Avelox

RedPharm Drug Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use AVELOX safely and effectively. See full prescribing information for AVELOX.Initial U.S. Approval: 1999 RECENT MAJOR CHANGES Boxed Warning 02/11Warnings and Precautions (5.2) 02/11BOXED WARNINGWARNING: Fluoroquinolones, including AVELOX®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk 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 [see Warnings and Precautions ( 5.1)]. Fluoroquinolones, including AVELOX, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid AVELOX in patients with known history of myasthenia gravis [see Warnings and Precautions (5.2).] MicrobiologyTo reduce the development of drug-resistant bacteria and maintain the effectiveness of AVELOX  and other antibacterial drugs, AVELOX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.INDICATIONS AND USAGEAVELOX is a fluoroquinolone antibacterial indicated for treating infections in adults ≥ 18 years of age caused by designated, susceptible bacteria. (1, 12.4) Acute Bacterial Sinusitis (1.1) Acute Bacterial Exacerbation of Chronic Bronchitis (1.2) Community Acquired Pneumonia (1.3) Skin and Skin Structure Infections: Uncomplicated (1.4) and Complicated (1.5) Complicated Intra-Abdominal Infections (1.6) DOSAGE AND ADMINISTRATION Type of Infection Dose Every 24 hours Duration (days) Acute Bacterial Sinusitis (1.1) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis (1.2) 400 mg 5 Community Acquired Pneumonia (1.3) 400 mg 7-14 Uncomplicated Skin and Skin Structure Infections (SSSI) (1.4) 400 mg 7 Complicated SSSI (1.5) 400 mg 7-21 Complicated Intra-Abdominal Infections (1.6) 400 mg 5-14 No dosage adjustment in patients with renal or hepatic impairment. (8.6, 8.7) AVELOX Tablets: Administer 4 hours before or 8 hours after antacids, sucralfate, multivitamins and other products with multivalent cations. (2.2) AVELOX IV: Slow IV infusion over 60 minutes. Avoid rapid or bolus IV. (2.3) Do not mix with other medications in IV bag or in IV line (2.3) DOSAGE FORMS AND STRENGTHS AVELOX Tablets 400 mg moxifloxacin hydrochloride AVELOX IV 250 mL flexibag containing 400 mg moxifloxacin hydrochloride in sodium chloride injection (3.2) CONTRAINDICATIONSKnown hypersensitivity to AVELOX or other quinolones (4, 5.4)WARNINGS AND PRECAUTIONS Increased risk of tendinitis and tendon rupture. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroids, and in patients with kidney, heart or lung transplants. Discontinue if pain or inflammation in a tendon occurs. (5.1, 8.5) Prolongation of the QT interval and isolated cases of torsade de pointes has been reported. Avoid use in patients with known prolongation, hypokalemia, and with drugs that prolong the QT interval. (5.3, 7.4, 8.5). Use caution in patients with proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia. (5.3) Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur after first or subsequent doses. Discontinue drug use at first sign of skin rash, jaundice or any other sign of hypersensitivity. (5.4, 5.5) Central nervous system (CNS) events including dizziness, confusion, hallucination, depression, and rarely suicidal thoughts or acts may occur after first dose. Use caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold. (5.6) Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs. (5.7) Peripheral neuropathy: Discontinue if symptoms occur. (5.8) Side Effects Most common reactions (≥3%) were nausea, diarrhea, headache, and dizziness (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Interacting Drug Interaction Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2) Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3) Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)  USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm (8.1) Geriatrics: Increased risk for severe tendon disorders further increased by concomitant corticosteroid therapy and increased risk of prolongation of the QT interval. (5.1, 5.3, 8.5)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING:
• 1 AVELOX INDICATIONS AND USAGE
  • 1.1 Acute Bacterial Sinusitis
  • 1.2 Acute Bacterial Exacerbation of Chronic Bronchitis
  • 1.3 Community Acquired Pneumonia
  • 1.4 Uncomplicated Skin and Skin Structure Infections
  • 1.5 Complicated Skin and Skin Structure Infections
  • 1.6 Complicated Intra-Abdominal Infections
• 2 AVELOX DOSAGE AND ADMINISTRATION
  • 2.1 Dosage in Adult Patients
  • 2.2 Drug Interactions with Multivalent Cations
  • 2.3 Administration Instructions
  • 2.4 Preparation for Administration of AVELOX IV
• 3 DOSAGE FORMS AND STRENGTHS
  • 3.1 AVELOX Tablets
  • 3.2 AVELOX IV
• 4 AVELOX CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Tendinopathy and Tendon Rupture
  • 5.2 Exacerbation of Myasthenia Gravis
  • 5.3 QT Prolongation
  • 5.4 Hypersensitivity Reactions
  • 5.5 Other Serious and Sometimes Fatal Reactions
  • 5.6 Central Nervous System Effects
  • 5.7 Clostridium Difficile-Associated Diarrhea
  • 5.8 Peripheral Neuropathy
  • 5.9 Arthropathic Effects in Animals
  • 5.10 Photosensitivity/Phototoxicity
  • 5.11 Development of Drug Resistant Bacteria
• 6 AVELOX ADVERSE REACTIONS
  • 6.1 Serious and Otherwise Important Adverse Reactions
  • 6.2 Clinical Trial Experience
  •  6.3 Laboratory Changes
  • 6.4 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Antacids, Sucralfate, Multivitamins and other products containing Multivalent Cations
  • 7.2 Warfarin
  • 7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
  • 7.4 Drugs that Prolong QT
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10 OVERDOSAGE
• 11 AVELOX DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
• 14 CLINICAL STUDIES
  • 14.1 Acute Bacterial Exacerbation of Chronic Bronchitis
  • 14.2 Community Acquired Pneumonia
  • 14.3 Community Acquired Pneumonia caused by Multi-Drug Resistant (MDRSP)*
  • 14.4 Acute Bacterial Sinusitis
  • 14.5 Uncomplicated Skin and Skin Structure Infections
  • 14.6 Complicated Skin and Skin Structure Infections
  •  14.7 Complicated Intra-Abdominal Infections
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 AVELOX Tablets
  • 16.2 AVELOX Intravenous Solution – Premix Bags
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Antibacterial Resistance
  • 17.2 Administration With Food, Fluids, and Drug Products Containing Multivalent Cations
  • 17.3 Serious and Potentially Serious Adverse Reactions
• MEDICATION GUIDE

