1.1 Acute Bacterial Sinusitis

AVELOX is indicated for the treatment of Acute Bacterial Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)].

1.2 Acute Bacterial Exacerbation of Chronic Bronchitis

AVELOX is indicated for the treatment of Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, methicillin-susceptible Staphylococcus aureus, or Moraxella catarrhalis [see Clinical Studies (14.1)].

1.3 Community Acquired Pneumonia

AVELOX is indicated for the treatment of Community Acquired Pneumonia caused by Streptococcus pneumoniae (including multi-drug resistant strains*), Haemophilus influenzae, Moraxella catarrhalis, methicillin-susceptible Staphylococcus aureus, Klebsiella pneumoniae, Mycoplasma pneumoniae, or Chlamydophilia pneumoniae.

* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (minimum inhibitory concentrations [MIC] ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole [see Clinical Studies (14.2)].

1.4 Uncomplicated Skin and Skin Structure Infections

AVELOX is indicated for the treatment of Uncomplicated Skin and Skin Structure Infections caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes [see Clinical Studies (14.5)].

1.5 Complicated Skin and Skin Structure Infections

AVELOX is indicated for the treatment of Complicated Skin and Skin Structure Infections caused by methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae [see Clinical Studies (14.6)].

1.6 Complicated Intra-Abdominal Infections

AVELOX is indicated for the treatment of Complicated Intra-Abdominal Infections including polymicrobial infections such as abscess caused by Escherichia coli, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, Enterococcus faecalis, Proteus mirabilis, Clostridium perfringens, Bacteroides thetaiotaomicron, or Peptostreptococcus species [see Clinical Studies (14.7)].

2.1 Dosage in Adult Patients

The dose of AVELOX is 400 mg (orally or as an intravenous infusion) once every 24 hours. The duration of therapy depends on the type of infection as described in Table 1.

 Intravenous formulation is indicated when it offers a route of administration advantageous to the patient (for example, patient cannot tolerate an oral dosage form). When switching from intravenous to oral formulation, no dosage adjustment is necessary. Patients whose therapy is started with AVELOX IV may be switched to AVELOX Tablets when clinically indicated at the discretion of the physician.

2.2 Drug Interactions with Multivalent Cations

Oral doses of AVELOX should be administered at least 4 hours before or 8 hours after products containing magnesium, aluminum, iron or zinc, including antacids, sucralfate, multivitamins and VIDEX® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

2.3 Administration Instructions

2.4 Preparation for Administration of AVELOX IV

To prepare AVELOX IV injection premix in flexible containers:

1. Close flow control clamp of administration set.
2. Remove cover from port at bottom of container.
3. Insert piercing pin from an appropriate transfer set (for example, one that does not require excessive force, such as ISO compatible administration set) into port with a gentle twisting motion until pin is firmly seated.

NOTE: Refer to complete directions that have been provided with the administration set.

3.1 AVELOX Tablets

• Containing moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin)
• Oblong, dull red film-coated tablets
• Imprinted with BAYER on one side and M400 on the other

3.2 AVELOX IV

• Containing 400 mg moxifloxacin in 0.8% saline (moxifloxacin hydrochloride in sodium chloride injection) with pH ranging from 4.1 to 4.6.
• Ready-to-use 250 mL latex-free flexibags. No further dilution is necessary
• Sterile, preservative free, 0.8% sodium chloride aqueous solution of moxifloxacin hydrochloride

5.1 Tendinopathy and Tendon Rupture

Fluoroquinolones, including AVELOX, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. AVELOX should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. [see Adverse Reactions (6.4) and Patient Counseling Information (17.3).]

5.2 Exacerbation of Myasthenia Gravis

Fluoroquinolones, including AVELOX, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid AVELOX in patients with known history of myasthenia gravis [see Patient Counseling Information (17.3)].

