FDA label fbcddb91-64a4-4875-b459-4e8a5b034d1b

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS • Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5.1 )], including: o Tendinitis and tendon rupture [see Warnings and Precautions ( 5.2 )] o Peripheral neuropathy [see Warnings and Precautions ( 5.3 )] o Central nervous system effects [see Warnings and Precautions ( 5.4 )] Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions [see Warnings and Precautions (5.1)] • Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Warnings and Precautions ( 5.5 )] . • Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 - 5.14 )], reserve levofloxacin for use in patients who have no alternative treatment options for the following indications: o Uncomplicated urinary tract infection [see Indications and Usage ( 1.12 )] o Acute bacterial exacerbation of chronic bronchitis [see Indications and Usage ( 1.13 )] o Acute bacterial sinusitis [see Indications and Usage ( 1.14 )]. WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning. • Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together (5.1) , including: o Tendinitis and tendon rupture (5.2) o Peripheral neuropathy (5.3) o Central nervous system effects (5.4) Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions (5.1 ) • Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Warnings and Precautions (5.5) ]. • Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions ( 5.1 - 5.14 ), reserve levofloxacin for use in patients who have no alternative treatment options for the following indications: o Uncomplicated urinary tract infection ( 1.12 ) o Acute bacterial exacerbation of chronic bronchitis (1.13) o Acute bacterial sinusitis ( 1.14 )

5 WARNINGS AND PRECAUTIONS 6. Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose ( 4 , 5.7 ) 7. Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses ( 5.6 ) 8. Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur (5.8) 9. Clostridium difficile -associated colitis: evaluate if diarrhea occurs (5.9) 10. Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval ( 5.10 , 8.5 ) 5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting levofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]. Discontinue levofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including levofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones. 5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including levofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. This adverse reaction most frequently involves the Achilles tendon And has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites. Tendinitis or tendon rupture can occur within hours or days of starting levofloxacin or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors 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 been reported in patients taking fluoroquinolones who do not have the above risk factors. Discontinue levofloxacin immediately 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. Avoid levofloxacin in patients who have a history of tendon disorders or tendon rupture [see Adverse Reactions (6.3) ; Patient Counseling Information ( 17.3 )]. 5.3 Peripheral Neuropathy Fluoroquinolones, including levofloxacin, have been associated with an increased risk of peripheral neuropathy. 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 fluoroquinolones, including levofloxacin. Symptoms may occur soon after initiation of levofloxacinand may be irreversible in some patients [see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6.1 , 6.2 )]. Discontinue levofloxacin immediately if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation. Avoid fluoroquinolones, including levofloxacin, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6) , Patient Counseling Information (17.3) ]. 5.4 Central Nervous System Effects Fluoroquinolones, including levofloxacin, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, toxic psychoses, increased intracranial pressure (including pseudotumor cerebri) . Fluoroquinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. Suicidal thoughts, and attempted or completed suicide may also occur, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving levofloxacin, discontinue levofloxacin and institute appropriate measures. As with other fluoroquinolones, levofloxacin should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). [see Adverse Reactions (6) ; Drug Interactions ( 7.4 , 7.5 ); Patient Counseling Information ( 17.3 )]. 5.5 Exacerbation of Myasthenia Gravis Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Adverse Reactions (6.3) ; Patient Counseling Information ( 17.3 )]. 5.6 Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, including levofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: 1. fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome); 2. vasculitis; arthralgia; myalgia; serum sickness; 3. allergic pneumonitis; 4. interstitial nephritis; acute renal insufficiency or failure; 5. hepatitis; jaundice; acute hepatic necrosis or failure; 6. anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities Discontinue levofloxacin immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures [see Adverse Reactions ( 6 ); Patient Counseling Information ( 17.3) ]. 5.7 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including levofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. Levofloxacin should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated [see Adverse Reactions ( 6 ); Patient Counseling Information ( 17.3 )]. 5.8 Hepatotoxicity Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity [see Warnings and Precautions (5.6) ]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions (6) ; Patient Counseling Information (17.3) ]. 5.9 Clostridium difficile -Associated Diarrhea Clostri dium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including levofloxacin, 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. diffi cile 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) , Patient Counseling Information ( 17.3 )]. 5.10 Prolongation of the QT Interval Some fluoroquinolones, including levofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Adverse Reactions (6.3) , Use in Specific Populations ( 8.5) , and Patient Counseling Information ( 17.3 )]. 5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals Levofloxacin is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague [see Indications and Usage ( 1.7 , 1.8 )]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving levofloxacin [see Use in Specific Populations ( 8.4 )]. In immature rats and dogs, the oral administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology ( 13.2 ) ]. 5.12 Blood Glucose Disturbances As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with levofloxacin, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with levofloxacin, levofloxacin should be discontinued and appropriate therapy should be initiated immediately [see Adverse Reactions ( 6.2 ); Drug Interactions (7.3) ; Patient Counseling Information (17.4 )]. 5.13 Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., 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 fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions (6.3) ; Patient Counseling Information (17.3 )]. 5.14 Development of Drug Resistant Bacteria Prescribing levofloxacin 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 (17.2 )].