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

AVELOX  Tablets and IV are indicated for the treatment of adults (≥ 18 years of age) with infections caused by susceptible strains of the designated microorganisms in the conditions listed below [see Dosage and Administration (2) and Use In Specific Populations (8.5)].

Culture and Susceptibility Testing

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to moxifloxacin [see Clinical Pharmacology (12.4)]. Therapy with AVELOX may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.

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 DOSAGE AND ADMINISTRATION

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

AVELOX Tablets

AVELOX Tablets can be taken with or without food, drink fluids liberally.

AVELOX IV

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

AVELOX IV should be administered by INTRAVENOUS infusion only. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

AVELOX IV should be administered by intravenous infusion over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in place. Caution: rapid or bolus intravenous infusion must be avoided.

Because only limited data are available on the compatibility of AVELOX intravenous injection with other intravenous substances, additives or other medications should not be added to AVELOX IV or infused simultaneously through the same intravenous line. If the same intravenous line or a Y-type line is used for sequential infusion of other drugs, or if the “piggyback” method of administration is used, the line should be flushed before and after infusion of AVELOX IV with an infusion solution compatible with AVELOX IV as well as with other drug(s) administered via this common line.

2.4 Preparation for Administration of AVELOX IV

To prepare AVELOX IV injection premix in flexible containers:

• Close flow control clamp of administration set.
• Remove cover from port at bottom of container.
• 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 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

AVELOX is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antimicrobial agents.

5 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

6.1 Serious and Otherwise Important Side Effects

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 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Because no adequate or well-controlled studies have been conducted in pregnant women, AVELOX should be used during pregnancy only if the potential benefit justifies 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/day (approximately 2 times the maximum recommended human dose based on body surface area (mg/m2) 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 during organogenesis resulted in decreased fetal body weights and delayed fetal skeletal ossification. When rib and vertebral malformations were combined, there was an increased fetal and litter incidence of these effects. Signs of maternal toxicity in rabbits at this dose included mortality, abortions, marked reduction of food consumption, decreased water intake, body weight loss and hypoactivity. There was no evidence of teratogenicity when pregnant cynomolgus monkeys were given oral doses as high as 100 mg/kg/day (2.5 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.