5.3 QT Prolongation

AVELOX has been shown to prolong the QT interval of the electrocardiogram in some patients. Following oral dosing with 400 mg of AVELOX the mean (± SD) change in QTc from the pre-dose value at the time of maximum drug concentration was 6 msec (± 26) (n = 787). Following a course of daily intravenous dosing (400 mg; 1 hour infusion each day) the mean change in QTc from the Day 1 pre-dose value was 10 msec (±22) on Day 1 (n=667) and 7 msec (± 24) on Day 3 (n = 667).

The drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia and patients receiving Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents, due to the lack of clinical experience with the drug in these patient populations.

Pharmacokinetic studies between AVELOX 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 caution should be exercised when AVELOX is given concurrently with these drugs. In premarketing clinical trials, the rate of cardiovascular adverse events was similar in 798 AVELOX and 702 comparator treated patients who received concomitant therapy with drugs known to prolong the QTc interval.

AVELOX should be used with caution in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia, acute myocardial ischemia. The magnitude of QT prolongation may increase with increasing concentrations of the drug or increasing rates of infusion of the intravenous formulation. Therefore the recommended dose or infusion rate should not be exceeded. QT prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes. No excess in cardiovascular morbidity or mortality attributable to QTc prolongation occurred with AVELOX treatment in over 15,500 patients in controlled clinical studies, including 759 patients who were hypokalemic at the start of treatment, and there was no increase in mortality in over 18,000 AVELOX tablet treated patients in a postmarketing observational study in which ECGs were not performed. Elderly patients using IV AVELOX may be more susceptible to drug-associated QT prolongation [see Use In Specific Populations (8.5)]. In addition, AVELOX should be used with caution in patients with mild, moderate, or severe liver cirrhosis [see Clinical Pharmacology (12.3) and Patient Counseling Information (17.3)].

5.4 Hypersensitivity Reactions

Serious anaphylactic reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including AVELOX . Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. AVELOX should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Oxygen, intravenous steroids, and airway management, including intubation, may be administered as indicated [see Adverse Reactions (6) and Patient Counseling Information (17.3)].

5.5 Other Serious and Sometimes Fatal Reactions

Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including AVELOX . 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 (for example, 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

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Patient Counseling Information (17.3) and Adverse Reactions (6.4).

5.6 Central Nervous System Effects

Quinolones, including AVELOX, may cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia [see Adverse Reactions (6.2, 6.4)].

Convulsions have been reported in patients receiving quinolones. Quinolones may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following 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 (for example, severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold [see Drug Interactions (7.4) Adverse Reactions (6.2, 6.4) and Patient Counseling Information (17.3)].

5.7 Clostridium Difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AVELOX, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions (6.2) and Patient Counseling Information (17.3)].

5.8 Peripheral Neuropathy

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 [see Adverse Reactions (6.2) and Patient Counseling Information (17.3)].

5.9 Arthropathic Effects in Animals

The oral administration of AVELOX caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology (13.2)].

5.10 Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs [see Adverse Reactions (6.4) and Pharmacokinetics (12.3)].

5.11 Development of Drug Resistant Bacteria

Prescribing AVELOX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Patient Counseling Information (17.1)].

6.1 Serious and Otherwise Important Adverse Reactions

The following serious and otherwise important adverse reactions are discussed in greater detail in the warnings and precautions section of the label:

• Tendinopathy and Tendon Rupture [see Warnings and Precautions (5.1)]
• QT Prolongation [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
• Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.5)]
• Central Nervous System Effects [see Warnings and Precautions (5.6)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.7)]
• Peripheral Neuropathy [see Warnings and Precautions (5.8)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.10)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.11)]

6.2 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to AVELOX in 14981 patients in 71 active controlled Phase II- IV clinical trials in different indications [see Indications and Usage (1)]. The population studied had a mean age of 50 years (approximately 73% of the population was <65 years of age), 50% were male, 63% were Caucasian, 12% were Asian and 9% were Black. Patients received AVELOX 400 mg once daily PO, IV, or sequentially (IV followed by PO). Treatment duration was usually 6-10 days, and the mean number of days on therapy was 9 days.