6 ADVERSE REACTIONS The most common reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness (6.2) . To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 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 drug reactions are discussed in greater detail in other sections of labeling: • Disabling and Potentially Irreversible Serious Adverse Reactions [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) ] • Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions ( 5.6 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.7) ] • Hepatotoxicity [see Warnings and Precautions ( 5.8 )] • Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.9 )] • Prolongation of the QT Interval [see Warnings and Precautions ( 5.10 )] • Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions ( 5.11 )] • Blood Glucose Disturbances [see Warnings and Precautions ( 5.12 )] • Photosensitivity/Phototoxicity [see Warnings and Precautions ( 5.13 )] • Development of Drug Resistant Bacteria [see Warnings and Precautions ( 5.14 )] Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration ( 2.5 )]. 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 levofloxacin in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with levofloxacin for a wide variety of infectious diseases [see Indications and Usage (1) ]. Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3 to 14 days, and the mean number of days on therapy was 10 days. The overall incidence, type and distribution of adverse reactions was similar in patients receiving levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%). Adverse reactions occurring in ≥1% of levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to <1% of levofloxacin-treated patients, are shown in Table 4 and Table 5, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness. Table 4: Common (≥1%) Adverse Reactions Reported in Clinical Trials with levofloxacin System/Organ Class Adverse Reaction % (N=7537) Infections and Infestations moniliasis 1 Psychiatric Disorders insomnia * [see Warnings and Precautions (5.4)] 4 Nervous System Disorders headache dizziness [see Warnings and Precautions ( 5.4) ] 6 3 Respiratory, Thoracic andMediastinal Disorders dyspnea [see Warnings and Precautions (5.7) ]. 1 Gastrointestinal Disorders nausea diarrhea constipation abdominal pain vomiting dyspepsia 7 5 3 2 2 2 Skin and SubcutaneousTissue Disorders rash [see Warnings and Precautions ( 5.7)] ruritus 2 1 Reproductive System andBreast Disorders vaginitis 1 † General Disorders andAdministration SiteConditions edema injection site reaction chest pain 1 1 1 * N = 7274 † N=3758 (women) Table 5 : Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with levofloxacin (N=7537) System/Organ Class Adverse Reaction Infections and Infestations genital moniliasis Blood and Lymphatic SystemDisorders anemia thrombocytopenia granulocytopenia [see Warnings and Precautions (5.6) ] Immune System Disorders allergic reaction [See Warnings and Precautions ( 5.6 , 5.7 )] Metabolism and NutritionDisorders hyperglycemia hypoglycemia [see Warnings and Precautions ( 5.12) ] hyperkalemia Psychiatric Disorders anxiety agitation confusion depression hallucination nightmare * [see Warnings and Precautions ( 5.4) ] sleep disorder * anorexia abnormal dreaming * Nervous System Disorders tremor convulsions [see Warnings and Precautions (5.4) ] paresthesia [see Warnings and Precautions ( 5.3 )] vertigo hypertonia hyperkinesias abnormal gait somnolence * syncope Respiratory, Thoracic andMediastinal Disorders epistaxis Cardiac Disorders cardiac arrest palpitation ventricular tachycardia ventricular arrhythmia Vascular Disorders phlebitis Gastrointestinal Disorders gastritis stomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembraneous/ C. difficile colitis [see Warnings and Precautions (5.9 )] Hepatobiliary Disorders abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase Skin and Subcutaneous TissueDisorders urticaria [see Warnings and Precautions (5.7) ] Musculoskeletal and ConnectiveTissue Disorders arthralgia tendinitis [see Warnings and Precautions (5.2) ] myalgia skeletal pain Renal and Urinary Disorders abnormal renal function acute renal failure [see Warnings and Precautions ( 5.6)] * N=7274 In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including levofloxacin. The relationship of the drugs to these events is not presently established. 