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)].

10 OVERDOSAGE

Single oral overdoses up to 2.8 g were not associated with any serious adverse events. In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. ECG monitoring is recommended due to the possibility of QT interval prolongation. The patient should be carefully observed and given 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.

Single oral AVELOX doses of 2000, 500, and 1500 mg/kg were lethal to rats, mice, and cynomolgus monkeys, respectively. The minimum lethal intravenous dose in mice and rats was 100 mg/kg. Adverse clinical signs included CNS and gastrointestinal effects such as decreased activity, somnolence, tremor, convulsions, vomiting and diarrhea.

11 DESCRIPTION

AVELOX (moxifloxacin hydrochloride) is a synthetic broad spectrum 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 C₂₁H₂₄FN₃O₄*HCl and its chemical structure is as follows:

12 CLINICAL PHARMACOLOGY

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).

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.

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 IV dose are summarized in Table 7. The rates of elimination of moxifloxacin from tissues generally parallel the elimination from plasma.

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, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.

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)].

Pediatric

The pharmacokinetics of moxifloxacin in pediatric subjects has not been studied [see Use In Specific Populations (8.4)].

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 AUC₂₄ 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 ( 5.3), 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. 

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.

It is difficult to ascribe relative photosensitivity/phototoxicity among various fluoroquinolones during actual patient use because other factors play a role in determining a subject’s susceptibility to this adverse event such as: a patient’s skin pigmentation, frequency and duration of sun and artificial ultraviolet light (UV) exposure, wearing of sunscreen and protective clothing, the use of other concomitant drugs and the dosage and duration of fluoroquinolone therapy [see Warnings and Precautions (5.10), Adverse Reactions ( 6.3), and Patient Counseling Information (17.3)].

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 quinolones [see Drug Interactions (7.1)].

Calcium, digoxin, itraconazole, morphine, probenecid, ranitidine, theophylline, 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, and warfarin [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 VIDEX^® (didanosine) chewable/ buffered tablets or the pediatric powder for oral solution. [see Dosage and Administration (2.2), 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), 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 a 400 mg dose of moxifloxacin with theophylline has not been studied, but it is not expected to be clinically significant based on in vitro metabolic data showing that moxifloxacin does not inhibit the CYP1A2 isoenzyme.

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 [see Adverse Reactions (6.2), Drug Interactions (7.2)].

12.4 Microbiology

Mechanism of Action

Moxifloxacin has in vitro activity against a wide range of Gram-positive and Gram-negative microorganisms. 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. 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, associated with the NorA or pmrA genes seen in certain Gram-positive bacteria.

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 and other fluoroquinolones. There is no known cross-resistance between moxifloxacin and other classes of antimicrobials.

Drug 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 x 10^–9 to < 1 x 10^–11 for Gram-positive bacteria.

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.

Activity in vitro and in vivo

Moxifloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Aerobic Gram-positive microorganisms

• Enterococcus faecalis (many strains are only moderately susceptible)
• Staphylococcus aureus (methicillin-susceptible strains only)
• Streptococcus anginosus
• Streptococcus constellatus
• Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]*)
• Streptococcus pyogenes

*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.

Aerobic Gram-negative microorganisms

• Enterobacter cloacae
• Escherichia coli
• Haemophilus influenzae
• Haemophilus parainfluenzae
• Klebsiella pneumoniae
• Moraxella catarrhalis
• Proteus mirabilis

Anaerobic microorganisms

• 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.
Moxifloxacin exhibits in vitro MICs of 2 mcg/mL or less against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of AVELOX in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-positive microorganisms

• Staphylococcus epidermidis (methicillin-susceptible strains only)
• Streptococcus agalactiae
• Streptococcus viridans group

Aerobic Gram-negative microorganisms

• Citrobacter freundii
• Klebsiella oxytoca
• Legionella pneumophila

Anaerobic microorganisms

• Fusobacterium species
• Prevotella species

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial 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 method¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of moxifloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae and methicillin-susceptible Staphylococcus aureus:

For testing Haemophilus influenzae and Haemophilus parainfluenzae ^a:

The current absence of data on resistant strains precludes defining any results other than “Susceptible.” Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococcus species including Streptococcus pneumoniae ^b and Enterococcus faecalis:

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard moxifloxacin powder should provide the following MIC values:

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-mcg moxifloxacin to test the susceptibility of microorganisms to moxifloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-mcg moxifloxacin disk should be interpreted according to the following criteria:

The following zone diameter interpretive criteria should be used for testing Enterobacteriaceae and methicillin-susceptible Staphylococcus aureus:

For testing Haemophilus influenzae and Haemophilus parainfluenzae ^e:

The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococcus species including Streptococcus pneumoniae ^f and Enterococcus faecalis:

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for moxifloxacin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-mcg moxifloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to moxifloxacin as MICs can be determined by standardized procedures³ such as reference agar dilution methodsⁱ. The MICs obtained should be interpreted according to the following criteria:

Acceptable ranges of MICs (mcg/mL) for control strains for reference agar dilution testing ^j:

13 NONCLINICAL TOXICOLOGY

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 (I_Kr) 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 CLINICAL STUDIES

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 (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), 2^nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Table 10: Clinical and Bacteriological Success Rates for AVELOX-Treated MDRSP CAP Patients (Population: Valid for Efficacy

Screening Susceptibility	Clinical Success		Bacteriological Success
	n/N	%	n/N	%
Penicillin-resistant	21/21	100%One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in the database based on the respiratory isolate.	21/21	100%One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in the database based on the respiratory isolate.
2nd generation cephalosporin-resistant	25/26	96%One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in the database based on the respiratory isolate.	25/26	96%One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in the database based on the respiratory isolate.
Macrolide-resistant	22/23	96%	22/23	96%
Trimethoprim/sulfamethoxazole-resistant	28/30	93%	28/30	93%
Tetracycline-resistant	17/18	94%	17/18	94%

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

Table 11: Clinical Success Rates and Microbiological Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia)

S. pneumoniae with MDRSP	Clinical Success	Bacteriological Eradication Rate
Resistant to 2 antimicrobials	12/13 (92.3 %)	12/13 (92.3 %)
Resistant to 3 antimicrobials	10/11 (90.9 %)One patient had a respiratory isolate resistant to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials. The patient was included in the category resistant to 5 antimicrobials.	10/11 (90.9 %)One patient had a respiratory isolate resistant to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials. The patient was included in the category resistant to 5 antimicrobials.
Resistant to 4 antimicrobials	6/6 (100%)	6/6 (100%)
Resistant to 5 antimicrobials	7/7 (100%)One patient had a respiratory isolate resistant to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials. The patient was included in the category resistant to 5 antimicrobials.	7/7 (100%)One patient had a respiratory isolate resistant to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials. The patient was included in the category resistant to 5 antimicrobials.
Bacteremia with MDRSP	9/9 (100%)	9/9 (100%)

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.

15 REFERENCES

• Clinical and Laboratory Standards Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Sixth Edition. Approved Standard CLSI Document M7-A6, Vol. 23, No. 2, CLSI, Wayne, PA, January, 2003.
• Clinical and Laboratory Standards Institute, Performance Standards for Antimicrobial Disk Susceptibility Tests-Eighth Edition. Approved Standard CLSI Document M2-A8, Vol. 23, No. 1, CLSI, Wayne, PA, January, 2003.
• Clinical and Laboratory Standards Institute, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard CLSI Document M11-A6, Vol. 24, No. 2, CLSI, Wayne, PA, 2004.

16 HOW SUPPLIED/STORAGE AND HANDLING

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 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide

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 Side Effects

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.

MEDICATION GUIDE

AVELOX^® (AV-eh-locks)
(moxifloxacin hydrochloride)
Tablets

AVELOX^® I.V.  (AV-eh-locks)
(moxifloxacin hydrochloride in sodium chloride injection)

Read the Medication Guide that comes with AVELOX^® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about AVELOX?

AVELOX belongs to a class of antibiotics called fluoroquinolones. AVELOX can cause side effects that may be serious or even cause death. If you get any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take AVELOX.