Discontinuation of AVELOX due to adverse events occurred in 5.0% of patients overall, 4.1% of patients treated with 400 mg PO, 3.9% with 400 mg IV and 8.2% with sequential therapy 400 mg PO/IV. The most common adverse events leading to discontinuation with the 400 mg PO doses were nausea (0.8%), diarrhea (0.5%), dizziness (0.5%), and vomiting (0.4%). The most common adverse event leading to discontinuation with the 400 mg IV dose was rash (0.5%). The most common adverse events leading to discontinuation with the 400 mg IV/PO sequential dose were diarrhea (0.5%), pyrexia (0.4%).

Adverse reactions occurring in ≥1% of AVELOX-treated patients and less common adverse reactions, occurring in 0.1 to <1% of AVELOX-treated patients, are shown in Tables 2 and Table 3, respectively. The most common adverse drug reactions (≥3%) are nausea, diarrhea, headache, and dizziness.

 6.3 Laboratory Changes

Changes in laboratory parameters, without regard to drug relationship, which are not listed above and which occurred in ≥ 2% of patients and at an incidence greater than in controls included: increases in MCH, neutrophils, WBCs, PT ratio, ionized calcium, chloride, albumin, globulin, bilirubin; decreases in hemoglobin, RBCs, neutrophils, eosinophils, basophils, PT ratio, glucose, pO2, bilirubin, and amylase. It cannot be determined if any of the above laboratory abnormalities were caused by the drug or the underlying condition being treated.

6.4 Postmarketing Experience

Table 4 lists adverse reactions that have been identified during post-approval use of Avelox. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7.1 Antacids, Sucralfate, Multivitamins and other products containing Multivalent Cations

Quinolones form chelates with alkaline earth and transition metal cations. Oral administration of quinolones with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as VIDEX® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution, may substantially interfere with the absorption of quinolones, resulting in systemic concentrations considerably lower than desired. Therefore, AVELOX should be taken at least 4 hours before or 8 hours after these agents [see Dosage and Administration (2.2), Pharmacokinetics (12.3), and Patient Counseling Information (17.2)].

7.2 Warfarin

Quinolones, including AVELOX, have been reported to enhance the anticoagulant effects of warfarin or its derivatives in the patient population. In addition, infectious disease and its accompanying inflammatory process, age, and general status of the patient are risk factors for increased anticoagulant activity. Therefore the prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if a quinolone is administered concomitantly with warfarin or its derivatives [see Adverse Reactions (6.2, 6.3), Pharmacokinetics (12.3), and Patient Counseling Information (17.3)].

7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Although not observed with AVELOX in preclinical and clinical trials, the concomitant administration of a nonsteroidal anti-inflammatory drug with a quinolone may increase the risks of CNS stimulation and convulsions [see Warnings and Precautions (5.6), and Patient Counseling Information (17.3)].

7.4 Drugs that Prolong QT

There is limited information available on the potential for a pharmacodynamic interaction in humans between AVELOX and other drugs that prolong the QTc interval of the electrocardiogram. Sotalol, a Class III antiarrhythmic, has been shown to further increase the QTc interval when combined with high doses of intravenous (IV) AVELOX in dogs. Therefore, AVELOX should be avoided with Class IA and Class III antiarrhythmics [see Warnings and Precautions, (5.3), Nonclinical Toxicology (13.2), and Patient Counseling Information (17.3)].

8.1 Pregnancy

8.3 Nursing Mothers

Moxifloxacin is excreted in the breast milk of rats. Moxifloxacin may also be excreted in human milk. Because of the potential for serious adverse reactions in infants who are nursing from mothers taking AVELOX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients and adolescents less than 18 years of age have not been established. AVELOX causes arthropathy in juvenile animals [see Boxed Warning, Warnings and Precautions (5.9), and Clinical Pharmacology (12.3)].

8.5 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, Warnings and Precautions (5.1), and Adverse Reactions (6.2)].

8.6 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)].

