1.1 Community Acquired Pneumonia

Moxifloxacin Injection is indicated in adults (18 years of age or older) for the treatment of Community Acquired Pneumonia caused by susceptible isolates of Streptococcus pneumoniae (including multi-drug resistant isolates*), Haemophilus influenzae, Moraxella catarrhalis, methicillin-susceptible Staphylococcus aureus, Klebsiella pneumoniae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae.

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

1.2 Uncomplicated Skin and Skin Structure Infections

Moxifloxacin Injection is indicated in adults (18 years of age or older) for the treatment of Uncomplicated Skin and Skin Structure Infections caused by susceptible isolates of methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes [see  Clinical Studies (14.5)].

1.3 Complicated Skin and Skin Structure Infections

Moxifloxacin Injection is indicated in adults (18 years of age or older) for the treatment of Complicated Skin and Skin Structure Infections caused by susceptible isolates of methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae [see  Clinical Studies (14.6)].

1.4 Complicated Intra-Abdominal Infections

Moxifloxacin Injection is indicated in adults (18 years of age or older) for the treatment of Complicated Intra-Abdominal Infections including polymicrobial infections such as abscess caused by susceptible isolates of Escherichia coli, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, Enterococcus faecalis, Proteus mirabilis, Clostridium perfringens, Bacteroides thetaiotaomicron, or Peptostreptococcus species [see  Clinical Studies (14.7)] .

1.5 Acute Bacterial Sinusitis

Moxifloxacin Injection is indicated in adults (18 years of age or older) for the treatment of Acute Bacterial Sinusitis (ABS) caused by susceptible isolates of Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see  Clinical Studies (14.4)] .

Because fluoroquinolones, including Moxifloxacin Injection, have been associated with serious adverse reactions [see  Warnings and Precautions (5.1 to 5.13)] and for some patients ABS is self-limiting, reserve Moxifloxacin Injection for treatment of ABS in patients who have no alternative treatment options.

1.6 Acute Bacterial Exacerbation of Chronic Bronchitis

Moxifloxacin Injection is indicated in adults (18 years of age or older) for the treatment of Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) caused by susceptible isolates of Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, methicillin-susceptible Staphylococcus aureus, or Moraxella catarrhalis [see  Clinical Studies (14.1)].

Because fluoroquinolones, including Moxifloxacin Injection, have been associated with serious adverse reactions [see  Warnings and Precautions (5.1 to 5.13)] and for some patients ABECB is self-limiting, reserve Moxifloxacin Injection for treatment of ABECB in patients who have no alternative treatment options.

1.7 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of moxifloxacin injection and other antibacterial drugs, moxifloxacin injection 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.

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 moxifloxacin may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.

2.1 Dosage in Adult Patients

The dose of moxifloxacin injection is 400 mg intravenously once every 24 hours.  The duration of therapy depends on the type of infection as described in Table 1.   

Table 1: Dosage and Duration of Therapy in Adult Patients

a Due to the designated pathogens [see  Indications and Usage (1), for IV use, seeUse in Specific Populations (8.5)]. 

b Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

When switching from intravenous to oral formulation, no dosage adjustment is necessary [see Clinical Pharmacology (12.4)] .  Patients whose therapy is started with moxifloxacin injection may be switched to moxifloxacin tablets when clinically indicated at the discretion of the physician.

2.2 Administration Instructions

Moxifloxacin Injection Solution for Infusion

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

Moxifloxacin injection should be administered by intravenous infusion only.  It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

Moxifloxacin injection 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 moxifloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to moxifloxacin injection 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 moxifloxacin injection with an infusion solution compatible with moxifloxacin injection as well as with other drug(s) administered via this common line.

Moxifloxacin Injection is compatible with the following intravenous solutions at ratios from 1:10 to 10:1

0.9% Sodium Chloride Injection, USP                            Sterile Water for Injection, USP

1 molar Sodium Chloride Injection                                   10% Dextrose for Injection, USP

5% Dextrose Injection, USP                                             Lactated Ringer’s for Injection

2.3 Preparation for Administration of Moxifloxacin Injection

To prepare moxifloxacin injection premix in flexible plastic containers:

1.  Close flow control clamp of administration set.

2.  Remove cover from port at bottom of container.

3.  Insert piercing pin from an appropriate transfer set (for example, one that does not require excessive force, such as ISO compatible administration set) into port with a gentle twisting motion until pin is firmly seated.