• Tendon rupture or swelling of the tendon (tendinitis)
  • Tendons are tough cords of tissue that connect muscles to bones.
  • Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites can happen in people of all ages who take fluoroquinolone antibiotics, including AVELOX. The risk of getting tendon problems is higher if you:
  • Are over 60 years of age
  • Are taking steroids (corticosteroids)
  • Have had a kidney, heart or lung transplant
• Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in patients who take fluoroquinolones who do not have the above risk factors.
• Other reasons for tendon ruptures can include:
  • Physical activity or exercise
  • Kidney failure
  • Tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking AVELOX until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is in the Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your healthcare provider about the risk of tendon rupture with continued use of AVELOX. You may need a different antibiotic that is not a fluoroquinolone to treat your infection.
• Tendon rupture can happen while you are taking or after you have finished taking AVELOX. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone.
• Get medical help right away if you get any of the following signs or symptoms of a tendon rupture:
  • Hear or feel a snap or pop in a tendon area
  • Bruising right after an injury in a tendon area
  • Unable to move the affected area or bear weight
• Worsening of myasthenia gravis (a disease which causes muscle weakness). Fluoroquinolones like AVELOX may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.

See the section “What are the possible side effects of AVELOX?” for more information about side effects.

What is AVELOX?

AVELOX is a fluoroquinolone antibiotic medicine used to treat certain types of infections caused by certain germs called bacteria in adults 18 years or older. It is not known if AVELOX is safe and works in people under 18 years of age. Children have a higher chance of getting bone, joint, and tendon (musculoskeletal) problems while taking fluoroquinolone antibiotic medicines.

Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics, including AVELOX, do not kill viruses.

Call your healthcare provider if you think your condition is not getting better while you are taking AVELOX.

Who should not take AVELOX?

Do not take AVELOX if you have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or if you are allergic to any of the ingredients in AVELOX. Ask your healthcare provider if you are not sure. See the list of ingredients in AVELOX at the end of this Medication Guide.

What should I tell my healthcare provider before taking AVELOX?

See “ What is the most important information I should know about AVELOX ?”

Tell your healthcare provider about all your medical conditions, including if you:

• Have tendon problems
• Have a disease that causes muscle weakness (myasthenia gravis)
• Have central nervous system problems (such as epilepsy)
• Have nerve problems
• Have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation”
• Have low blood potassium (hypokalemia)
• Have a slow heartbeat (bradycardia)
• Have a history of seizures
• Have kidney problems
• Have rheumatoid arthritis (RA) or other history of joint problems
• Are pregnant or planning to become pregnant. It is not known if AVELOX will harm your unborn child.
• Are breast-feeding or planning to breast-feed. It is not known if AVELOX passes into breast milk. You and your healthcare provider should decide whether you will take AVELOX or breast-feed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal and dietary supplements. AVELOX and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:

• An NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take AVELOX or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See “What are the possible side effects of AVELOX?”
• A blood thinner (warfarin, Coumadin, Jantoven)
• A medicine to control your heart rate or rhythm (antiarrhythmic) See “What are the possible side effects of AVELOX?”
• An anti-psychotic medicine
• A tricyclic antidepressant
• Erythromycin
• A water pill (diuretic)
• A steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. See “What is the most important information I should know about AVELOX?”
• Certain medicines may keep AVELOX from working correctly. Take AVELOX either 4 hours before or 8 hours after taking these products:
• An antacid, multivitamin, or other product that has magnesium, aluminum, iron, or zinc
• Sucralfate (Carafate)
• Didanosine (Videx^®, Videx EC^®)

Ask your healthcare provider if you are not sure if any of your medicines are listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take AVELOX?

• Take AVELOX once a day exactly as prescribed by your healthcare provider.
• Take AVELOX at about the same time each day.
• AVELOX Tablets should be swallowed.
• AVELOX can be taken with or without food.
• Drink plenty of fluids while taking AVELOX.
• AVELOX IV is given to you by intravenous (IV) infusion into your vein slowly, over 60 minutes, as prescribed by your healthcare provider.
• Do not skip any doses, or stop taking AVELOX even if you begin to feel better, until you finish your prescribed treatment, unless:
  • You have tendon effects (see “What is the most important information I should know about AVELOX?”),
  • You have a serious allergic reaction (see “What are the possible side effects of AVELOX?”), or your healthcare provider tells you to stop.
  • This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to AVELOX. If this happens, AVELOX and other antibiotic medicines may not work in the future.
• If you miss a dose of AVELOX, take it as soon as you remember. Do not take more than 1 dose of AVELOX in one day.
• If you take too much, call your healthcare provider or get medical help immediately.