8.7 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 (5.3), and Clinical Pharmacology, (12.3)].

12.1 Mechanism of Action

AVELOX is a member of the flouroquinolone class of antibacterial agents [see Clinical Pharmacology (12.4)].

12.3 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 significantly affect the extent or rate of systemic absorption (AUC).

Table 5: Mean (± SD) Cmax and AUC values following single and multiple doses of 400 mg moxifloxacin given orally

	Cmax (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
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

Table 6: Mean (± SD) Cmax and AUC values following single and multiple doses of 400 mg moxifloxacin given by 1 hour IV infusion

	Cmax (mg/L)	AUC (mg•h/L)	Half-life (hr)
Single Dose IV
Healthy young male/female (n = 56)	3.9 ± 0.9	39.3 ± 8.6	8.2 - 15.4
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 IV
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 (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

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 IV Infusion (n=12)

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed.

Moxifloxacin was not mutagenic in 4 bacterial strains (TA 98, TA 100, TA 1535, TA 1537) used in the Ames Salmonella reversion assay. As with other quinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were used. Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.

Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately 12 times the maximum recommended human dose based on body surface area (mg/m2), or at intravenous doses as high as 45 mg/kg/day, approximately equal to the maximum recommended human dose based on body surface area (mg/m2). At 500 mg/kg orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology

Quinolones have been shown to cause arthropathy in immature animals. In studies in juvenile dogs oral doses of moxifloxacin ≥ 30 mg/kg/day (approximately 1.5 times the maximum recommended human dose based upon systemic exposure) for 28 days resulted in arthropathy. There was no evidence of arthropathy in mature monkeys and rats at oral doses up to 135 and 500 mg/kg/day, respectively.

Moxifloxacin at an oral dose of 300 mg/kg did not show an increase in acute toxicity or potential for CNS toxicity (for example, seizures) in mice when used in combination with NSAIDs such as diclofenac, ibuprofen, or fenbufen. Some quinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs).

A QT-prolonging effect of moxifloxacin was found in dog studies, at plasma concentrations about five times the human therapeutic level. The combined infusion of sotalol, a Class III antiarrhythmic agent, with moxifloxacin induced a higher degree of QTc prolongation in dogs than that induced by the same dose (30 mg/kg) of moxifloxacin alone. Electrophysiological in vitro studies suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr) as an underlying mechanism.

No signs of local intolerability were observed in dogs when moxifloxacin was administered intravenously. After intra-arterial injection, inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of AVELOX should be avoided.

14.1 Acute Bacterial Exacerbation of Chronic Bronchitis

AVELOX Tablets (400 mg once daily for five days) were evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared AVELOX with clarithromycin (500 mg twice daily for 10 days) and enrolled 629 patients. Clinical success was assessed at 7-17 days post-therapy. The clinical success for AVELOX was 89% (222/250) compared to 89% (224/251) for clarithromycin.

 The microbiological eradication rates (eradication plus presumed eradication) in AVELOX treated patients were Streptococcus pneumoniae 100%, Haemophilus influenzae 89%, Haemophilus parainfluenzae 100%, Moraxella catarrhalis 85%, Staphylococcus aureus 94%, and Klebsiella pneumoniae 85%.

14.2 Community Acquired Pneumonia

A randomized, double-blind, controlled clinical trial was conducted in the US to compare the efficacy of AVELOX Tablets (400 mg once daily) to that of high-dose clarithromycin (500 mg twice daily) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 474 patients (382 of whom were valid for the efficacy analysis conducted at the 14 - 35 day follow-up visit). Clinical success for clinically evaluable patients was 95% (184/194) for AVELOX and 95% (178/188) for high dose clarithromycin.

A randomized, double-blind, controlled trial was conducted in the US and Canada to compare the efficacy of sequential IV/PO AVELOX 400 mg QD for 7-14 days to an IV/PO fluoroquinolone control (trovafloxacin or levofloxacin) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 516 patients, 362 of whom were valid for the efficacy analysis conducted at the 7-30 day post-therapy visit. The clinical success rate was 86% (157/182) for AVELOX therapy and 89% (161/180) for the fluoroquinolone comparators.

