FDA label 49b41069-802f-2ff8-e054-00144ff8d46c

Boxed Warning section Fluoroquinolones , including AVELOX ® , are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. [ see Warnings and Precautions ( 5.1 )]. Fluoroquinolones , including AVELOX, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid AVELOX in patients with known history of myasthenia gravis [see Warnings and Precautions ( 5.2 )].

WARNINGS AND PRECAUTIONS •Increased risk of tendinitis and tendon rupture. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroids, and in patients with kidney, heart or lung transplants. Discontinue if pain or inflammation in a tendon occurs. ( 5.1 , 8.5 )•Prolongation of the QT interval and isolated cases of torsade de pointes has been reported. Avoid use in patients with known prolongation, hypokalemia, and with drugs that prolong the QT interval. ( 5.3 , 7.4 , 8.5 ). Use caution in patients with proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia. ( 5.3 )•Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur after first or subsequent doses. Discontinue drug use at first sign of skin rash, jaundice or any other sign of hypersensitivity. ( 5.4 , 5.5 )•Central nervous system (CNS) events including dizziness, confusion, hallucination, depression, and rarely suicidal thoughts or acts may occur after first dose. Use caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold. ( 5.6 )•Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs. ( 5.7 )•Peripheral neuropathy: Discontinue if symptoms occur. ( 5.8 ) Fluoroquinolones, including AVELOX, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, 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. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. AVELOX should be discontinued 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 ( 17.3 ).] Fluoroquinolones, including AVELOX, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid AVELOX in patients with known history of myasthenia gravis [see Patient Counseling Information ( 17.3 )]. AVELOX has been shown to prolong the QT interval of the electrocardiogram in some patients. Following oral dosing with 400 mg of AVELOX 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 AVELOX and other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants have not been performed. An additive effect of AVELOX and these drugs cannot be excluded; therefore caution should be exercised when AVELOX is given concurrently with these drugs. In premarketing clinical trials, the rate of cardiovascular adverse events was similar in 798 AVELOX and 702 comparator treated patients who received concomitant therapy with drugs known to prolong the QTc interval. AVELOX 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 formulation. Therefore the recommended dose or infusion rate should not be exceeded. QT prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes. No excess in cardiovascular morbidity or mortality attributable to QTc prolongation occurred with AVELOX treatment in over 15,500 patients in controlled clinical studies, including 759 patients who were hypokalemic at the start of treatment, and there was no increase in mortality in over 18,000 AVELOX tablet treated patients in a postmarketing observational study in which ECGs were not performed. Elderly patients using IV AVELOX may be more susceptible to drug-associated QT prolongation. [ see Use In Specific Populations, ( 8.5 ).] In addition, AVELOX should be used with caution in patients with mild, moderate, or severe liver cirrhosis. [See Clinical Pharmacology ( 12.3 ) and Patient Counseling Information ( 17.3 ).] Serious anaphylactic reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including AVELOX. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. AVELOX should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Oxygen, intravenous steroids, and airway management, including intubation, may be administered as indicated. [ see Adverse Reactions ( 6 ) and Patient Counseling Information ( 17.3 ).] Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including AVELOX . These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: •Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome)•Vasculitis; arthralgia; myalgia; serum sickness•Allergic pneumonitis•Interstitial nephritis; acute renal insufficiency or failure•Hepatitis; jaundice; acute hepatic necrosis or failure•Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Patient Counseling Information ( 17.3 ) and Adverse Reactions ( 6.4 ). Fluoroquinolones, including AVELOX, may cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia [see Adverse Reactions ( 6.2 , 6.4 )]. Convulsions and increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones. Fluoroquinolones may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving AVELOX, the drug should be discontinued and appropriate measures instituted. As with all fluoroquinolones, AVELOX 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 ( 7.4 ) Adverse Reactions ( 6.2 , 6.4 ) and Patient Counseling Information ( 17.3 ).] Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AVELOX, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions ( 6.2 ) and Patient Counseling Information ( 17.3 )]. Rare 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 quinolones including AVELOX. AVELOX should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition [see Adverse Reactions ( 6.2 , 6.4 ) and Patient Counseling Information ( 17.3 )]. The oral administration of AVELOX caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. [See Animal Toxicology and/or Pharmacology ( 13.2 ).] Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs. [ see Adverse Reactions ( 6.4 ) and Pharmacokinetics ( 12.3 ).] Prescribing AVELOX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Patient Counseling Information ( 17.1 )].

