FDA label 6fdafb53-4fe1-449d-98cd-aaa175da52fd

WARNING: THROMBOCYTOPENIA AND GLOMERULONEPHRITIS Thrombocytopenia TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. One clinical trial patient died from intracranial hemorrhage. TEGSEDI is contraindicated in patients with a platelet count below 100 x 10 9 /L [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Prior to starting TEGSEDI, obtain a platelet count [see Dosage and Administration ( 2.3 )]. During treatment, monitor platelet counts weekly if values are 75 x 10 9 /L or greater, and more frequently if values are less than 75 x 10 9 /L [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )] . If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional TEGSEDI unless a platelet count is determined to be interpretable and acceptable by a medical professional [see Warnings and Precautions ( 5.1 )] . Following discontinuation of treatment for any reason, continue to monitor platelet count for 8 weeks, or longer if platelet counts are less than 100 x 10 9 /L, to verify that platelet counts remain above 75 x 10 9 /L [see Dosage and Administration ( 2.4 )] . Glomerulonephritis TEGSEDI can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. One clinical trial patient who developed glomerulonephritis and did not receive immunosuppressive treatment remained dialysis-dependent. In clinical trials, cases of glomerulonephritis were accompanied by nephrotic syndrome, which can have manifestations of edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection [see Warnings and Precautions ( 5.2 )] . TEGSEDI should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 )] . Prior to starting TEGSEDI, measure the serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and perform a urinalysis [see Dosage and Administration ( 2.3 )] . During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every two weeks. TEGSEDI should not be given to patients who develop a UPCR of 1000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m 2 , pending further evaluation of the cause. If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m 2 , UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In patients with UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 )] . TEGSEDI REMS Program Because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring, TEGSEDI is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program [see Warnings and Precautions ( 5.3 )] . WARNING: THROMBOCYTOPENIA AND GLOMERULONEPHRITIS See full prescribing information for complete boxed warning. Thrombocytopenia TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. ( 5.1 ) Testing prior to treatment and monitoring during treatment is required ( 2.3 , 2.4 , 5.1 ) Glomerulonephritis TEGSEDI can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. ( 5.2 ) Testing prior to treatment and monitoring during treatment is required ( 2.3 , 2.4 , 5.2 ) TEGSEDI is available only through a restricted distribution program called the TEGSEDI REMS Program ( 5.3 ).

5 WARNINGS AND PRECAUTIONS Stroke and Cervicocephalic Arterial Dissection: These adverse events occurred within 2 days of first dose and with symptoms of cytokine release. Educate patients on symptoms of stroke and central nervous system arterial dissection. ( 5.4 ) Inflammatory and Immune Effects : Serious neurologic adverse reactions consistent with inflammatory and immune effects occurred. ( 5.5 ) Liver Injury: Monitor alanine amino-transferase, aspartate aminotransferase, and total bilirubin every 4 months during treatment and in case of symptoms of hepatic dysfunction. ( 5.6 ) Hypersensitivity Reactions: If these occur, discontinue and initiate appropriate therapy. ( 5.7 ) Uninterpretable Platelet Counts: Reaction between Antiplatelet Antibodies and ethylenediaminetetra-acetic acid : Platelet clumping can cause uninterpretable platelet measurement; repeat test if this is suspected. ( 5.8 ) Reduced Serum Vitamin A Levels and Recommended Supplementation: Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ( 5.9 ) 5.1 Thrombocytopenia TEGSEDI causes reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1 [see Clinical studies ( 14 )] , platelet counts below 100 x 10 9 /L occurred in 25% of TEGSEDI-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 x 10 9 /L occurred in 14% of TEGSEDI-treated patients, compared to no patient on placebo. In Study 1 and its extension study, 39% of TEGSEDI-treated patients with a baseline platelet count below 200 x10 9 /L had a nadir platelet count below 75 x 10 9 /L, compared to 6% of patients with baseline platelet counts 200 x10 9 /L or higher. Three TEGSEDI-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25 x 10 9 /L), which can have potentially fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage. One patient in a clinical trial experienced a fatal intracranial hemorrhage. In clinical trials, all 3 patients with