MOXIFLOXACIN HYDROCHLORIDE

Moxifloxacin hydrochloride is a synthetic broad spectrum 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: Chemical Structure 11.1 Moxifloxacin Hydrochloride Tablets Moxifloxacin hydrochloride tablets are available as film-coated tablets containing moxifloxacin hydrochloride USP (equivalent to 400 mg moxifloxacin). The inactive ingredients are hypromellose, iron oxide red, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of moxifloxacin hydrochloride tablets and other antibacterial drugs, moxifloxacin hydrochloride tablets 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. Moxifloxacin hydrochloride tablets are indicated for the treatment of adults (≥ 18 years of age) with infections caused by susceptible isolates of the designated microorganisms in the conditions listed below [see Dosage and Administration (2) and Use in Specific Populations (8.5) ] . 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 hydrochloride tablets may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued. Moxifloxacin hydrochloride tablets are a fluoroquinolone antibacterial indicated for treating infections in adults ≥ 18 years of age caused by designated, susceptible bacteria. (1 , 12.4) Acute Bacterial Sinusitis (1.1) Acute Bacterial Exacerbation of Chronic Bronchitis (1.2) Community Acquired Pneumonia (1.3) Skin and Skin Structure Infections: Uncomplicated (1.4) and Complicated (1.5) Complicated Intra-Abdominal Infections (1.6) 1.1 Acute Bacterial Sinusitis Moxifloxacin hydrochloride tablets are indicated for the treatment of Acute Bacterial Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae , or Moraxella catarrhalis [see Clinical Studies (14.4) ] . 1.2 Acute Bacterial Exacerbation of Chronic Bronchitis Moxifloxacin hydrochloride tablets are indicated for the treatment of Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, methicillin-susceptible Staphylococcus aureus, or Moraxella catarrhalis [see Clinical Studies (14.1) ] . 1.3 Community Acquired Pneumonia Moxifloxacin hydrochloride tablets are indicated for the treatment of Community Acquired Pneumonia caused by 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), 2 nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole [see Clinical Studies (14.2) ] . 1.4 Uncomplicated Skin and Skin Structure Infections Moxifloxacin hydrochloride tablets are indicated for the treatment of Uncomplicated Skin and Skin Structure Infections caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes [see Clinical Studies (14.5) ] . 1.5 Complicated Skin and Skin Structure Infections Moxifloxacin hydrochloride tablets are indicated for the treatment of Complicated Skin and Skin Structure Infections caused by methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae [see Clinical Studies (14.6) ] . 1.6 Complicated Intra-Abdominal Infections Moxifloxacin hydrochloride tablets are indicated for the treatment of Complicated Intra-Abdominal Infections including polymicrobial infections such as abscess caused by Escherichia coli, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, Enterococcus faecalis, Proteus mirabilis, Clostridium perfringens, Bacteroides thetaiotaomicron, or Peptostreptococcus species [see Clinical Studies (14.7) ] .

Type of Infection Dose Every 24 hours Duration (days) Acute Bacterial Sinusitis (1.1) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis (1.2) 400 mg 5 Community Acquired Pneumonia (1.3) 400 mg 7-14 Uncomplicated Skin and Skin Structure Infections (SSSI) (1.4) 400 mg 7 Complicated SSSI (1.5) 400 mg 7-21 Complicated Intra-Abdominal Infections (1.6) 400 mg 5-14 No dosage adjustment in patients with renal or hepatic impairment. (8.6 , 8.7) Administer 4 hours before or 8 hours after antacids, sucralfate, multivitamins and other products with multivalent cations. (2.2) 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 Type of Infection a Dose Every 24 hours Duration b (days) 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. Acute Bacterial Sinusitis (1.1) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis (1.2) 400 mg 5 Community Acquired Pneumonia 400 mg 7-14 Uncomplicated Skin and Skin Structure Infections (SSSI ) (1.4) 400 mg 7 Complicated SSSI (1.5) 400 mg 7-21 Complicated Intra-Abdominal Infections (1.6) 400 mg 5-14 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 IV may be switched to moxifloxacin hydrochloride tablets when clinically indicated at the discretion of the physician. 2.2 Drug Interactions with Multivalent Cations Oral doses of moxifloxacin should be administered at least 4 hours before or 8 hours after products containing magnesium, aluminum, iron or zinc, including antacids, sucralfate, multivitamins and VIDEX ® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 2.3 Administration Instructions Moxifloxacin hydrochloride tablets can be taken with or without food, drink fluids liberally.