ADVERSE REACTIONS Most common reactions (≥3%) were nausea, diarrhea, headache, and dizziness (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 [see Warnings and Precautions ( 5.8 )] •Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.10 )] •Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.11 )] 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 AVELOX in 14981 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 AVELOX 400 mg once daily PO, IV, or sequentially (IV followed by PO). Treatment duration was usually 6-10 days, and the mean number of days on therapy was 9 days. Discontinuation of AVELOX due to adverse events occurred in 5.0% 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 AVELOX-treated patients and less common adverse reactions, occurring in 0.1 to <1% of AVELOX-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 (≥ 1.0%) Adverse Reactions Reported in Active-Controlled Clinical Trials with AVELOX System Organ Class Adverse Reactions * % (N=14,981) Blood and Lymphatic System Disorders Anemia 1.1 Gastrointestinal Disorders Nausea 6.9 Diarrhea 6.0 Vomiting 2.4 Constipation 1.9 Abdominal pain 1.5 Abdominal pain upper 1.1 Dyspepsia 1.0 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 3.0 Psychiatric Disorders Insomnia 1.9 MedDRA Version 12.0 Table 3 Less Common (0.1 to <1.0%) Adverse Reactions Reported in Active-Controlled Clinical Trials with AVELOX (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 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. Table 4 lists adverse reactions that have been identified during post-approval use of AVELOX. 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, 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 ( 5.10 )] Stevens-Johnson syndrome Toxic epidermal necrolysis [see Warnings and Precautions ( 5.5 )]

<table ID="_RefID0EVJAG"> <caption>Table 2 Common (&#x2265; 1.0%) Adverse Reactions Reported in Active-Controlled Clinical Trials with AVELOX</caption> <col span="1" width="56%"/> <col span="1" width="37%"/> <col span="1" width="15%"/> <tbody> <tr> <td> <paragraph> <content styleCode="bold">System Organ Class</content> </paragraph> </td> <td> <paragraph> <content styleCode="bold">Adverse Reactions</content> <linkHtml href="#footnote-1">*</linkHtml> </paragraph> </td> <td> <paragraph> <content styleCode="bold">%</content> </paragraph> <paragraph> <content styleCode="bold">(N=14,981)</content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Blood and Lymphatic System Disorders</content> </paragraph> </td> <td> <paragraph>Anemia</paragraph> </td> <td> <paragraph>1.1</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> <td> <paragraph>Nausea</paragraph> </td> <td> <paragraph>6.9</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Diarrhea</paragraph> </td> <td> <paragraph>6.0</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Vomiting</paragraph> </td> <td> <paragraph>2.4</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Constipation</paragraph> </td> <td> <paragraph>1.9</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Abdominal pain</paragraph> </td> <td> <paragraph>1.5</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Abdominal pain upper</paragraph> </td> <td> <paragraph>1.1</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Dyspepsia</paragraph> </td> <td> <paragraph>1.0</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> <td> <paragraph>Pyrexia</paragraph> </td> <td> <paragraph>1.1</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Investigations</content> </paragraph> </td> <td> <paragraph>Alanine aminotransferase increased </paragraph> </td> <td> <paragraph>1.1</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Metabolism and Nutritional Disorder</content> </paragraph> </td> <td> <paragraph>Hypokalemia</paragraph> </td> <td> <paragraph>1</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> <td> <paragraph>Headache</paragraph> </td> <td> <paragraph>4.2</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Dizziness</paragraph> </td> <td> <paragraph>3.0</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Psychiatric Disorders</content> </paragraph> </td> <td> <paragraph>Insomnia</paragraph> </td> <td> <paragraph>1.9</paragraph> </td> </tr> <tr> <td> </td> </tr> </tbody> </table>

<table ID="_RefID0EVPAG"> <caption>Table 3 Less Common (0.1 to &lt;1.0%) Adverse Reactions Reported in Active-Controlled Clinical Trials with AVELOX (N=14,981)</caption> <col span="1" width="56%"/> <col span="1" width="47%"/> <tbody> <tr> <th colspan="1"> <content styleCode="bold">System Organ Class</content> </th> <th colspan="1"> <content styleCode="bold">Adverse </content> <content styleCode="bold">Reactions ^a </content> </th> </tr> <tr> <td> <paragraph> <content styleCode="bold">Blood and Lymphatic System Disorders</content> </paragraph> </td> <td> <paragraph>Thrombocythemia </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Eosinophilia </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Neutropenia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Thrombocytopenia </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Leukopenia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Leukocytosis</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Cardiac Disorders</content> </paragraph> </td> <td> <paragraph>Atrial fibrillation </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Palpitations</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Tachycardia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Cardiac failure congestive</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Angina pectoris </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Cardiac failure</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Cardiac arrest</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Bradycardia</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Ear and Labyrinth Disorders</content> </paragraph> </td> <td> <paragraph>Vertigo</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Tinnitus</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Eye Disorders</content> </paragraph> </td> <td> <paragraph>Vision blurred</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> <td> <paragraph>Dry