severe thrombocytopenia had treatment-emergent antiplatelet IgG antibodies detected shortly before or at the time of the severe thrombocytopenia. In 2 patients, platelet clumping caused uninterpretable platelet measurements that delayed the diagnosis and treatment of severe thrombocytopenia. Platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA) [see Warnings and Precautions ( 5.8 )] . Monitoring and Dosing Patients who are not able to adhere to the recommended laboratory monitoring or to the related treatment recommendations must not receive TEGSEDI. Do not initiate TEGSEDI in patients with a platelet count below 100 x 10 9 /L. Follow recommended monitoring and treatment recommendations for platelet count [see Dosage and Administration ( 2.4 )] . If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold TEGSEDI dosing unless the platelet count is confirmed to be acceptable. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample) [see Warnings and Precautions ( 5.8 )] . Hold TEGSEDI dosing until an acceptable platelet count is confirmed with an interpretable blood sample. Concomitant Medications with Platelet Effects When considering use of TEGSEDI concomitantly with antiplatelet drugs or anticoagulants, be aware of the risk of potential bleeding from thrombocytopenia with TEGSEDI, and consider discontinuation of these drugs in patients with a platelet count less than 50 x 10 9 /L [see Drug Interactions ( 7.1 )] . Symptoms of Thrombocytopenia Symptoms of thrombocytopenia can include unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness or atypical severe headache. Patients and caregivers should be instructed to be vigilant for symptoms of thrombocytopenia and seek immediate medical help if they have concerns. Severe Thrombocytopenia: Treatment with Glucocorticoids Glucocorticoid therapy is strongly recommended in patients with a platelet count below 50 x 10 9 /L, and in patients with suspected immune-mediated thrombocytopenia. Avoid using TEGSEDI in patients for whom glucocorticoid treatment is not advised. 5.2 Glomerulonephritis and Renal Toxicity TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1 [see Clinical studies ( 14 )] , glomerulonephritis occurred in three (3%) TEGSEDI-treated patients vs. no patient on placebo. In these patients, stopping TEGSEDI alone was not sufficient to resolve manifestations of glomerulonephritis, and treatment with an immunosuppressive medication was necessary. One patient did not receive immunosuppressive treatment and remained dialysis-dependent. If glomerulonephritis is suspected, pursue prompt diagnosis and initiate immunosuppressive treatment as soon as possible. Cases of glomerulonephritis were accompanied by nephrotic syndrome. Possible complications of nephrotic syndrome can include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. TEGSEDI-treated patients who develop glomerulonephritis will require monitoring and treatment for nephrotic syndrome and its manifestations. Accumulation of antisense oligonucleotides in proximal tubule cells of the kidney, sometimes leading to increased tubular proteinuria, has been described in nonclinical studies. Urine protein to creatinine ratio (UPCR) greater than 5 times the upper limit of normal occurred in 15% of TEGSEDI-treated patients, compared to 8% of patients on placebo. Increase from baseline in serum creatinine greater than 0.5 mg/dL occurred in 11% of TEGSEDI-treated patients, compared to 2% of patients on placebo. Follow recommended monitoring and treatment recommendations for renal parameters [see Dosage and Administration ( 2.4 )] . TEGSEDI should generally not be initiated in patients with a UPCR of 1000 mg/g or greater. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued [see Contraindications ( 4 )] . Use caution with nephrotoxic drugs and other drugs that may impair renal function. Because immunosuppressive treatment is necessary for the treatment of glomerulonephritis, avoid using TEGSEDI in patients for whom immunosuppressive treatment is not advised. 5.3 TEGSEDI REMS Program TEGSEDI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program, because of risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis [see Warnings and Precautions ( 5.1 , 5.2 )] . Important requirements of the TEGSEDI Prescribing Program include: Prescribers must be certified within the program by enrolling and completing training. Patients must enroll in the program and comply with ongoing monitoring requirements [see Warnings and Precautions ( 5.1 ) and Dosage and Administration ( 2.4 )] . Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive TEGSEDI. Further information, including a list of qualified pharmacies/distributors, is available at www.TEGSEDIREMS.com or 1-844-483-4736. 