Moxifloxacin

Boxed Warning 5/2016 Indications and Usage 5/2016 Dosage and Administration 5/2016 Warnings and Precautions 5/2016

1 INDICATIONS AND USAGE 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 ) 1.1 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 o …

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 Acute Bacterial Sinusitis ( 1.5 ) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.6 ) 400 mg 5 No dosage adjustment in patients with renal or hepatic impairment. ( 8.6 , 8.7 ) Moxifloxacin Injection: Slow Intravenous infusion over 60 minutes. Avoid rapid or bolus Intravenous infusion. ( 2.2 ) Do not mix with other medications in intravenous bag or in intravenous line. ( 2.2 ) 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 , see Use in Specific Populations ( 8.5 )] . b Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. 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 Acute Bacterial Sinusitis ( 1.5 ) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis ( 1.6 ) 400 mg 5 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 bags: Close flow control clamp of administration set. Remove cover from port at bottom of container. Insert piercing pin from an appropriate transfer set (for example, one that does not require excessive force, such as ISO compatible administration set) into port with a gentle twisting motion until pin is firmly seated. NOTE: Refer to complete directions that have been provided with the administration set …

3 DOSAGE FORMS AND STRENGTHS Injection: 400 mg moxifloxacin in 250 mL single-dose flexible bag. (3.1) Moxifloxacin Injection Each single-dose flexible bag contains 400 mg of moxifloxacin in 250 mL, each mL contains 1.6 mg of moxifloxacin.

4 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 )

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 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions ( 5.8 )] Clostridioides Difficile -Associated Diarrhea [see Warnings and Precautions ( 5.10 )] Blood Glucose Disturbances [see Warnings and Precautions ( 5.13 )] Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.14 )] Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.15 )] Most common reactions (≥ 3%) were nausea, diarrhea, headache, and dizziness. ( 6.1 ) 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. 6.1 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 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 a MedDRA Version 12.0 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 1.1 Investigations Alanine aminotransferase increased 1.1 Metabolism and Nutritional Disorder Hypokalemia 1 Nervous System Disorders Headache 4.2 Dizziness 3 Psychiatric Disorders Insomnia 1.9 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 System Organ Class Adverse Reactions a Blood and Lymphatic System Disorders Thrombocythemia Eosi …

7 DRUG INTERACTIONS Interacting Drug Interaction Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( 6.2 , 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. ( 5.13 , 7.2 ) 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 [see Adverse Reactions ( 6 , 6.1 ,), 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 ( 5.13 ), Adverse Reactions ( 6.1 ), 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 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. ( 5.2 , 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, Moxifloxacin Injection may cause fetal harm. Moxifloxacin did not cause fetal malformations when administered to pregnant rats (IV and oral), rabbits (IV) and monkeys (oral) at exposures that were 0.24-2.5 times of those at the human clinical dose (400mg/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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Animal reproductive and development studies were done in rats, rabbits and cynomolgus macaques. Moxifloxacin did not cause fetal malformations 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). Fetal malformations were not observed at intravenous doses as high as 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) in litters of pregnant rats that received moxifloxacin 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. Fetal malformations were not observed 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 ex …

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

11 DESCRIPTION Moxifloxacin is a synthetic broad spectrum antibacterial agent for intravenous administration. Moxifloxacin, a fluoroquinolone, is available as a buffered monohydrochloride salt of 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6- fluoro-8-methoxy-1,4-dihydro-4-oxo-3 quinoline carboxylic acid. It is a slightly yellow to yellow crystalline substance. Its chemical structure is as follows: Moxifloxacin Injection is sterile solution for infusion in a ready-to-use, single-dose flexible bag. Chemical Structure Moxifloxacin Injection * 400 mg moxifloxacin equivalent to 437.5 mg of moxifloxacin hydrochloride. **The pH may have been adjusted with sulfuric acid. The pH is 5.0 to 6.0. Component Function Dosage Formulation Moxifloxacin* Active ingredient 400 mg* Sodium acetate (added as a trihydrate) Tonicity adjuster 1,702.5 mg Disodium sulfate Tonicity adjuster 2,840 mg Sulfuric acid ** pH adjustment As needed Water for injection vehicle q.s. 250 mL Each mL contains 1.6 mg of moxifloxacin. The appearance of the intravenous solution is clear. The flexible bag is fabricated from a specially designed multilayer plastic (freeflex ® ). Solution is in contact with the polypropylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The leachable compounds were all within acceptable limits based on animal toxicology studies. Moxifloxacin Injection contains approximately 52.5 mEq (1,207 mg) of sodium in 250 mL.

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

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Moxifloxacin Injection 400 mg/250 mL is a sterile solution available in a single-use, ready-to-use flexible plastic container. No further dilution is necessary. Product No. NDC No. Strength Bag Size 850174 66298-8507-4 400 mg per 250 mL (1.6 mg per mL) 300 mL Parenteral drug products should be inspected visually for particulate matter prior to administration. Samples containing visible particulates should not be used. Because the premix flexible plastic containers are for single-use only, any unused portion should be discarded. Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not refrigerate - Product precipitates upon refrigeration. Use immediately once removed from the overwrap. Product is sensitive to light. The container closure is not made with natural rubber latex. Non-PVC, Non-DEHP. Sterile.