An open-label ex-US study that enrolled 628 patients compared AVELOX to sequential IV/PO amoxicillin/clavulanate (1.2 g IV q8h/625 mg PO q8h) with or without high-dose IV/PO clarithromycin (500 mg BID). The intravenous formulations of the comparators are not FDA approved. The clinical success rate at Day 5-7 for AVELOX therapy was 93% (241/258) and demonstrated superiority to amoxicillin/clavulanate ± clarithromycin (85%, 239/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.9%, 13.2%)]. The clinical success rate at the 21-28 days post-therapy visit for AVELOX was 84% (216/258), which also demonstrated superiority to the comparators (74%, 208/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.6%, 16.3%)].

The clinical success rates by pathogen across four CAP studies are presented in Table 9.

Table 9: Clinical Success Rates By Pathogen (Pooled CAP Studies)

14.3 Community Acquired Pneumonia caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP)*

Avelox was effective in the treatment of community acquired pneumonia (CAP) caused by multi-drug resistant Streptococcus pneumoniae MDRSP* isolates. Of 37 microbiologically evaluable patients with MDRSP isolates, 35 patients (95%) achieved clinical and bacteriological success post-therapy. The clinical and bacteriological success rates based on the number of patients treated are shown in Table 10.

* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are strains 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.

 Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 11.

 14.4 Acute Bacterial Sinusitis

In a controlled double-blind study conducted in the US, AVELOX Tablets (400 mg once daily for ten days) were compared with cefuroxime axetil (250 mg twice daily for ten days) for the treatment of acute bacterial sinusitis. The trial included 457 patients valid for the efficacy analysis. Clinical success (cure plus improvement) at the 7 to 21 day post-therapy test of cure visit was 90% for AVELOX and 89% for cefuroxime.

An additional non-comparative study was conducted to gather bacteriological data and to evaluate microbiological eradication in adult patients treated with AVELOX 400 mg once daily for seven days. All patients (n = 336) underwent antral puncture in this study. Clinical success rates and eradication/presumed eradication rates at the 21 to 37 day follow-up visit were 97% (29 out of 30) for Streptococcus pneumoniae, 83% (15 out of 18) for Moraxella catarrhalis, and 80% (24 out of 30) for Haemophilus influenzae.

14.5 Uncomplicated Skin and Skin Structure Infections

A randomized, double-blind, controlled clinical trial conducted in the US compared the efficacy of AVELOX 400 mg once daily for seven days with cephalexin HCl 500 mg three times daily for seven days. The percentage of patients treated for uncomplicated abscesses was 30%, furuncles 8%, cellulitis 16%, impetigo 20%, and other skin infections 26%. Adjunctive procedures (incision and drainage or debridement) were performed on 17% of the AVELOX treated patients and 14% of the comparator treated patients. Clinical success rates in evaluable patients were 89% (108/122) for AVELOX and 91% (110/121) for cephalexin HCl.

14.6 Complicated Skin and Skin Structure Infections

Two randomized, active controlled trials of cSSSI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential IV/PO AVELOX 400 mg QD for 7-14 days to an IV/PO beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 617 patients, 335 of which were valid for the efficacy analysis. A second open-label International study compared AVELOX 400 mg QD for 7-21 days to sequential IV/PO beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 804 patients, 632 of which were valid for the efficacy analysis. Surgical incision and drainage or debridement was performed on 55% of the AVELOX treated and 53% of the comparator treated patients in these studies and formed an integral part of therapy for this indication. Success rates varied with the type of diagnosis ranging from 61% in patients with infected ulcers to 90% in patients with complicated erysipelas. These rates were similar to those seen with comparator drugs. The overall success rates in the evaluable patients and the clinical success by pathogen are shown in Tables 12 and 13.

