should not be exceeded (see Dosage and Administration).

QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsades de Pointes. It has been observed with other drugs that prolong the QT interval that females may be at greater risk compared to males for developing Torsades de Pointes.

In 787 patients with paired valid ECGs in Phase III clinical trials, the mean±SD prolongation of the QTc interval after oral dosing with AVELOX 400 mg was 6±26 msec. In patients with paired valid ECGs in Phase III clinical trials, the mean±SD prolongation of the QTc interval within 0-4 hours after a one hour infusion of intravenous moxifloxacin hydrochloride 400 mg was 9±24 msec (Day 1; n=176) and 3±29 msec (Day 3; n=290) (see Action and Clinical Pharmacology).

No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with AVELOX treatment in clinical trials involving over 4000 patients. However, certain predisposing conditions may increase the risk for ventricular arrhythmias.

When intravenous therapy is initiated, patients should be appropriately monitored. If signs of cardiac arrhythmia occur during treatment with AVELOX, treatment should be stopped and an ECG should be performed.

To assure safe and effective use of AVELOX, patients should be advised of the following information and instructions when appropriate:

• that AVELOX may produce changes in the electrocardiogram (QTc interval prolongation)

  
  

• that AVELOX should be avoided if they are currently receiving Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic agents

  
  

• that AVELOX may add to the QTc prolonging effects of other drugs such as cisapride, erythromycin, antipsychotics and tricyclic antidepressants

  
  

• to inform their physician of any personal or family history of QTc prolongation or proarrhythmic conditions such as recent hypokalemia, significant bradycardia, acute myocardial ischemia, clinically relevant heart failure with reduced left-ventricular ejection fraction or previous history of symptomatic arrhythmias

  
  

• to contact their physician if they experience palpitations or fainting spells while taking AVELOX

  
  

• to inform their physician of any other medications being taken concurrently with AVELOX, including over-the-counter medications.

Pharmacokinetics are linear in the range of 50-800 mg (single dose) and up to 600 mg (once daily oral dosing over 10 days).

The mean (±SD) C_max and AUC values at steady-state with a 400 mg oral once daily dosage regimen are 4.5±0.53 g/L and 48±2.7 mg·h/L, respectively. C_max is attained 1 to 3 hours after oral dosing. The mean (±SD) trough concentration is 0.95±0.10 mg/L. The mean (±SD) C_max and AUC values at steady-state with a once daily dosage regimen of 400 mg intravenous moxifloxacin hydrochloride infused over 60 minutes in healthy young males are 4.2±0.8 g/L and 38±4.7 mg·h/L, respectively. C_max is achieved at the end of a 60 minute infusion (see Dosage and Administration).

Plasma concentrations increase proportionately with dose up to the highest dose tested (1200 mg single oral dose). Moxifloxacin hydrochloride is eliminated from plasma by first-order process. 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. The time course of plasma concentrations of moxifloxacin hydrochloride following steady-state oral and intravenous administration is illustrated in Figure 1, and pharmacokinetic parameters of moxifloxacin hydrochloride are presented in Table 9.

Moxifloxacin hydrochloride, given as an oral tablet, is well absorbed from the gastrointestinal tract. The absolute bioavailability of moxifloxacin hydrochloride is approximately 90 percent. Co-administration with a high fat meal (i.e., 500 calories from fat) does not affect absorption of moxifloxacin hydrochloride.

Consumption of one cup of yogurt with moxifloxacin does not significantly affect the extent or rate of systemic absorption (AUC).

Approximately 45% of an oral 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±2.0 L/hr and 2.6±0.5 L/hr, respectively.

One pharmacokinetic study in 9 male and 9 female healthy volunteers showed that at the expected time of peak plasma concentrations and at a heart rate of 75 beats/minute, a 400 mg oral dose of moxifloxacin was associated with a mean QT prolongation (uncorrected for heart-rate) of 14±13 msec (3.8%±3.5%) compared to baseline. Exercise data indicated the absence of a reverse-rate dependence.

In clinical pharmacology studies (n=112 subjects), the aggregate mean prolongation of the QTc interval at the expected time of peak plasma concentrations after a single oral dose of 400 mg moxifloxacin was 7±23 msec (1.8%±5.6%). One patient had an increase in QTc greater than 60 msec.