What should I avoid while taking AVELOX?

• AVELOX can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how AVELOX affects you.
• Avoid sunlamps, tanning beds, and try to limit your time in the sun. AVELOX can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking AVELOX, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.

What are the possible side effects of AVELOX?

AVELOX can cause side effects that may be serious or even cause death. See “What is the most important information I should know about AVELOX?”

Other serious side effects of AVELOX include:

• Central Nervous System effects 

Seizures have been reported in people who take fluoroquinolone antibiotics including AVELOX. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking AVELOX will change your risk of having a seizure.

Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of AVELOX. Talk to your healthcare provider right away if you have any of these side effects, or other changes in mood or behavior:

• Feeling dizzy
• Seizures
• Hear voices, see things, or sense things that are not there (hallucinations)
• Feel restless
• Tremors
• Feel anxious or nervous
• Confusion
• Depression
• Trouble sleeping
• Feel more suspicious (paranoia)
• Suicidal thoughts or acts
• Nightmares
• Serious allergic reactions

Allergic reactions can happen in people taking fluoroquinolones, including AVELOX, even after only one dose. Stop taking AVELOX and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:

• Hives
• Trouble breathing or swallowing
• Swelling of the lips, tongue, face
• Throat tightness, hoarseness
• Rapid heartbeat
• Faint
• Yellowing of the skin or eyes. Stop taking AVELOX and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to AVELOX (a liver problem).
• Skin rash

Skin rash may happen in people taking AVELOX even after only one dose. Stop taking AVELOX at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to AVELOX.

• Serious heart rhythm changes (QT prolongation and torsade de pointes)

Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. AVELOX may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this event are higher in people:

• Who are elderly
• With a family history of prolonged QT interval
• With low blood potassium (hypokalemia)
• Who take certain medicines to control heart rhythm (antiarrhythmics)
• Intestine infection (Pseudomembranous colitis)

Pseudomembranous colitis can happen with most antibiotics, including AVELOX. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.

• Changes in sensation and possible nerve damage (Peripheral Neuropathy) 

Damage to the nerves in arms, hands, legs, or feet can happen in people taking fluoroquinolones, including AVELOX. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:

• Pain
• Burning
• Tingling
• Numbness
• Weakness

AVELOX may need to be stopped to prevent permanent nerve damage.

• Sensitivity to sunlight (photosensitivity)

See “What should I avoid while taking AVELOX ?”

The most common side effects of AVELOX include nausea and diarrhea.

These are not all the possible side effects of AVELOX. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store AVELOX?

AVELOX Tablets

• Store AVELOX 59–86°F (15–30°C)
• Keep AVELOX away from moisture (humidity)

Keep AVELOX and all medicines out of the reach of children.

General Information about AVELOX

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AVELOX for a condition for which it is not prescribed. Do not give AVELOX to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about AVELOX. If you would like more information about AVELOX, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about AVELOX that is written for healthcare professionals. For more information go to www.AVELOX.com or call 1-800-526-4099.

What are the ingredients in AVELOX?

• AVELOX Tablets:
  • Active ingredient: moxifloxacin hydrochloride
  • Inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, and ferric oxide
• AVELOX IV:
  • Active ingredient: moxifloxacin hydrochloride
  • Inactive ingredients: sodium chloride, USP, water for injection, USP, and may include hydrochloric acid and/or sodium hydroxide for pH adjustment

Revised February 2011

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Bayer HealthCare Pharmaceuticals Inc.
Wayne, NJ 07470

Avelox Tablets made in Germany
Avelox IV made in Germany
or
Avelox IV made in Norway by
Fresenius Kabi Norge AS
NO-1753 Halden, Norway

Distributed by: Schering Corporation, a subsidiary of

MERCK& CO., INC.

Whitehouse Station, NJ 08889, USA

AVELOX is a registered trademark of Bayer Aktiengesellschaft and is used under license by Schering Corporation.

Rx Only

81532312, R.5 02/11 15830

©2011 Bayer HealthCare Pharmaceuticals Inc. Printed in U.S.A.