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

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

Fluoroquinolones, including Moxifloxacin Injection, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient.  Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion).  These reactions can occur within hours to weeks after starting moxifloxacin.  Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see  Warnings and Precautions (5.2,5.3,5.4)] .

Discontinue Moxifloxacin Injection immediately at the first signs or symptoms of any serious adverse reaction.  In addition, avoid the use of fluoroquinolones, including moxifloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture

Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see  Warnings and Precautions (5.1) and  Adverse Reactions (6.2)] .  This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons.  Tendinitis or tendon rupture can occur within hours or days of starting moxifloxacin or as long as several months after completion of therapy.  Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.  Other factors 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.  Discontinue moxifloxacin 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)].   Avoid fluoroquinolones, including moxifloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture [see  Adverse Reactions (6.2)] .

5.3 Peripheral Neuropathy

Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of peripheral neuropathy.  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 fluoroquinolones including moxifloxacin.  Symptoms may occur soon after initiation of moxifloxacin and may be irreversible in some patients [see  Warnings and Precautions (5.1) and  Adverse Reactions (6.1,6.2)] .

Discontinue moxifloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation.  Avoid fluoroquinolones, including moxifloxacin, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6.2,6.4) and  Patient Counseling Information  (17)]. 

5.4 Central Nervous System Effects

Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of central nervous system (CNS) reactions, including: convulsions and increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis.  Fluoroquinolones may also cause CNS reactions of nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts [see Adverse Reactions (6.2,6.4)].

These reactions may occur following the first dose.  If these reactions occur in patients receiving moxifloxacin, discontinue moxifloxacin immediately and institute appropriate measures.  As with all fluoroquinolones, moxifloxacin 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 (7.3), Adverse Reactions (6.2,6.4) and  Patient Counseling Information (17)].

5.5 Exacerbation of Myasthenia Gravis

Fluoroquinolones, including moxifloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis.  Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis.  Avoid moxifloxacin in patients with known history of myasthenia gravis [see  Patient Counseling Information (17)].

5.6 QT Prolongation

Moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some patients.  Following oral dosing with 400 mg of moxifloxacin 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 moxifloxacin and other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants have not been performed.  An additive effect of moxifloxacin and these drugs cannot be excluded; therefore caution should be exercised when moxifloxacin is given concurrently with these drugs.  In premarketing clinical trials, the rate of cardiovascular adverse events was similar in 798 moxifloxacin and 702 comparator treated patients who received concomitant therapy with drugs known to prolong the QTc interval.

Moxifloxacin 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 torsades de pointes.  No excess in cardiovascular morbidity or mortality attributable to QTc prolongation occurred with moxifloxacin 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 moxifloxacin tablet treated patients in a postmarketing observational study in which ECGs were not performed.  Elderly patients using moxifloxacin injection may be more susceptible to drug-associated QT prolongation [see Use in Specific Populations (8.5)].   In addition, moxifloxacin should be used with caution in patients with mild, moderate, or severe liver cirrhosis [see  Clinical Pharmacology (12.3) and  Patient Counseling Information (17)].

5.7 Hypersensitivity Reactions

Serious anaphylactic reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including moxifloxacin.  Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching.  Discontinue Moxifloxacin Injection at the first appearance of a skin rash or any other sign of hypersensitivity [see Warnings and Precautions (5.7),  Adverse Reactions (6) and  Patient Counseling Information (17)].

5.8 Other Serious and Sometimes Fatal Adverse Reactions

Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including moxifloxacin.  These events may be severe and generally occur following the administration of multiple doses.  Clinical manifestations may include one or more of the following:

• Fever, rash, or severe dermatologic reactions (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

Discontinue Moxifloxacin Injection 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) and  Adverse Reactions (6.4)].