5.4 Stroke and Cervicocephalic Arterial Dissection TEGSEDI may cause stroke and cervicocephalic arterial dissection. In clinical studies, 1 of 161 (0.6%) TEGSEDI-treated patients experienced carotid artery dissection and stroke. These events occurred within 2 days of the first TEGSEDI dose, a time when the patient also had symptoms of cytokine release (e.g., nausea, vomiting, muscular pain and weakness) and a high sensitivity C-reactive protein level greater than 100 mg/L. Educate patients on the symptoms of stroke and central nervous system arterial dissection. Instruct patients to seek help as soon as possible if symptoms of stroke or arterial dissection occur. 5.5 Inflammatory and Immune Effects Inflammatory and immune changes are an effect of some antisense oligonucleotide drugs, including TEGSEDI. In clinical studies, serious inflammatory and immune adverse reactions occurred in TEGSEDI-treated patients, including immune thrombocytopenia and glomerulonephritis, as well as a single case of antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis [see Warnings and Precautions ( 5.2 ) and ( 5.3 )] . Neurologic Serious Adverse Reactions In clinical studies, neurologic serious adverse reactions consistent with inflammatory and immune effects occurred in TEGSEDI-treated patients, in addition to stroke and carotid artery dissection [see Warnings and Precautions ( 5.5 )] . Two months after the first TEGSEDI dose, one patient developed a change in gait that progressed over 6 months to paraparesis, in the absence of radiologic evidence of spinal cord compression. Another patient developed progressive lumbar pain, weight loss, headache, vomiting, and impaired speech 7 months after starting TEGSEDI. Cerebrospinal fluid analysis findings included elevated protein, a lymphocyte-predominant pleocytosis, and testing that was negative for infection. The patient recovered after empiric therapy (high-dose steroids, antibiotics) and resumed TEGSEDI without recurrence of symptoms. 5.6 Liver Injury The liver is a site of accumulation of antisense oligonucleotides. In clinical studies, 8% of TEGSEDI-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the upper limit of normal (ULN), compared to 3% of patients on placebo; 3% of TEGSEDI-treated patients had an ALT at least 8 times the ULN, compared to no patient on placebo. One clinical study patient experienced an increased ALT more than 30 times the ULN. After a course of corticosteroids and discontinuation of TEGSEDI, the patient’s ALT returned to normal levels. Some patients had resolution of the liver laboratory abnormalities with continued use of TEGSEDI. In clinical studies, demonstrated or possible cases of immune-mediated biliary disease occurred in TEGSEDI-treated patients. There was a single case of autoimmune hepatitis with primary biliary cirrhosis in a patient with a family history of primary biliary cirrhosis, as well as a single case of biliary obstruction of unclear etiology. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin at baseline and monthly during treatment with TEGSEDI. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt treatment with TEGSEDI, as appropriate. If a patient is suspected to have developed liver injury induced by TEGSEDI treatment, TEGSEDI should be discontinued. Liver Transplant Rejection In a clinical study, cases of liver transplant rejection were reported 2-4 months after starting TEGSEDI in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting TEGSEDI. In these cases, the patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of TEGSEDI. In patients with a history of liver transplant, monitor ALT, AST, and total bilirubin monthly. Discontinue TEGSEDI in patients who develop signs of liver transplant rejection. 5.7 Hypersensitivity Reactions/Antibody Formation TEGSEDI can cause hypersensitivity reactions. In clinical studies, 6 of 161 (4%) TEGSEDI-treated patients stopped treatment because of a hypersensitivity reaction. Antibodies to TEGSEDI were present when the reactions occurred. These reactions generally occurred within 2 hours of administration of TEGSEDI and included headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms. If a hypersensitivity reaction occurs, discontinue administration of TEGSEDI, and initiate appropriate therapy. Do not use in patients who have a history of hypersensitivity reaction to TEGSEDI. 5.8 Uninterpretable Platelet Counts: Reaction between Antiplatelet Antibodies and ethylenediaminetetra-acetic acid (EDTA) In Study 1 [see Clinical Studies ( 14 )] , 23% of TEGSEDI-treated patients had at least 1 uninterpretable platelet count caused by platelet clumping, compared to 13% of patients on placebo. In 2 cases of severe thrombocytopenia with platelet count below 25 x 10 9 /L, one of which resulted in death, clumped platelet samples caused a delay in diagnosis and treatment. Both subjects had tested positive for treatment-emergent anti-platelet IgG antibodies detected shortly before, or at the time of the severe reduction in platelet count. Although platelet clumping can have a variety of causes (e.g., incompletely mixed or inadequately anticoagulated samples), platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetra-acetic acid (EDTA). In Study 1, 7 of the 9 (78%) TEGSEDI-treated patients with treatment-emergent positive antiplatelet antibody testing had at least 1 clumped platelet sample. If there is suspicion of EDTA-mediated platelet clumping, perform a repeat platelet count using a different anticoagulant (e.g., sodium citrate, heparin) in the blood collection tube. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable. Hold TEGSEDI dosing until an acceptable platelet count is confirmed with an interpretable blood sample. 5.9 Reduced Serum Vitamin A Levels and Recommended Supplementation TEGSEDI treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking TEGSEDI. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with TEGSEDI, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Thrombocytopenia [see Warnings and Precautions ( 5.1 )] Glomerulonephritis and Renal Toxicity [see Warnings and Precautions ( 5.2 )] Stroke and Cervicocephalic Arterial Dissection [see Warnings and Precautions ( 5.4 )] Inflammatory and Immune Effects [see Warnings and Precautions ( 5.5 )] Liver Injury [see Warnings and Precautions ( 5.6 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] Reducted Serum Vitamin A Levels and Recommended Supplementation [see Warnings and Precautions ( 5.9 )] The most common adverse reactions (those that occurred in at least 20% of TEGSEDI-treated patients and more frequently than on placebo) were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sobi, Inc. at 1-833-642-5232 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of TEGSEDI cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. A total of 112 adult patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) received TEGSEDI in Study 1 and 60 patients received placebo. The, mean age of the study patients was 59 years (27 to 78 years of age). Of the TEGSEDI-treated patients, 69% were male and 94% were Caucasian, with a mean exposure of 385 days, and median exposure of 449 days. Baseline disease characteristics were largely similar in TEGSEDI-treated patients and patients in the placebo control group. Sixty-seven percent of patients were in Stage 1 of the disease at baseline, and 33% in Stage 2. Fifty-two percent of patients had Val30Met mutations in the TTR gene, with the remaining 48% comprised of 26 different other point mutations. Table 2 presents common adverse reactions that occurred in at least 5% of TEGSEDI-treated patients and that occurred at least 5% more frequently or two times more frequently than on placebo. The most common adverse reactions that occurred in at least 20% of TEGSEDI-treated patients and more frequently than on placebo were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. Serious adverse reactions were more frequent in TEGSEDI-treated patients (32%) than in patients on placebo (21%). The most common adverse reactions leading to discontinuation were thrombocytopenia and cachexia. Table 2: Adverse Reactions Reported in At Least 5% TEGSEDI-Treated Patients and that Occurred At Least 5% More Frequently or At Least Two Times More Frequently than Placebo Patients (Study 1) a Includes bruising, erythema, hematoma, hemorrhage, induration, inflammation, mass, edema, pain, pruritus, rash, swelling, and urticaria. b Includes arrhythmia, atrial fibrillation, atrial flutter, bradyarrhythmia, bradycardia, extrasystoles, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, tachycardia, and ventricular extrasystoles. c Includes bacteremia, cellulitis staphylococcal, clostridium difficile infection, conjunctivitis bacterial, cystitis Escherichia, Helicobacter gastritis, Helicobacter infection, Staphylococcal infection. TEGSEDI (N=112) % Placebo (N=60) % Injection site reactions a 49 10 Nausea 31 12 Headache 26 12 Fatigue 25 20 Thrombocytopenia 24 2 Fever 20 8 Peripheral edema 19 10 Chills 18 3 Anemia 17 3 Vomiting 15 5 Myalgia 15 10 Decreased renal function 14 5 Arrhythmia b 13 5 Arthralgia 13 8 Pre-syncope or syncope 13 5 Decreased appetite 10 0 Paresthesia 10 3 Dyspnea 9 3 Elevated liver function test 9 3 Orthostasis 8 2 Influenza-like illness 8 3 Contusion 7 2 Bacterial infection c 7 3 Eosinophilia 5 0 Dry mouth 5 2 6.2 Immunogenicity The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TEGSEDI in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In Study 1, 30% of TEGSEDI-treated patients tested positive for anti-drug antibodies (ADA) following 65 weeks of treatment [see Warnings and Precautions ( 5.7 , 5.8 )] . However, the assay measured only IgG isotypes and the existence of other isotypes may be possible. In many cases adverse reactions occurred in patients with ADA, although the available data are too limited to make definitive conclusions about the relationship.