6.3 Postmarketing Experience Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin. Because these reactions 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 6: Postmarketing Reports Of Adverse Drug Reactions System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions ( 5.6 )] eosinophilia Immune System Disorders hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness [see Warnings and Precautions ( 5.6 , 5.7 )] Psychiatric Disorders psychosis paranoia isolated reports of suicidal ideation, suicide attempt and completed suicide [see Warnings and Precautions ( 5.4 )] Nervous System Disorders exacerbation of myasthenia gravis [see Warnings and Precautions ( 5.5 )] anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautions ( 5.3 )] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions ( 5.4 )] Eye Disorders uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma Ear and Labyrinth Disorders hypoacusis tinnitus Cardiac Disorders isolated reports of torsade de pointes electrocardiogram QT prolonged [see Warnings and Precautions ( 5.10 )] tachycardia Vascular Disorders vasodilatation Respiratory, Thoracic andMediastinal Disorders isolated reports of allergic pneumonitis [see Warnings and Precautions ( 5.6 )] Hepatobiliary Disorders hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions (5.6 ), ( 5.8 )] Skin and Subcutaneous TissueDisorders bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis Acute Generalized Exanthematous Pustulosis (AGEP) fixed drug eruptions erythema multiforme [see Warnings and Precautions ( 5.6 )]] photosensitivity/phototoxicity reaction [see Warnings and Precautions ( 5.13 )] leukocytoclastic vasculitis Musculoskeletal and ConnectiveTissue Disorders tendon rupture [see Warnings and Precautions ( 5.2 )] muscle injury, including rupture rhabdomyolysis Renal and Urinary Disorders interstitial nephritis [see Warnings and Precautions (5.6) ] General Disorders andAdministration Site Conditions multi-organ failure pyrexia Investigations prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased

<table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">System/Organ Class</content> </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">% (N=7537)</content> </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> <td valign="top"> <paragraph>moniliasis</paragraph> </td> <td valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Psychiatric Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>insomnia^* [see Warnings and Precautions <linkHtml href="#_31eca02b-738e-cb3d-4733-66b6713215d0">(5.4)]</linkHtml> </paragraph> </td> <td valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>headache</paragraph> <paragraph>dizziness [see Warnings and Precautions (<linkHtml href="#_31eca02b-738e-cb3d-4733-66b6713215d0">5.4)</linkHtml>]</paragraph> </td> <td valign="top"> <paragraph>6</paragraph> <paragraph>3</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Respiratory, Thoracic andMediastinal Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>dyspnea [see Warnings and Precautions <linkHtml href="#_01346183-5ca4-c55f-82d4-547d1e82e1ad">(5.7)</linkHtml>].</paragraph> </td> <td valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>nausea</paragraph> <paragraph>diarrhea </paragraph> <paragraph>constipation </paragraph> <paragraph>abdominal pain </paragraph> <paragraph>vomiting </paragraph> <paragraph>dyspepsia</paragraph> </td> <td valign="top"> <paragraph>7</paragraph> <paragraph>5</paragraph> <paragraph>3</paragraph> <paragraph>2</paragraph> <paragraph>2</paragraph> <paragraph>2</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Skin and SubcutaneousTissue Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>rash [see Warnings and Precautions (<linkHtml href="#_01346183-5ca4-c55f-82d4-547d1e82e1ad">5.7)]</linkHtml> </paragraph> <paragraph>ruritus</paragraph> </td> <td valign="top"> <paragraph>2</paragraph> <paragraph>1</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Reproductive System andBreast Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>vaginitis</paragraph> </td> <td valign="top"> <paragraph>1^&#x2020; </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">General Disorders andAdministration SiteConditions</content> </paragraph> </td> <td valign="top"> <paragraph>edema</paragraph> <paragraph>injection site reaction </paragraph> <paragraph>chest pain</paragraph> </td> <td valign="top"> <paragraph>1</paragraph> <paragraph>1</paragraph> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph>* N = 7274</paragraph> <paragraph> ^&#x2020; N=3758 (women) </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> </paragraph> </td> </tr> </tbody> </table>