5.9 Clostridium Difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including moxifloxacin, 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)].

5.10 High Sodium Load

Each unit dose of moxifloxacin injection contains 52.5 mEq (1,207 mg) of sodium.  Avoid use of moxifloxacin injection in patients with congestive heart failure, elderly, and those with restricted sodium intake [see Use in Specific Populations (8.5),  Description (11)] .

5.11 Arthropathic Effects in Animals

The oral administration of moxifloxacin 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  Nonclinical Toxicology (13.2)] .

5.12 Blood Glucose Disturbances

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with moxifloxacin.  In moxifloxacin-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (for example, sulfonylurea) or with insulin.  In diabetic patients, careful monitoring of blood glucose is recommended [see Adverse Reactions (6.2)] .  If a hypoglycemic reaction occurs, moxifloxacin should be discontinued and appropriate therapy should be initiated immediately [see  Adverse Reactions (6.2) and  Patient Counseling Information (17)] . 

5.13 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  Clinical Pharmacology (12.3)]. 

5.14 Development of Drug Resistant Bacteria

Prescribing moxifloxacin 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)].

6.1 Serious and Otherwise Important Adverse Reactions

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

• Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects [see  Warnings and Precautions (5.1)]

• Tendinitis and Tendon Rupture [see Warnings and Precautions (5.2)]

• Peripheral Neuropathy [see  Warnings and Precautions (5.3)]

• Central Nervous System Effects [see  Warnings and Precautions (5.4)]

• Exacerbation of Myasthenia Gravis [see  Warnings and Precautions (5.5)]

• QT Prolongation [see  Warnings and Precautions (5.6)]

• Hypersensitivity Reactions [see  Warnings and Precautions (5.7)]

• Other Serious and Sometimes Fatal Adverse Reactions [see  Warnings and Precautions (5.8)]

• Clostridium Difficile-Associated Diarrhea [see  Warnings and Precautions (5.9)]

• Blood Glucose Disturbances [see  Warnings and Precautions( 5.12)]

• Photosensitivity/Phototoxicity [see  Warnings and Precautions (5.13)]

• Development of Drug Resistant Bacteria [see  Warnings and Precautions (5.14)]

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 moxifloxacin in 14,981 patients in 71 active controlled Phase II - IV clinical trials in different indications [seeIndications 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 moxifloxacin 400 mg once daily PO, IV, or sequentially (IV followed by PO).  Treatment duration was usually 6 to 10 days, and the mean number of days on therapy was 9 days. 

Discontinuation of moxifloxacin due to adverse events occurred in 5% 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%) and pyrexia (0.4%).

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

Table 2: Common (≥ 1%) Adverse Reactions Reported in Active-Controlled Clinical Trials with Moxifloxacin

a MedDRA Version 12.0

Table 3: Less Common (0.1 to < 1%) Adverse Reactions Reported in Active-Controlled

                                          Clinical Trials with Moxifloxacin (N=14,981)

a MedDRA Version 12.0

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, pO 2, 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 moxifloxacin.  Because these reactions 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. 

Table 4: Postmarketing Reports of Adverse Drug Reactions

7.1 Warfarin

Quinolones, including moxifloxacin, 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 [seeAdverse Reactions (6.2, 6.3) , Clinical Pharmacology (12.3), and Patient Counseling Information (17)].

7.2 Antidiabetic Agents

Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent.  Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered.  If a hypoglycemic reaction occurs, moxifloxacin should be discontinued and appropriate therapy should be initiated immediately [see  Warnings and Precautions (5.12),  Adverse Reactions (6.2), and  Patient Counseling Information (17)].

7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Although not observed with moxifloxacin 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 (5.4), and Patient Counseling Information (17)] .  

7.4 Drugs that Prolong QT

There is limited information available on the potential for a pharmacodynamic interaction in humans between moxifloxacin 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) moxifloxacin in dogs.  Therefore, moxifloxacin should be avoided with Class IA and Class III antiarrhythmics [see  Warnings and Precautions (5.6), Nonclinical Toxicology (13.2), and  Patient Counseling Information (17)].