 14.7 Complicated Intra-Abdominal Infections

Two randomized, active controlled trials of cIAI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential IV/PO AVELOX 400 mg QD for 5-14 days to IV/ piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of patients with cIAI, including peritonitis, abscesses, appendicitis with perforation, and bowel perforation. This study enrolled 681 patients, 379 of which were considered clinically evaluable. A second open-label international study compared AVELOX 400 mg QD for 5-14 days to IV ceftriaxone plus IV metronidazole followed by PO amoxicillin/clavulanic acid in the treatment of patients with cIAI. This study enrolled 595 patients, 511 of which were considered clinically evaluable. The clinically evaluable population consisted of subjects with a surgically confirmed complicated infection, at least 5 days of treatment and a 25-50 day follow-up assessment for patients at the Test of Cure visit. The overall clinical success rates in the clinically evaluable patients are shown in Table 14.

16.1 AVELOX Tablets

AVELOX (moxifloxacin hydrochloride) Tablets are available as oblong, dull red film-coated tablets containing 400 mg moxifloxacin.

The tablet is coded with the word “BAYER” on one side and “M400” on the reverse side.

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Avoid high humidity.

16.2 AVELOX Intravenous Solution – Premix Bags

AVELOX IV (moxifloxacin hydrochloride in sodium chloride injection) is available in ready-to-use 250 mL latex-free flexible bags containing 400 mg of moxifloxacin in 0.8% saline. NO FURTHER DILUTION OF THIS PREPARATION IS NECESSARY.

Parenteral drug products should be inspected visually for particulate matter prior to administration. Samples containing visible particulates should not be used.

Because the premix flexible containers are for single-use only, any unused portion should be discarded.

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

DO NOT REFRIGERATE – PRODUCT PRECIPITATES UPON REFRIGERATION.

17.1 Antibacterial Resistance

Antibacterial drugs including AVELOX should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When AVELOX is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AVELOX or other antibacterial drugs in the future.

17.2 Administration With Food, Fluids, and Drug Products Containing Multivalent Cations

Patients should be informed that AVELOX tablets may be taken with or without food. Patients should be advised to drink fluids liberally.

AVELOX tablets should be taken at least 4 hours before or 8 hours after multivitamins (containing iron or zinc), antacids (containing magnesium or aluminum), sucralfate, or VIDEX® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution.

17.3 Serious and Potentially Serious Adverse Reactions

To assure safe and effective use of AVELOX, patients should be informed of the following serious adverse reactions that have been associated with AVELOX and other fluoroquinolone use:

• Tendon Disorders: Patients should contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue AVELOX treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• Exacerbation of Myasthenia Gravis: fluoroquinolones like AVELOX may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems.
• Prolongation of the QT interval: AVELOX may produce changes in the electrocardiogram (QTc interval prolongation). AVELOX should be avoided in patients receiving Class IA (for example quinidine, procainamide) or Class III (for example amiodarone, sotalol) antiarrhythmic agents. AVELOX may add to the QTc prolonging effects of other drugs such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. The patients should inform their physician of any personal or family history of QTc prolongation or proarrhythmic conditions such as recent hypokalemia, significant bradycardia, and acute myocardial ischemia. Patients should contact their physician if they experience palpitations or fainting spells while taking AVELOX.
• Hypersensitivity Reactions: Patients should be advised that AVELOX may be associated with hypersensitivity reactions, including anaphylactic reactions, even following a single dose. Patients should discontinue AVELOX at the first sign of a skin rash or other signs of an allergic reaction.
• Convulsions: Convulsions have been reported in patients receiving quinolones, and they should notify their physician before taking AVELOX if there is a history of this condition. Patients should also inform their physician if they are taking NSAIDs concurrently with AVELOX.
• Neurologic Adverse Effects (for example, dizziness, lightheadedness): AVELOX may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.
• Peripheral Neuropathies: If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should discontinue AVELOX and contact their physician.
• Photosensitivity/Phototoxicity: Patients should be informed that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician.
• Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.