In clinical pharmacology studies (n=29) with 400 mg intravenous moxifloxacin, the aggregate mean prolongation of the QTc interval at the end of a one hour infusion was 20.6±23 msec (5.5%±5.9%). Two patients had an increase in QTc greater than 60 msec (see Warnings and Precautions).

Moxifloxacin Concentrations (mean±SD) in Plasma and Tissues After Oral or Intravenous Dosing with 400 mg^a

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.

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 dose is converted to a glucuronide conjugate (M2), which is found 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. The sulfate (M1) and glucuronide (M2) conjugates are not microbiologically active.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia.

Following oral administration of 400 mg moxifloxacin for 10 days in 16 elderly (8 male; 8 female) and 16 young (8 male; 8 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 oral dose of 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 Phase I studies, the pharmacokinetics in elderly patients following infusion of 400 mg were similar to those observed in young patients.

Resistance mechanisms which inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. There is no cross-resistance between moxifloxacin and these agents. Plasmid-mediated resistance has not been observed to date.

It appears that the C8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of Gram-positive bacteria compared to the C8-H moiety. The presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, a proposed mechanism of fluoroquinolone resistance.

In vitro resistance to moxifloxacin develops slowly via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8×10⁻⁹ to <1×10^-11 in one strain of S. aureus and one strain of S. pneumoniae.

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 that in 18 healthy controls. The mean peak concentration (C_max) was 79% and 84%, respectively, of control values.

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 8.0-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), respectively. 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. No dosage adjustment is recommended for mild or moderate hepatic insufficiency (Child Pugh Classes A and B). Due to limited clinical data, the use of moxifloxacin is not recommended with severe hepatic insufficiency (Child Pugh Class C) (see Warnings and Precautions and Dosage and Administration).

AVELOX (moxifloxacin hydrochloride) is a synthetic fluoroquinolone with a broad spectrum of activity and a bactericidal mode of action. The bactericidal action results from the interference of moxifloxacin with bacterial topoisomerases II (DNA gyrase) and IV. Topoisomerases are essential enzymes which control DNA topology and assist in DNA replication, repair and transcription.

Killing curves demonstrated that moxifloxacin exhibits a concentration dependent bactericidal effect. Minimum bactericidal concentrations are in the range of minimum inhibitory concentrations.

Fluoroquinolones, including moxifloxacin, differ in chemical structure and mechanism of action from macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin. Conversely, microorganisms resistant to fluoroquinolones may be susceptible to other classes of antimicrobial agents. Although cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram negative bacteria, Gram positive bacteria resistant to other fluoroquinolones may be susceptible to moxifloxacin. Conversely, Gram positive bacteria that are resistant to moxifloxacin may be susceptible to other fluoroquinolones.

Steady state moxifloxacin pharmacokinetics in male Japanese subjects were similar to those determined in Caucasians, with a mean C_max of 4.1 mg/L, an AUC²⁴ of 47 mg·h/mL, and an elimination half-life of 14 hours following 400 mg daily PO.

The pharmacokinetic parameters of moxifloxacin are not significantly altered by mild, moderate, or severe renal impairment. No dosage adjustment is necessary in patients with renal impairment, including those patients on 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 22% and 21% 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. The sulfate and glucuronide conjugates are not microbiologically active, and the clinical implication of increased exposure to these metabolites in patients with renal impairment has not been studied.

The pharmacokinetics of single- 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). Pharmacokinetic comparisons are to historical pharmacokinetic values from healthy volunteers (Cl_cr>90 mL/min; administered a single 400 mg oral dose of moxifloxacin). 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 subjects. 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 7.3 to 13.2, 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 moxifloxacin once daily 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 28% lower in HD patients but were comparable between CAPD patients and healthy volunteers. Moxifloxacin and the glucuronide conjugate (M2) were removed from the body by HD (approximately 9% and 4%, respectively) and by CAPD (approximately 3% and 2%, respectively). Systemic exposure (AUC) to M2 was equal to or greater than moxifloxacin exposure in HD and CAPD subjects following single dosing and at steady state (see Warnings and Precautions and Dosage and Administration).

The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.