8.1 Pregnancy

Pregnancy Category C. Because no adequate or well-controlled studies have been conducted in pregnant women, moxifloxacin 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) 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 moxifloxacin, 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.  Moxifloxacin causes arthropathy in juvenile animals [see Boxed Warning,  Warnings and Precautions (5.11),  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 moxifloxacin.  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 moxifloxacin to elderly patients especially those on corticosteroids.  Patients should be informed of this potential side effect and advised to discontinue moxifloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see  Boxed Warning,Warnings and Precautions (5.1,5.2), and  Adverse Reactions (6.4)] . 

Moxifloxacin injection contains 1,207 mg (52.5 mEq) of sodium per unit dose.  The geriatric population may respond with a blunted natriuresis to salt loading.  This may be clinically important with regard to such diseases as congestive heart failure [see  Warnings and Precautions (5.10)] . 

In controlled multiple-dose clinical trials, 23% of patients receiving oral moxifloxacin were greater than or equal to 65 years of age and 9% were greater than or equal to 75 years of age.  The clinical trial data demonstrate that there is no difference in the safety and efficacy of oral moxifloxacin in patients aged 65 or older compared to younger adults.  

In trials of intravenous use, 42% of moxifloxacin patients were greater than or equal to 65 years of age, and 23% were greater than or equal to 75 years of age.  The clinical trial data demonstrate that the safety of intravenous moxifloxacin in patients aged 65 or older was similar to that of comparator-treated patients.  In general, elderly patients may be more susceptible to drug-associated effects of the QT interval.  Therefore, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval (for example, Class IA or Class III antiarrhythmics) or in patients with risk factors for torsades de pointes (for example, known QT prolongation, uncorrected hypokalemia) [see  Warnings and Precautions (5.6),  Drug Interactions (7.4), and Clinical Pharmacology (12.3)]. 

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, moxifloxacin should be used with caution in these patients [see  Warnings and Precautions (5.6), and  Clinical Pharmacology (12.3)] . 

12.1 Mechanism of Action

Moxifloxacin is a member of the fluoroquinolone class of antibacterial agents [seeMicrobiology (12.4)]. 

12.3 Pharmacokinetics

The mean (± SD) pharmacokinetic parameters of moxifloxacin following single and multiple dose of 400 mg moxifloxacin given by 1 hour intravenous infusion are summarized in Table 5.  The mean (± SD) elimination half-life from plasma is 12 ± 1.3 hours; steady-state is achieved after at least three days with a 400 mg once daily regimen.  The absolute bioavailability of moxifloxacin is approximately 90 percent.  When switching from intravenous to oral formulation, no dosage adjustment is necessary [seeDosage and Administration (2.1)].

Table 5: Mean (± SD) Cmaxand AUC Values Following Single and Multiple

Doses of 400 mg Moxifloxacin Given by 1 Hour Intravenous Infusion

a Range of means from different studies

b Expected C max (concentration obtained around the time of the end of the infusion)

Distribution

Moxifloxacin is approximately 30 to 50% bound to serum proteins, independent of drug concentration.  The volume of distribution of moxifloxacin ranges from 1.7 to 2.7 L/kg.  Moxifloxacin is widely distributed throughout the body, with tissue concentrations often exceeding plasma concentrations.  Moxifloxacin has been detected in the saliva, nasal and bronchial secretions, mucosa of the sinuses, skin blister fluid, subcutaneous tissue, skeletal muscle, and abdominal tissues and fluids following oral or intravenous administration of 400 mg.  Moxifloxacin concentrations measured post-dose in various tissues and fluids following a 400 mg oral or intravenous dose are summarized in Table 6.  The rates of elimination of moxifloxacin from tissues generally parallel the elimination from plasma.

Table 6: Moxifloxacin Concentrations (mean ± SD) in Tissues and the Corresponding Plasma
                           Concentrations After a Single 400 mg Oral or Intravenous Dose a

a All moxifloxacin concentrations were measured 3 hours after a single 400 mg dose, except the abdominal tissue and exudate concentrations which were measured at 2 hours post-dose and the sinus concentrations which were measured 3 hours post-dose after 5 days of dosing.

b N = 5

c N = 7

d N = 12

e Reflects only non-protein bound concentrations of drug.

