Moxifloxacin Hydrochloride Tablets, 400 mg

Warnings and Precautions ( 5.4, 5.11 ) 10/2018

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 hydrochloride and other antibacterial drugs. Moxifloxacin hydrochloride 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), 2 nd 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 Structure Infections caused by susceptible isolates of methicillin- susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae [see Clinical Studies (14.5)]. 1.4 Complicated Intra-Abdominal Infections Moxifloxacin tablets are indicated in adult patients for the treatment of Complicated Intra-Abdominal Infections (cIAI) 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 (14.6)] . 1.5 Plague Moxifloxacin tablets are indicated in adult patients for the treatment of plague, including pneumonic and septicemic plague, due to susceptible isolates of Yersinia pestis and prophylaxis of plague in adult patients. Efficacy studies of moxifloxacin could not be conducted in humans with plague for feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [see Clinical Studies (14.7)]. 1.6 Acute Bacterial Sinusitis Moxifloxacin tablets are indicated in adult patients (18 years of age and older) for the treatment of Acute Bacterial Sinusitis (ABS) caused by susceptible isolates of Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.1)]. Because fluoroquinolones, including moxifloxacin tablets, have been associated with serious adverse reactions [see Warnings and Precautions (5.1 - 5.13 )] and for some patients ABS is self-limiting, reserve moxifloxacin tablets for treatment of ABS in patients who have no alternative treatment options. 1.7 Acute Bacterial Exacerbation of Chronic Bronchitis Moxifloxacin tablets are indicated in adult patients for the treatment of Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) caused by susceptible isolates of Streptococcus pneu …

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 tablets 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 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 a) Due to the designated pathogens [see Indications and Usage (1) ]. b) Sequential therapy (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 . 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 Moxifloxacin Tablets 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.

3 DOSAGE FORMS AND STRENGTHS Tablets: Moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin) ( 3.1 ) 3.1 Moxifloxacin Tablets, USP Moxifloxacin Tablets, USP are available as dull red colored, caplet shaped, film coated tablets, debossed with "M" on one side and "400" on other side.

4 CONTRAINDICATIONS Moxifloxacin hydrochloride is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antibacterials [see Warnings and Precautions (5.8) ]. Known hypersensitivity to Moxifloxacin hydrochloride or other quinolones ( 4 , 5.8 )

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) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] • Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.9) ] • Blood Glucose Disturbances [see Warnings and Precautions (5.11) ] • Photosensitivity/Phototoxicity [see Warnings and Precautions (5.12)] • Development of Drug Resistant Bacteria [see Warnings and Precautions (5.13)] Most common reactions (3% or greater) were nausea, diarrhea, headache, and dizziness ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceutical LLC at 1-855-668-2369 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 reactions 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 Table 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 Disorders 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 Sy …

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. ( 5.11 , 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), 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 (5.11) and Adverse Reactions (6.1)] . 7.4 Nonsteroidal Anti-Inflammatory Drugs The concomitant administration of a nonsteroidal anti-inflammatory drug (NSAID) with a fluoroquinolones, 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 (IV) moxifloxacin 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) .]

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data may cause fetal harm. ( 8.1 ) • Geriatrics: Increased risk for severe tendon disorders further increased by concomitant corticosteroid therapy and increased risk of prolongation of the QT interval. ( 5.1 , 5.6 , 8.5 ) 8.1 Pregnancy Risk Summary There are no available human data establishing a drug associated risk with the use of moxifloxacin. Based on animal studies with moxifloxacin, moxifloxacin may cause fetal harm. Moxifloxacin was not teratogenic when administered to pregnant rats (IV and oral), rabbits (IV), and monkeys (oral) at exposures that were 0.25–2.5 times of those at the human clinical dose (400 mg/day moxifloxacin). However, when moxifloxacin was administered to rats and rabbits during pregnancy and throughout lactation (rats only) at doses associated with maternal toxicity, decreased neonatal body weights, increased incidence of skeletal variations (rib and vertebra combined), and increased fetal loss were observed (see Data). Advise pregnant women of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Animal reproductive and development studies were done in rats, rabbits and cynomolgus macaques. Moxifloxacin was not teratogenic when administered to pregnant rats during organogenesis (gestation days 6 to 17) 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 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 (Gestation days 6 to 17). There was no evidence of teratogenicity at intravenous doses as high as 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) in pregnant rats during organogenesis (Gestation days 6 to 17). 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 (gestation days 6 to 20) 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 in rabbits. 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 macaques were given oral doses as high as 100 mg/kg/day (2.5 times the maximum recommended human dose based upon systemic exposure) during organogenesis (gestation days 20 to 50). An increased incidence of smaller fetuses was observed at 100 mg/kg/day in macaques. In a pre-and postnatal development study conducted in rats given oral doses from Gestation day 6, throughout gestation and rearing to Postpartum day 21, effects observed at 500 mg/kg/day (0.24 times the maximum recommended human dose based on systemic exposure (AUC)) 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. 8.2 Lactation Risk Summary It is not known if moxifloxacin is present in human milk. Based on animal studies in rats, moxifloxacin may be excreted in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother …

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

11 DESCRIPTION Moxifloxacin hydrochloride, USP is a synthetic antibacterial agent for oral administration. Moxifloxacin, a fluoroquinolone, is available as the monohydrochloride salt of 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3 quinoline carboxylic acid. It is a slightly yellow to yellow powder or crystals, slightly hygroscopic substance with a molecular weight of 437.9. Its molecular formula is C 21 H 24 FN 3 O 4 *HCl and its chemical structure is as follows: structure 11.1 Moxifloxacin Tablets, USP Moxifloxacin tablets, USP are available as film-coated tablets containing moxifloxacin hydrochloride USP (equivalent to 400 mg moxifloxacin). The inactive ingredients are Lactose Monohydrate, Povidone, Lactose Anhydrous, Croscarmellose sodium, Colloidal silicon dioxide, Magnesium stearate, hypromellose, Titanium dioxide, Polyethylene glycol and Iron oxide red.

10 OVERDOSAGE Single oral overdoses up to 2.8 g were not associated with any serious adverse events. In the event of acute overdose, Empty the stomach and maintain adequate hydration. Monitor ECG due to the possibility of QT interval prolongation. Carefully observe the patient and give supportive treatment. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic moxifloxacin exposure. About 3% and 9% of the dose of moxifloxacin, as well as about 2% and 4.5% of its glucuronide metabolite are removed by continuous ambulatory peritoneal dialysis and hemodialysis, respectively.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Moxifloxacin Tablets, USP Moxifloxacin Tablets, USP are available as dull red colored, caplet shaped, film coated tablets containing 400 mg moxifloxacin. The tablet is debossed with "M" on one side and "400" on other side. Package NDC Code Bottles of 30 72205-001-30 Bottles of 500 72205-001-05 Cartons of 50 (5 x 10 ) Unit-dose Tablets 72205-001-31 Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Avoid high humidity.