Moxifloxacin hydrochloride tablets are contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antimicrobial agents. Known hypersensitivity to moxifloxacin hydrochloride tablets or other quinolones. (4, 5.4)

Most common reactions (≥3%) were nausea, diarrhea, headache, and dizziness. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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: Tendinopathy and Tendon Rupture [see Warnings and Precautions (5.1) ] QT Prolongation [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.5) ] Central Nervous System Effects [see Warnings and Precautions (5.6) ] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.7) ] Peripheral Neuropathy that may be irreversible [see Warnings and Precautions (5.8) ] Blood Glucose Disturbances [see Warnings and Precautions (5.10) ] Photosensitivity/Phototoxicity [see Warnings and Precautions (5.11) ] Development of Drug Resistant Bacteria [see Warnings and Precautions (5.12) ] 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 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 <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%), pyrexia (0.4%). 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%) Adverse Reactions Reported in Active-Controlled Clinical Trials with Moxifloxacin Hydrochloride System Organ Class Adverse Reactions a % (N=14,981) a) MedDRA Version 12.0 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 Disorders 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 Hydrochloride (N=14,981) System Organ Class Adverse Reactions a a) MedDRA Version 12.0 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 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 hydrochloride. Because these events 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 (5.5) ] Cardiac Disorders Ventricular tachyarrhythmias (including in very rare cases cardiac arrest and torsade 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) Hepatobiliary Disorders Hepatitis (predominantly cholestatic) Hepatic failure (including fatal cases) Jaundice Acute hepatic necrosis [see Warnings and Precautions (5.5) ] Immune System Disorders Anaphylactic reaction Anaphylactic shock Angioedema (including laryngeal edema) [see Warnings and Precautions (5.4 , 5.5) ] Musculoskeletal and Connective Tissue Disorders Tendon rupture [see Warnings and Precautions (5.1) ] Nervous System Disorders Altered coordination Abnormal gait [see Warnings and Precautions (5.8) ] Myasthenia gravis (exacerbation of) [see Warnings and Precautions (5.2) ] Muscle weakness Peripheral neuropathy (that may be irreversible), polyneuropathy [see Warnings and Precautions (5.8) ] Psychiatric Disorders Psychotic reaction (very rarely culminating in self-injurious behavior, such as suicidal ideation/thoughts or suicide attempts [see Warnings and Precautions (5.6) ] Renal and Urinary Disorders Renal dysfunction Interstitial nephritis [see Warnings and Precautions (5.5) ] Respiratory, Thoracic and Mediastinal Disorders Allergic pneumonitis [see Warnings and Precautions (5.5) ] Skin and Subcutaneous Tissue Disorders Photosensitivity/phototoxicity reaction [see Warnings and Precautions (5.11) ] Stevens-Johnson syndrome Toxic epidermal necrolysis [see Warnings and Precautions (5.5) ] To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected] ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Interacting Drug Interaction Antacids, sucralfate, multivitamins, and other products containing multivalent cations Moxifloxacin absorption is decreased. Administer moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. ( 2.2 , 7.1 , 12.3 , 17 ) Warfarin Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( 6.4 , 7.2 , 12.3 ) Class IA and Class III antiarrhythmics: Proarrhythmic effect may be enhanced. Avoid concomitant use. ( 5.3 , 7.5 ) Antidiabetic agents Carefully monitor blood glucose ( 5.10 , 7.3 ) 7.1 Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations Quinolones form chelates with alkaline earth and transition metal cations. Oral administration of quinolones 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 VIDEX ® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution, may substantially interfere with the absorption of quinolones, 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) , Pharmacokinetics (12.3) , and Patient Counseling Information (17) .] 7.2 Warfarin Quinolones, 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 a quinolone is administered concomitantly with warfarin or its derivatives. [See Adverse Reactions (6.2 , 6.3) , Pharmacokinetics (12.3) , and Patient Counseling Information (17) .] 7.3 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 hydrochloride should be discontinued and appropriate therapy should be initiated immediately. [See Warnings and Precautions (5.10) , Adverse Reactions (6.2) , and Patient Counseling Information (17) .] 7.4 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Although not observed with moxifloxacin hydrochloride 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 ( 5.6) , and Patient Counseling Information (17) ] . 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 (5.3) , Nonclinical Toxicology (13.2) , and Patient Counseling Information (17) .]