Metabolism

Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation.  The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin.  The sulfate conjugate (M1) accounts for approximately 38% of the dose, and is eliminated primarily in the feces.  Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2), which is excreted exclusively in the urine.  Peak plasma concentrations of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are generally less than 10% those of moxifloxacin.  

In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, 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 to 75 years) and 24 healthy females (19 to 70 years), the mean AUC and C max were 8% and 16% higher, respectively, in females compared to males.  There are no significant differences in moxifloxacin pharmacokinetics between male and female subjects when differences in body weight are taken into consideration.  

A 400 mg single dose study was conducted in 18 young males and females.  The comparison of moxifloxacin pharmacokinetics in this study (9 young females and 9 young males) showed no differences in AUC or C max due to gender.  Dosage adjustments based on gender are not necessary.                        

Race

Steady-state moxifloxacin pharmacokinetics in male Japanese subjects were similar to those determined in Caucasians, with a mean C max of 4.1 mcg/mL, an AUC 24 of 47 mcg•h/mL, and an elimination half-life of 14 hours, following 400 mg p.o. daily.  

Renal Insufficiency

The pharmacokinetic parameters of moxifloxacin are not significantly altered in mild, moderate, severe, or end-stage renal disease.  No dosage adjustment is necessary in patients with renal impairment, including those patients requiring hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).  

In a single oral dose study of 24 patients with varying degrees of renal function from normal to severely impaired, the mean peak concentrations (C max) of moxifloxacin were reduced by 21% and 28% in the patients with moderate (CL CR ≥ 30 and ≤ 60 mL/min) and severe (CL CR < 30 mL/min) renal impairment, respectively.  The mean systemic exposure (AUC) in these patients was increased by 13%.  In the moderate and severe renally impaired patients, the mean AUC for the sulfate conjugate (M1) increased by 1.7-fold (ranging up to 2.8-fold) and mean AUC and C max for the glucuronide conjugate (M2) increased by 2.8-fold (ranging up to 4.8-fold) and 1.4-fold (ranging up to 2.5-fold), respectively [see Use in Specific Populations (8.6)]. 

The pharmacokinetics of single dose and multiple dose moxifloxacin were studied in patients with CL CR < 20 mL/min on either hemodialysis or continuous ambulatory peritoneal dialysis (8 HD, 8 CAPD).  Following a single 400 mg oral dose, the AUC of moxifloxacin in these HD and CAPD patients did not vary significantly from the AUC generally found in healthy volunteers.  C max values of moxifloxacin were reduced by about 45% and 33% in HD and CAPD patients, respectively, compared to healthy, historical controls.  The exposure (AUC) to the sulfate conjugate (M1) increased by 1.4- to 1.5-fold in these patients.  The mean AUC of the glucuronide conjugate (M2) increased by a factor of 7.5, whereas the mean C max values of the glucuronide conjugate (M2) increased by a factor of 2.5 to 3, compared to healthy subjects.  The sulfate and the glucuronide conjugates of moxifloxacin are not microbiologically active, and the clinical implication of increased exposure to these metabolites in patients with renal disease including those undergoing HD and CAPD has not been studied.  

Oral administration of 400 mg QD moxifloxacin 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, moxifloxacin should be used with caution in these patients [see Warnings and Precautions (5.6) and  Use in Specific Populations (8.7)].

In 400 mg single oral dose studies in 6 patients with mild (Child-Pugh Class A) and 10 patients with moderate (Child-Pugh Class B) hepatic insufficiency, moxifloxacin mean systemic exposure (AUC) was 78% and 102%, respectively, of 18 healthy controls and mean peak concentration (C max) was 79% and 84% of controls.  