mouth</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Abdominal discomfort</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Flatulence </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Abdominal distention</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Gastritis</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Gastroesophageal reflux disease</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> <td> <paragraph>Fatigue</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Chest pain</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Asthenia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Edema peripheral</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Pain</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Malaise</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Infusion site extravasation</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Edema</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Chills</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Chest discomfort</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Facial pain</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Hepatobiliary</content> <content styleCode="bold"> disorders</content> </paragraph> </td> <td> <paragraph>Hepatic function abnormal</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> <td> <paragraph>Vulvovaginal candidiasis</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Oral candidiasis</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Vulvovaginal mycotic infection</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Candidiasis</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Vaginal infection</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Oral fungal infection</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Fungal infection</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Gastroenteritis</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Investigations</content> </paragraph> </td> <td> <paragraph>Aspartate aminotransferase increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Gamma-glutamyltransferase increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood alkaline phosphatase increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hepatic enzyme increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Electrocardiogram QT prolonged</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood lactate dehydrogenase increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Platelet count increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood amylase increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood glucose increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Lipase increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hemoglobin decreased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood creatinine increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Transaminases increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>White blood cell count increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood urea increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Liver function test abnormal</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hematocrit decreased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Prothrombin time prolonged</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Eosinophil count increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Activated partial thromboplastin time prolonged</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood bilirubin increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood triglycerides increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood uric acid increased</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Blood pressure increased</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </paragraph> </td> <td> <paragraph>Hyperglycemia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Anorexia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hypoglycemia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hyperlipidemia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Decreased appetite</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Dehydration</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </paragraph> </td> <td> <paragraph>Back pain</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Pain in extremity </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Arthralgia </paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Myalgia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Muscle spasms</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Musculoskeletal chest pain</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Musculoskeletal pain</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> <td> <paragraph>Dysgeusia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Somnolence</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Tremor</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Lethargy</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Paresthesia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Tension headache</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hypoesthesia</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Syncope</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Psychiatric Disorders</content> </paragraph> </td> <td> <paragraph>Anxiety</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Confusional state</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Agitation</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Depression</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Nervousness</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Restlessness</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hallucination</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Disorientation</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Renal and Urinary Disorders</content> </paragraph> </td> <td> <paragraph>Renal failure</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Dysuria</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Renal failure acute</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Reproductive