<table cellpadding="0pt" cellspacing="0pt" width="100%"> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">System/Organ Class</content> </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> <td valign="top"> <paragraph>genital moniliasis</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic SystemDisorders</content> </paragraph> </td> <td valign="top"> <paragraph>anemia</paragraph> <paragraph>thrombocytopenia </paragraph> <paragraph>granulocytopenia</paragraph> <paragraph>[see Warnings and Precautions <linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">(5.6)</linkHtml>]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Immune System Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>allergic reaction [See Warnings and Precautions (<linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">5.6</linkHtml>, <linkHtml href="#_01346183-5ca4-c55f-82d4-547d1e82e1ad">5.7</linkHtml>)]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Metabolism and NutritionDisorders</content> </paragraph> </td> <td valign="top"> <paragraph>hyperglycemia</paragraph> <paragraph>hypoglycemia</paragraph> <paragraph>[see Warnings and Precautions (<linkHtml href="#_fb7652c0-25c0-c5c8-3d84-23046142f3ef">5.12)</linkHtml> <content styleCode="bold">]</content> </paragraph> <paragraph>hyperkalemia</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Psychiatric Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>anxiety</paragraph> <paragraph>agitation </paragraph> <paragraph>confusion </paragraph> <paragraph>depression </paragraph> <paragraph>hallucination </paragraph> <paragraph>nightmare^* </paragraph> <paragraph>[see Warnings and Precautions (<linkHtml href="#_31eca02b-738e-cb3d-4733-66b6713215d0">5.4)</linkHtml> <content styleCode="bold">]</content> </paragraph> <paragraph>sleep disorder^* </paragraph> <paragraph>anorexia</paragraph> <paragraph>abnormal dreaming^* </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>tremor</paragraph> <paragraph>convulsions</paragraph> <paragraph>[see Warnings and Precautions <linkHtml href="#_31eca02b-738e-cb3d-4733-66b6713215d0">(5.4)</linkHtml>]</paragraph> <paragraph>paresthesia [see Warnings and Precautions (<linkHtml href="#_c06ffaea-afa6-2cfc-1dff-dec6ff6fbf72">5.3</linkHtml>)]</paragraph> <paragraph>vertigo </paragraph> <paragraph>hypertonia </paragraph> <paragraph>hyperkinesias</paragraph> <paragraph>abnormal gait </paragraph> <paragraph>somnolence^* </paragraph> <paragraph>syncope</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Respiratory, Thoracic andMediastinal Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>epistaxis</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Cardiac Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>cardiac arrest</paragraph> <paragraph>palpitation</paragraph> <paragraph>ventricular tachycardia </paragraph> <paragraph>ventricular arrhythmia</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Vascular Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>phlebitis</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>gastritis</paragraph> <paragraph>stomatitis </paragraph> <paragraph>pancreatitis </paragraph> <paragraph>esophagitis</paragraph> <paragraph>gastroenteritis</paragraph> <paragraph>glossitis</paragraph> <paragraph>pseudomembraneous/ <content styleCode="italics">C. difficile</content> colitis [see Warnings and Precautions <linkHtml href="#_3dd86671-a364-dddb-34f5-87ff4874d579">(5.9</linkHtml>)]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Hepatobiliary Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>abnormal hepatic function</paragraph> <paragraph>increased hepatic enzymes </paragraph> <paragraph>increased alkaline phosphatase</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Skin and Subcutaneous TissueDisorders</content> </paragraph> </td> <td valign="top"> <paragraph>urticaria [see Warnings and Precautions <linkHtml href="#_01346183-5ca4-c55f-82d4-547d1e82e1ad">(5.7)</linkHtml>]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and ConnectiveTissue Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>arthralgia</paragraph> <paragraph>tendinitis</paragraph> <paragraph>[see Warnings and Precautions <linkHtml href="#_a7864089-d05c-d65a-0200-9dc6f8594218">(5.2)</linkHtml>]</paragraph> <paragraph>myalgia </paragraph> <paragraph>skeletal pain</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph> <content styleCode="bold">Renal and Urinary Disorders</content> </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph>abnormal renal function</paragraph> <paragraph>acute renal failure [see Warnings and Precautions (<linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">5.6)]</linkHtml> </paragraph> </td> </tr> </tbody> </table>

