Moxifloxacin

12.1 Mechanism of Action Moxifloxacin hydrochloride is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4) ] .

1 INDICATIONS AND USAGE Moxifloxacin tablets are a fluoroquinolone antibacterial indicated for treating infections in adults 18 years of age and older caused by designated susceptible bacteria, in the conditions listed below: Community Acquired Pneumonia ( 1.1 ) Skin and Skin Structure Infections: Uncomplicated ( 1.2 ) and Complicated ( 1.3 ) Complicated Intra-Abdominal Infections ( 1.4 ) Plague ( 1.5 ) Acute Bacterial Sinusitis ( 1.6 ) Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.7 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of moxifloxacin tablets and other antibacterial drugs. Moxifloxacin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.8 ) 1.1 Community Acquired Pneumonia Moxifloxacin tablets are indicated in adult patients for the treatment of Community Acquired Pneumonia caused by susceptible isolates of Streptococcus pneumoniae (including multi-drug resistant Streptococcus pneumoniae [MDRSP]) , Haemophilus influenzae, Moraxella catarrhalis, methicillin-susceptible Staphylococcus aureus, Klebsiella pneumoniae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Clinical Studies (14.3) ] . MDRSP isolates are isolates resistant to two or more of the following antibacterial drugs: penicillin (minimum inhibitory concentrations [MIC] ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. 1.2 Uncomplicated Skin and Skin Structure Infections Moxifloxacin tablets are indicated in adult patients 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 (14.4) ]. 1.3 Complicated Skin and Skin Structure Infections Moxifloxacin tablets are indicated in adult patients for the treatment of Complicated Skin and Skin S

2 DOSAGE AND ADMINISTRATION Type of Infection Dose Every 24 hours Duration (days) Community Acquired Pneumonia ( 1.1 ) 400 mg 7 to 14 Uncomplicated Skin and Skin Structure Infections (SSSI) ( 1.2 ) 400 mg 7 Complicated SSSI ( 1.3 ) 400 mg 7 to 21 Complicated Intra-Abdominal Infections ( 1.4 ) 400 mg 5 to 14 Plague ( 1.5 ) 400 mg 10 to 14 Acute Bacterial Sinusitis ( 1.6 ) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.7 ) 400 mg 5 No dosage adjustment in patients with renal or hepatic impairment. ( 8.6 , 8.7 ) 2.1 Dosage in Adult Patients The dose of moxifloxacin is 400 mg (orally) 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) ] . b) Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician c) Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis . Type of Infection a Dose Every 24 hours Duration b (days) Community Acquired Pneumonia ( 1.1 ) 400 mg 7 to 14 Uncomplicated Skin and Skin Structure Infections (SSSI) ( 1.2 ) 400 mg 7 Complicated SSSI ( 1.3 ) 400 mg 7 to 21 Complicated Intra-Abdominal Infections ( 1.4 ) 400 mg 5 to 14 Plague ( 1.5 ) C 400 mg 10 to 14 Acute Bacterial Sinusitis (ABS) ( 1.6 ) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) ( 1.7 ) 400 mg 5 Conversion of Intravenous to Oral Dosing in Adults Intravenous formulation is indicated when it offers a route of administration advantageous to the patient (for example, patient cannot tolerate an oral dosage form). When switching from intravenous to oral formulation, no dosage adjustment is necessary. Patients whose therapy is started with moxifloxacin hydrochloride injection may be switched to moxifloxacin tablets when clinically indicated at the discretion of the physician. 2.2 Important Administration Instructions With Multivalent Cations Administer moxifloxacin tablets at least 4 hours before or 8 hours after products containing magnesium, aluminum, iron or zinc, including antacids, sucralfate, multivitamins and didanosine buffered tablets for oral suspension or the pediatric powder for oral solution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. With Food Moxifloxacin tablets can be taken with or without food, drink fluids liberally. Missed Doses If a dose is missed, it should be taken anytime but not later than 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