The mean AUC of the sulfate conjugate of moxifloxacin (M1) increased by 3.9-fold (ranging up to 5.9-fold) and 5.7-fold (ranging up to 8-fold) in the mild and moderate groups, respectively.  The mean C max of M1 increased by approximately 3-fold in both groups (ranging up to 4.7- and 3.9-fold).  The mean AUC of the glucuronide conjugate of moxifloxacin (M2) increased by 1.5-fold (ranging up to 2.5-fold) in both groups.  The mean C max of M2 increased by 1.6- and 1.3-fold (ranging up to 2.7- and 2.1-fold), respectively.  The clinical significance of increased exposure to the sulfate and glucuronide conjugates has not been studied.  In a subset of patients participating in a clinical trial, the plasma concentrations of moxifloxacin and metabolites determined approximately at the moxifloxacin T max following the first intravenous or oral moxifloxacin 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 moxifloxacin does not show phototoxicity in comparison to placebo.  The minimum erythematous dose (MED) was measured before and after treatment with moxifloxacin (200 mg or 400 mg once daily), lomefloxacin (400 mg once daily), or placebo.  In this study, the MED measured for both doses of moxifloxacin 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 (5.13), Adverse Reactions (6.3), andPatient Counseling Information (17)].

Drug-Drug Interactions

The following drug interactions were studied in healthy volunteers or patients.   

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, cyclosporine and warfarin [see  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.  

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.  

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 7th 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)andDrug Interactions (7.1)].

12.4 Microbiology

Mechanism of Action

The bactericidal action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication, transcription, repair, and recombination.  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.

Mechanism of Resistance

The mechanism of action for fluoroquinolones, including moxifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin.  Resistance to fluoroquinolones occurs primarily by a mutation in topoisomerase II (DNA gyrase) or topoisomerase IV genes, decreased outer membrane permeability or drug efflux.  In vitro resistance to moxifloxacin develops slowly via multiple-step mutations.  Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8 x 10 -9 to < 1 x 10 -11 for Gram-positive bacteria.

Cross-Resistance

Cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria.  Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to moxifloxacin.  There is no known cross-resistance between moxifloxacin and other classes of antimicrobials. 

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

Gram-positive bacteria

• Enterococcus faecalis

• Staphylococcus aureus

• Streptococcus anginosus

• Streptococcus constellatus

• Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]**)

• Streptococcus pyogenes

**MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antibacterial drugs: penicillin (MIC) ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Gram-negative bacteria

• Enterobacter cloacae

• Escherichia coli

• Haemophilus influenzae

• Haemophilus parainfluenzae

• Klebsiella pneumoniae

• Moraxella catarrhalis

• Proteus mirabilis

Anaerobic bacteria

• Bacteroides fragilis

• Bacteroides thetaiotaomicron

• Clostridium perfringens

• Peptostreptococcus species

Other microorganisms

• Chlamydophila pneumoniae

• Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown.  At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 1 mcg/mL for moxifloxacin.  However, the efficacy of moxifloxacin in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.

Gram-positive bacteria

• Staphylococcus epidermidis

• Streptococcus agalactiae

• Streptococcus viridans group

Gram-negative bacteria

• Citrobacter freundii

• Klebsiella oxytoca

• Legionella pneumophila

Anaerobic bacteria

• Fusobacterium species

• Prevotella species

Susceptibility Tests Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community acquired pathogens.  These reports should aid the physician in selecting an antibacterial drug product for treatment.

• Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs).  These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds.  The MICs should be determined using a standardized procedure.  Standardized procedures are based on a dilution method (broth and/or agar). 1  The MIC values should be interpreted according to the criteria in Table 7.

• Diffusion Techniques:

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.  The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds.  The zone size prove should be determined using a standardized test method. 2,3  This procedure uses paper disks impregnated with 5 mcg moxifloxacin to test the susceptibility of bacteria to moxifloxacin.  The disc diffusion interpretive criteria are provided in Table 7.

• Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to moxifloxacin can be determined by a standardized test method. 4  The MIC values obtained should be interpreted according to the criteria provided in Table 7.

                Table 7: Susceptibility Test Interpretive Criteria for Moxifloxacin

S=susceptible, I=Intermediate, and R=resistant.

a The current absence of data on moxifloxacin-resistant isolates precludes defining any  

   results other than “Susceptible”.  Isolates yielding test results (MIC or zone diameter) other

   than susceptible, should be submitted to a reference laboratory for additional testing.

