Moxifloxacin injection is a fluoroquinolone antibacterial drug indicated for treating infections in adults ≥ 18 years of age caused by designated, susceptible bacteria. ( 1 , 12.4 ) Community Acquired Pneumonia ( 1.1 ) Skin and Skin Structure Infections: Uncomplicated ( 1.2 ) and Complicated ( 1.3 ) Complicated Intra-Abdominal Infections ( 1.4 ) Acute Bacterial Sinusitis ( 1.5 ) Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.6 )
1.1Community 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) ] .
1.2Uncomplicated 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) ].
1.3Complicated 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) ].
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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) ] .
1.5Acute 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.
1.6Acute 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.
1.7Usage
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.
Contraindications
Moxifloxacin is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antimicrobial agents. Known hypersensitivity to moxifloxacin or other quinolones. ( 4 , 5.7 )
Warnings and precautions
Prolongation of the QT interval and isolated cases of torsades de pointes has been reported. Avoid use in patients with known prolongation, hypokalemia, and with drugs that prolong the QT interval. ( 5.6 , 7.4 , 8.5 ). Use caution in patients with proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia. ( 5.6 ) Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur after first or subsequent doses.
Discontinue moxifloxacin at the first sign of skin rash, jaundice or any other sign of hypersensitivity. ( 5.7 , 5.8 ) Clostridium difficile -associated diarrhea: Evaluate if diarrhea occurs. ( 5.9 ) High sodium load: each unit dose contains 52.5 mEq (1,207 mg) of sodium. Avoid in patients with sodium restriction. ( 5.10 )
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.
5.2Tendinitis 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) ] .
5.3Peripheral 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) ].
5.4Central 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) ].
5.5Exacerbation 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) ].
5.6QT 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 formulat
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Interactions
Interacting Drug Interaction Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( 6.4 , 7.1 , 12.3 ) Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. ( 5.6 , 7.4 ) Antidiabetic agents Carefully monitor blood glucose. ( 5.12 , 7.2 )
7.1Warfarin
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 [see Adverse Reactions (6.2 , 6.3 ) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] .
7.2Antidiabetic 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)] .
7.3Nonsteroidal 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) ].
Pregnancy and breastfeeding
8.1Pregnancy 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.
Adverse reactions
Most common reactions (≥ 3%) were nausea, diarrhea, headache, and dizziness. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Serious 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) ]
6.2Clinical 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 [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 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 System Organ Class Adverse Reactions a % (N=14,981) Blood and Lymphatic System Disorders Anemia
1.1 Gastrointestinal Disorders Nausea
6.9 Diarrhea 6 Vomiting
2.4 Constipation
1.9 Abdominal pain
1.5 Abdominal pain upper
1.1 Dyspepsia 1 General Disorders and Administration Site Conditions Pyrexia
1.1Investigations
Alanine aminotransferase increased
1.1 Metabolism and Nutritional Disorder Hypokalemia 1 Nervous System Disorders Headache Dizziness 4.2 3 Psychiatric Disorders Insomnia 1.9 a MedDRA Version
12.0Table 3: Less Common (0.1
to < 1%) Adverse Reactions Reported in Active-Controlled Clinical Trials with Moxifloxacin (N=14,981) System Organ Class Adverse Reactions a Blood and Lymphatic System Disorders Thrombocythemia Eosinophilia Neutropenia Thrombocytopenia Leukopenia Leukocytosis Cardiac Disorders Atrial fibrillation Palpitations Tachycardia Cardiac failure congestive Angina pectoris Cardiac failure Cardiac arrest Bradycardia Ear and Labyrinth Disorders Vertigo Tinnitus Eye Disorders Vision blurred Gastrointestinal Disorders Dry mouth Abdominal discomfort Flatulence Abdominal distention Gastritis Gastroesophageal reflux disease General Disorders and Administration Site Conditions Fatigue Chest pain Asthenia Edema peripheral Pain Malaise Infusion site extravasation Edema Chills Chest discomfort Facial pain Hepatobiliary Disorders Hepatic function abnormal Infections and Infestations Vulvovaginal candidiasis Oral candidiasis Vulvovaginal mycotic infection Candidiasis Vaginal infection Oral fungal infection Fungal infection Gastroenteritis Investigations Aspartate aminotransferase increased Gamma-glutamyltransferase increased Blood alkaline phosphatase increased Hepatic enzyme increased Electrocardiogram QT prolonged Blood lactate dehydrogenase increased Platelet count increased Blood amylase increased Blood glucose increased Lipase increased Hemoglobin decreased Blood creatinine increased Transaminases increased White blood cell count increased Blood urea increased Liver function test abnormal Hematocrit decreased Prothrombin time prolonged Eosinophil count increased Activated partial thromboplastin time prolonged Blood bilirubin increased Blood triglycerides increased Blood uric acid increased Blood pressure increased Metabolism and Nutrition Disorders Hyperglycemia Anorexia Hypoglycemia Hyperlipidemia Decreased appetite Dehydration Musculoskeletal and Connective Tissue Disorders Back pain Pain in extremity Arthralgia Myalgia Muscle spasms Musculoskeletal chest pain Musculoskeletal pain Nervous System Disorders Dysgeusia Somnolence Tremor Lethargy Paresthesia Tension headache Hypoesthesia Syncope Psychiatric Disorders Anxiety Confusional state Agitation Depression Nervousness Restlessness Hallucination Disorientation Renal and Urinary Disorders Renal failure Dysuria Renal failure acute Reproductive System and Breast Disorders Vulvovaginal pruritus Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Asthma Wheezing Bronchospasm Skin and Subcutaneous Tissue Disorders Rash Pruritus Hyperhidrosis Erythema Urticaria Dermatitis allergic Night sweats Vascular Disorders Hypertension Hypotension Phlebitis a MedDRA Version 12.0
6.3Laboratory 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.
6.4Postmarketing 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 System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders Agranulocytosis Pancytopenia [see Warnings and Precautions (5.8) ] Cardiac Disorders Ventricular tachyarrhythmias (including in very rare cases cardiac arrest and torsades de pointes, and usually in patients with concurrent severe underlying proarrhythmic conditions) Ear and Labyrinth Disorders Hearing impairment, including deafness (reversible in majority of cases) Eye Disorders Vision loss (especially in the course of CNS reactions, transient in majority of cases) Hepato
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