<table cellpadding="0.3pt" width="100%"> <col width="48%"/> <col width="52%"/> <tbody> <tr> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">System/Organ Class </content> </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction </content> </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic System Disorders </content> </paragraph> </td> <td valign="top"> <paragraph>pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions (<linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">5.6</linkHtml>)] eosinophilia </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Immune System Disorders </content> </paragraph> </td> <td valign="top"> <paragraph> hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness [see Warnings and Precautions (<linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">5.6</linkHtml>, <linkHtml href="#_01346183-5ca4-c55f-82d4-547d1e82e1ad">5.7</linkHtml>)]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Psychiatric Disorders </content> </paragraph> </td> <td valign="top"> <paragraph> psychosis paranoia isolated reports of suicidal ideation, suicide attempt and completed suicide [see Warnings and Precautions (<linkHtml href="#_31eca02b-738e-cb3d-4733-66b6713215d0">5.4</linkHtml>)] </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> exacerbation of myasthenia gravis [see Warnings and Precautions (<linkHtml href="#_6e67c430-aa55-684d-77cb-0271af4ede20">5.5</linkHtml>)] anosmia ageusia parosmia dysgeusia peripheral neuropathy (may be irreversible) [see Warnings and Precautions (<linkHtml href="#_c06ffaea-afa6-2cfc-1dff-dec6ff6fbf72">5.3</linkHtml>)] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia pseudotumor cerebri [see Warnings and Precautions (<linkHtml href="#_31eca02b-738e-cb3d-4733-66b6713215d0">5.4</linkHtml>)]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Eye Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> uveitis vision disturbance, including diplopia visual acuity reduced vision blurred scotoma</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Ear and Labyrinth Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> hypoacusis tinnitus</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Cardiac Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> isolated reports of torsade de pointes electrocardiogram QT prolonged [see Warnings and Precautions (<linkHtml href="#_9697f448-d255-5ba4-05a0-d00b0688a83f">5.10</linkHtml>)] tachycardia</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Vascular Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> vasodilatation</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Respiratory, Thoracic andMediastinal Disorders</content> </paragraph> </td> <td valign="top"> <paragraph>isolated reports of allergic pneumonitis [see Warnings and Precautions (<linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">5.6</linkHtml>)]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Hepatobiliary Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions <linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">(5.6</linkHtml>), (<linkHtml href="#_01a3ec62-a6c2-74df-8cf9-0890545025a5">5.8</linkHtml>)]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Skin and Subcutaneous TissueDisorders</content> </paragraph> </td> <td valign="top"> <paragraph> bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis Acute Generalized Exanthematous Pustulosis (AGEP) fixed drug eruptions erythema multiforme [see Warnings and Precautions (<linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">5.6</linkHtml>)]] photosensitivity/phototoxicity reaction [see Warnings and Precautions (<linkHtml href="#_98e992f2-b0e1-7db5-63ec-fee63f4d5400">5.13</linkHtml>)] leukocytoclastic vasculitis</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and ConnectiveTissue Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> tendon rupture [see Warnings and Precautions (<linkHtml href="#_a7864089-d05c-d65a-0200-9dc6f8594218">5.2</linkHtml>)] muscle injury, including rupture rhabdomyolysis</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Renal and Urinary Disorders</content> </paragraph> </td> <td valign="top"> <paragraph> interstitial nephritis [see Warnings and Precautions <linkHtml href="#_b7f637da-2ab4-ae34-2aba-7d78138281c3">(5.6)</linkHtml>]</paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">General Disorders andAdministration Site Conditions</content> </paragraph> </td> <td valign="top"> <paragraph> multi-organ failure pyrexia</paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph> <content styleCode="bold">Investigations</content> </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> prothrombin time prolonged international normalized ratio prolonged muscle enzymes increased</paragraph> </td> </tr> </tbody> </table>