System and Breast Disorders</content> </paragraph> </td> <td> <paragraph>Vulvovaginal pruritus</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Respiratory, Thoracic, and </content> <content styleCode="bold">Mediastinal</content> <content styleCode="bold"> Disorders</content> </paragraph> </td> <td> <paragraph>Dyspnea</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Asthma</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Wheezing</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Bronchospasm</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </paragraph> </td> <td> <paragraph>Rash</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Pruritus</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hyperhidrosis</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Erythema</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Urticaria</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Dermatitis allergic</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Night sweats</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Vascular Disorders</content> </paragraph> </td> <td> <paragraph>Hypertension</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Hypotension</paragraph> </td> </tr> <tr> <td/> <td> <paragraph>Phlebitis</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID0E3IBG"> <caption>Table 4 Postmarketing Reports of Adverse Drug Reactions</caption> <col span="1" width="53%"/> <col span="1" width="47%"/> <tbody> <tr> <td> <paragraph> <content styleCode="bold">System/Organ Class</content> </paragraph> </td> <td> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Blood and Lymphatic System Disorders </content> </paragraph> </td> <td> <paragraph>Agranulocytosis</paragraph> <paragraph>Pancytopenia</paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_763c40cc-7b6a-4082-8d28-870552e88104">5.5</linkHtml>)] </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Cardiac Disorders </content> </paragraph> </td> <td> <paragraph>Ventricular tachyarrhythmias (including in very rare cases cardiac arrest and torsade de pointes, and usually in patients with concurrent severe underlying proarrhythmic conditions)</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Ear and Labyrinth Disorders</content> </paragraph> </td> <td> <paragraph>Hearing impairment, including deafness <content styleCode="underline"> (reversible in majority of cases)</content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Eye Disorders</content> </paragraph> </td> <td> <paragraph>Vision loss (especially in the course of CNS reactions, transient in majority of cases)</paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Hepatobiliary</content> <content styleCode="bold"> Disorders </content> </paragraph> </td> <td> <paragraph>Hepatitis (predominantly cholestatic)</paragraph> <paragraph>Hepatic failure (including fatal cases)</paragraph> <paragraph>Jaundice </paragraph> <paragraph>Acute hepatic necrosis </paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_763c40cc-7b6a-4082-8d28-870552e88104">5.5</linkHtml>)] </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Immune System Disorders </content> </paragraph> </td> <td> <paragraph>Anaphylactic reaction</paragraph> <paragraph>Anaphylactic shock </paragraph> <paragraph>Angioedema (including laryngeal edema)</paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_125cfcb1-371f-4816-b09a-24e61bee16fd">5.4</linkHtml>, <linkHtml href="#ID_763c40cc-7b6a-4082-8d28-870552e88104">5.5</linkHtml>)] </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders </content> </paragraph> </td> <td> <paragraph>Tendon rupture </paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_991f3830-51e6-4949-9b52-c7f36026a5ac">5.1</linkHtml>)] </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Nervous System Disorders </content> </paragraph> </td> <td> <paragraph>Altered coordination</paragraph> <paragraph>Abnormal gait</paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_ba0c26f6-e4dd-415e-b21c-c095f31b5717">5.8</linkHtml>)] </content> </paragraph> <paragraph>Myasthenia gravis (exacerbation of)</paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_ad1b8fbd-4d2e-4b90-90d1-ec3c7a5baae0">5.2</linkHtml>)] </content> </paragraph> <paragraph>Muscle weakness</paragraph> <paragraph>Peripheral neuropathy, polyneuropathy</paragraph> <paragraph> <content styleCode="italics"> <content styleCode="underline">[see Warnings and Precautions (</content> <linkHtml href="#ID_ba0c26f6-e4dd-415e-b21c-c095f31b5717">5.8</linkHtml> <content styleCode="underline">)]</content> </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Psychiatric Disorders </content> </paragraph> </td> <td> <paragraph>Psychotic reaction (very rarely culminating in self-injurious behavior, such as suicidal ideation/thoughts or suicide attempts <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_0d5d19be-2dcf-43bf-a80e-86a937e02283">5.6</linkHtml>)] </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Renal and Urinary Disorders </content> </paragraph> </td> <td> <paragraph>Renal dysfunction</paragraph> <paragraph>Interstitial nephritis </paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_763c40cc-7b6a-4082-8d28-870552e88104">5.5</linkHtml>)] </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Respiratory, Thoracic and </content> <content styleCode="bold">Mediastinal</content> <content styleCode="bold"> Disorders</content> </paragraph> </td> <td> <paragraph>Allergic pneumonitis</paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_763c40cc-7b6a-4082-8d28-870552e88104">5.5</linkHtml>)] </content> </paragraph> </td> </tr> <tr> <td> <paragraph> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders </content> </paragraph> </td> <td> <paragraph>Photosensitivity/phototoxicity reaction</paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_15b33f8c-1abd-4c3a-8f35-a8add295130d">5.10</linkHtml>)] </content> </paragraph> <paragraph>Stevens-Johnson syndrome</paragraph> <paragraph>Toxic epidermal necrolysis</paragraph> <paragraph> <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#ID_763c40cc-7b6a-4082-8d28-870552e88104">5.5</linkHtml>)] </content> </paragraph> </td> </tr> </tbody> </table>