6 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) ] Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions (5.7) ] Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions (5.9) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.10) ] 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) ] Most common reactions (3% or greater) were nausea, diarrhea, headache, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 hydrochloride in 14981 patients in 71 active controlled Phase II to 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 less than 65 years of age), 50% were male, 63% were Caucasian, 12% were Asian and 9% were Black. Patients received moxifloxacin 400 mg once daily oral, intravenous, or sequentially (intravenous followed by oral). 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 reactions occurred in 5% of patients overall, 4% of patients treated with 400 mg PO, 4% with 400 mg intravenous and 8% with sequential therapy 400 mg oral/intravenous. The most common adverse reactions (>0.3%) leading to discontinuation with the 400 mg oral doses were nausea, diarrhea, dizziness, and vomiting. The most common adverse reaction leading to discontinuation with the 400 mg intravenous dose was rash. The most common adverse reactions leading to discontinuation with the 400 mg intravenous/oral sequential dose were diarrhea, pyrexia. Adverse reactions occurring in 1% of moxifloxacin hydrochloride-treated patients and less common adverse reactions, occurring in 0.1 to 1% of moxifloxacin hydrochloride-treated patients, are shown in Tables 2 and Table 3, respectively. The most common adverse drug reactions (3%) are nausea, diarrhea, headache, and dizziness. Table 2: Common (1% or more) Adverse Reactions Reported in Active-Controlled Clinical Trials with Moxifloxacin Hydrochloride System Organ Class Adverse Reactions % (N=14,981) Blood and Lymphatic System Disorders Anemia 1 Gastrointestinal Disorders Nausea 7 Diarrhea 6 Vomiting 2 Constipation 2 Abdominal pain 2 Dyspepsia 1 General Disorders and Administration Site Conditions Pyrexia 1 Investigations Alanine aminotransferase increased 1 Metabolism and Nutritional Disorder Hypokalemia 1 Nervous System Disorders Headache 4 Dizziness 3 Psychiatric Disorders Insomnia 2 Table 3: Less Common (0.1 to less than 1%) Adverse Reactions Reported in Active-Controlled Clinical Trials with Moxifloxacin Hydrochloride (N=14,981) System Organ Class Adverse Reactions Blood and Lymphatic System Disorders Thrombocythemia Eosinophilia Neutropenia Thrombocytopenia Leukopenia Leukocytosis Cardiac Disorders Atrial fibrillation Palpitations Tachycardia 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 Pain Malaise Infusion site extravasation Edema Chills Chest discomfort Facial pain Hepatobiliary disorders Hepatic function abnormal Infections and Infestations Candidiasis Vaginal infection Fungal infection Gastroenteritis Investigations Aspartate aminotransferase increased Gamma-glutamyltransferase increased Blood alkaline phosphatase increased Electrocardiogram QT prolonged Blood lactate dehydrogenase increased Blood amylase

7 DRUG INTERACTIONS Interacting Drug Interaction Multivalent cation-containing products including: antacids, sucralfate, multivitamins Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin tablet at least 4 hours before or 8 hours after these products. ( 2.2 , 7.1 , 12.3 ) Warfarin Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( 6 , 7.2 , 12.3 ) Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. ( 5.6 , 7.5 ) Antidiabetic agents Carefully monitor blood glucose. ( 5.12 , 7.3 ) 7.1 Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations Fluoroquinolones, including moxifloxacin hydrochloride, form chelates with alkaline earth and transition metal cations. Oral administration of moxifloxacin hydrochloride with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as didanosine buffered tablets for oral suspension or the pediatric powder for oral solution, may substantially interfere with the absorption of moxifloxacin hydrochloride, resulting in systemic concentrations considerably lower than desired. Therefore, moxifloxacin hydrochloride should be taken at least 4 hours before or 8 hours after these agents [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ]. 7.2 Warfarin Fluoroquinolones, including moxifloxacin hydrochloride, 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 moxifloxacin hydrochloride is administered concomitantly with warfarin or its derivatives [see Adverse Reactions (6.2) and Clinical Pharmacology (12.3) ]. 7.3 Antidiabetic Agents Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones, including moxifloxacin hydrochloride, and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered. If a hypoglycemic reaction occurs, moxifloxacin hydrochloride should be discontinued and appropriate therapy should be initiated immediately [see Warnings and Precautions (5.12) and Adverse Reactions (6.1) ]. 7.4 Nonsteroidal Anti-Inflammatory Drugs The concomitant administration of a nonsteroidal anti-inflammatory drug (NSAID) with a fluoroquinolone, including moxifloxacin hydrochloride, may increase the risks of CNS stimulation and convulsions [see Warnings and Precautions (5.4) ]. 7.5 Drugs that Prolong QT There is limited information available on the potential for a pharmacodynamic interaction in humans between moxifloxacin hydrochloride 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 moxifloxacin hydrochloride in dogs. Therefore, moxifloxacin hydrochloride should be avoided with Class IA and Class III antiarrhythmics [see Warnings and Precautions (5.6) , and Nonclinical Toxicology (13.2) ].