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen.  A report of “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 the drug product can be used.  This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation.  A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

• Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test. 1,2,3,4  Standard moxifloxacin powder should provide the following range of MIC values noted in Table 8.  For the diffusion technique using the 5 mcg moxifloxacin disk, the criteria in Table 8 should be achieved.

Table 8: Acceptable Quality Control Ranges for Moxifloxacin

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), or at intravenous doses as high as 45 mg/kg/day, (approximately equal to the maximum recommended human dose based on body surface area).  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 moxifloxacin should be avoided. 

14.1 Acute Bacterial Exacerbation of Chronic Bronchitis

Moxifloxacin 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 moxifloxacin with clarithromycin (500 mg twice daily for 10 days) and enrolled 629 patients.  Clinical success was assessed at 7 to 17 days post-therapy.  The clinical success for moxifloxacin was 89% (222/250) compared to 89% (224/251) for clarithromycin. 

Table 9: Clinical Success Rates at Follow-Up Visit for
Clinically Evaluable Patients by Pathogen (Acute Bacterial
                  Exacerbation of Chronic Bronchitis)

The microbiological eradication rates (eradication plus presumed eradication) in moxifloxacin-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 moxifloxacin 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 to 35 day follow-up visit).  Clinical success for clinically evaluable patients was 95% (184/194) for moxifloxacin 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 moxifloxacin 400 mg QD for 7 to 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 to 30 day post-therapy visit.  The clinical success rate was 86% (157/182) for moxifloxacin therapy and 89% (161/180) for the fluoroquinolone comparators.

An open-label ex-US study that enrolled 628 patients compared moxifloxacin 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 to 7 for moxifloxacin 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 to 28 days post-therapy visit for moxifloxacin 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 10. 

Table 10: Clinical Success Rates by 
    Pathogen (Pooled CAP Studies)

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

Moxifloxacin was effective in the treatment of community acquired pneumonia (CAP) caused by multi-drug resistant 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 11.

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

    Table 11: Clinical and Bacteriological Success Rates for Moxifloxacin-Treated

                    MDRSP CAP Patients (Population: Valid for Efficacy)

a n = number of patients successfully treated; N = number of patients with MDRSP (from a

  total of   37 patients)

b n = number of patients successfully treated (presumed eradication or eradication);

   N = number of patients with MDRSP (from a total of 37 patients)

c 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.

d Azithromycin, clarithromycin, and erythromycin were the macrolide antimicrobials tested.

Not all isolates were resistant to all antimicrobial classes tested.  Success and eradication rates are summarized in Table 12.

Table 12: Clinical Success Rates and Microbiological Eradication Rates for Resistant

            Streptococcus pneumoniae (Community Acquired Pneumonia)

a 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.

14.4 Acute Bacterial Sinusitis

In a controlled double-blind study conducted in the US, moxifloxacin 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 moxifloxacin 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 moxifloxacin 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 moxifloxacin 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 moxifloxacin-treated patients and 14% of the comparator treated patients.  Clinical success rates in evaluable patients were 89% (108/122) for moxifloxacin 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 moxifloxacin 400 mg QD for 7 to 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 moxifloxacin 400 mg QD for 7 to 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 moxifloxacin-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 13 and 14.

Table 13: Overall Clinical Success Rates in Patients with Complicated

                                Skin and Skin Structure Infections

* of difference in success rates between moxifloxacin and comparator (moxifloxacin - comparator)

Table 14: Clinical Success Rates by Pathogen in Patients with Complicated

                           Skin and Skin Structure Infections

a  methicillin susceptibility was only determined in the North American Study  

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 moxifloxacin 400 mg QD for 5 to 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 moxifloxacin 400 mg QD for 5 to 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 to 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 15.

Table 15: Clinical Success Rates in Patients with Complicated Intra-Abdominal Infections

a of difference in success rates between moxifloxacin and comparator (moxifloxacin –

  comparator)

b Excludes 2 patients who required additional surgery within the first 48 hours.

c NA – not applicable