<table styleCode="Noautorules" ID="table2" width="750"><caption>Table 2: Adverse Reactions Reported in At Least 5% TEGSEDI-Treated Patients and that Occurred At Least 5% More Frequently or At Least Two Times More Frequently than Placebo Patients (Study 1)</caption><col width="40%" align="left"/><col width="30%" align="center"/><col width="30%" align="center"/><tfoot><tr><td colspan="3" align="left">^a Includes bruising, erythema, hematoma, hemorrhage, induration, inflammation, mass, edema, pain, pruritus, rash, swelling, and urticaria. ^b Includes arrhythmia, atrial fibrillation, atrial flutter, bradyarrhythmia, bradycardia, extrasystoles, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, tachycardia, and ventricular extrasystoles. ^c Includes bacteremia, cellulitis staphylococcal, clostridium difficile infection, conjunctivitis bacterial, cystitis Escherichia, <content styleCode="italics">Helicobacter</content> gastritis, <content styleCode="italics">Helicobacter</content> infection, Staphylococcal infection.</td></tr></tfoot><tbody><tr valign="middle"><td styleCode="Toprule Botrule Rrule Lrule"/><td styleCode="Toprule Botrule Rrule Lrule">TEGSEDI (N=112) % </td><td styleCode="Toprule Botrule Rrule Lrule">Placebo (N=60) % </td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Injection site reactions^a</td><td styleCode="Toprule Botrule Rrule Lrule">49</td><td styleCode="Toprule Botrule Rrule Lrule">10</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Nausea</td><td styleCode="Toprule Botrule Rrule Lrule">31</td><td styleCode="Toprule Botrule Rrule Lrule">12</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Headache</td><td styleCode="Toprule Botrule Rrule Lrule">26</td><td styleCode="Toprule Botrule Rrule Lrule">12</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Fatigue</td><td styleCode="Toprule Botrule Rrule Lrule">25</td><td styleCode="Toprule Botrule Rrule Lrule">20</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Thrombocytopenia</td><td styleCode="Toprule Botrule Rrule Lrule">24</td><td styleCode="Toprule Botrule Rrule Lrule">2</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Fever</td><td styleCode="Toprule Botrule Rrule Lrule">20</td><td styleCode="Toprule Botrule Rrule Lrule">8</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Peripheral edema</td><td styleCode="Toprule Botrule Rrule Lrule">19</td><td styleCode="Toprule Botrule Rrule Lrule">10</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Chills</td><td styleCode="Toprule Botrule Rrule Lrule">18</td><td styleCode="Toprule Botrule Rrule Lrule">3</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Anemia</td><td styleCode="Toprule Botrule Rrule Lrule">17</td><td styleCode="Toprule Botrule Rrule Lrule">3</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Vomiting</td><td styleCode="Toprule Botrule Rrule Lrule">15</td><td styleCode="Toprule Botrule Rrule Lrule">5</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Myalgia</td><td styleCode="Toprule Botrule Rrule Lrule">15</td><td styleCode="Toprule Botrule Rrule Lrule">10</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Decreased renal function</td><td styleCode="Toprule Botrule Rrule Lrule">14</td><td styleCode="Toprule Botrule Rrule Lrule">5</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Arrhythmia^b</td><td styleCode="Toprule Botrule Rrule Lrule">13</td><td styleCode="Toprule Botrule Rrule Lrule">5</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Arthralgia</td><td styleCode="Toprule Botrule Rrule Lrule">13</td><td styleCode="Toprule Botrule Rrule Lrule">8</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Pre-syncope or syncope</td><td styleCode="Toprule Botrule Rrule Lrule">13</td><td styleCode="Toprule Botrule Rrule Lrule">5</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Decreased appetite</td><td styleCode="Toprule Botrule Rrule Lrule">10</td><td styleCode="Toprule Botrule Rrule Lrule">0</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Paresthesia</td><td styleCode="Toprule Botrule Rrule Lrule">10</td><td styleCode="Toprule Botrule Rrule Lrule">3</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Dyspnea</td><td styleCode="Toprule Botrule Rrule Lrule">9</td><td styleCode="Toprule Botrule Rrule Lrule">3</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Elevated liver function test </td><td styleCode="Toprule Botrule Rrule Lrule">9</td><td styleCode="Toprule Botrule Rrule Lrule">3</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Orthostasis</td><td styleCode="Toprule Botrule Rrule Lrule">8</td><td styleCode="Toprule Botrule Rrule Lrule">2</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Influenza-like illness</td><td styleCode="Toprule Botrule Rrule Lrule">8</td><td styleCode="Toprule Botrule Rrule Lrule">3</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Contusion</td><td styleCode="Toprule Botrule Rrule Lrule">7</td><td styleCode="Toprule Botrule Rrule Lrule">2</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Bacterial infection^c</td><td styleCode="Toprule Botrule Rrule Lrule">7</td><td styleCode="Toprule Botrule Rrule Lrule">3</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Eosinophilia</td><td styleCode="Toprule Botrule Rrule Lrule">5</td><td styleCode="Toprule Botrule Rrule Lrule">0</td></tr><tr valign="top"><td styleCode="Toprule Botrule Rrule Lrule">Dry mouth</td><td styleCode="Toprule Botrule Rrule Lrule">5</td><td styleCode="Toprule Botrule Rrule Lrule">2</td></tr></tbody></table>