BESREMi

WARNING: RISK OF SERIOUS DISORDERS Risk of Serious Disorders: Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy [see Warnings and Precautions ( 5.1 , 5,2 , 5.3 , 5.4 ) and Adverse Reactions ( 6.1 )] . WARNING: RISK OF SERIOUS DISORDERS See full prescribing information for complete boxed warning. Risk of Serious Disorders: Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely and withdraw therapy with persistently severe or worsening signs or symptoms of the above disorders. ( 5.1 , 5.2 , 5.3 , 5.4 )

5 WARNINGS AND PRECAUTIONS • Depression and Suicide: Monitor for symptoms and need for treatment. ( 5.1 ) • Endocrine Toxicity: Discontinue if endocrine disorders occur that cannot be medically managed. ( 5.2 ) • Cardiovascular Toxicity: Avoid use in patients with severe or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently. ( 5.3 ) • Hematologic and Hemorrhagic Disorders: Perform blood counts at baseline, every 2 weeks during titration, and at least every 3-6 months during maintenance treatment. ( 5.4 ) • Hypersensitivity Reactions: Stop treatment and immediately manage reaction. ( 5.5 ) • Pancreatitis: Consider discontinuation if confirmed pancreatitis. ( 5.6 ) • Colitis: Discontinue if signs or symptoms of colitis. ( 5.7 ) • Pulmonary Toxicity: Discontinue if pulmonary infiltrates or pulmonary function impairment. ( 5.8 ) • Ophthalmologic Toxicity: Monitor for ocular toxicity. Promptly evaluate eye symptoms and discontinue if new or worsening eye disorders. ( 5.9 ) • Hyperlipidemia: Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. ( 5.10 ) • Hepatotoxicity: Monitor liver enzymes and hepatic function at baseline and during treatment. Reduce dose or discontinue depending on severity. ( 5.11 ) • Renal Toxicity: Monitor serum creatinine at baseline and during therapy. Discontinue if severe renal impairment develops. ( 5.12 ) • Dental and Periodontal Toxicity: Advise on good oral hygiene and regular dental examinations. ( 5.13 ) • Dermatologic Toxicity: Consider discontinuing if clinically significant dermatologic toxicity. ( 5.14 ) • Driving and Operating Machinery: Advise patients to avoid driving or using machinery if they experience dizziness, somnolence, or hallucination. ( 5.15 ) • Embryo-Fetal Toxicity: Can cause fetal harm. ( 5.16 ) 5.1 Depression and Suicide Life-threatening or fatal neuropsychiatric reactions have occurred in patients receiving interferon alfa products, including BESREMi. These reactions may occur in patients with and without previous psychiatric illness. Psychiatric reactions have been observed in 10% of BESREMi-treated patients with essential thrombocythemia including depression, adjustment disorder with depressed mood, and depressed mood. Serious neuropsychiatric reactions have been observed in 3% of BESREMi-treated patients with polycythemia vera, including depression, depressive symptoms, depressed mood, and listlessness. Of these cases, 3.4% of the patients recovered with temporary drug interruption and 2.8% stopped BESREMi treatment. Other central nervous system effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa products. BESREMi is contraindicated in patients with a history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt [see Contraindications ( 4 )] . Closely monitor patients for any symptoms of psychiatric disorders and consider psychiatric consultation and treatment if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue BESREMi therapy. 5.2 Endocrine Toxicity Endocrine toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include worsening hypothyroidism and hyperthyroidism. Autoimmune thyroiditis and hyperglycemia, including new onset type 1 diabetes, have been reported in patients receiving interferon alfa-2b products. Endocrine toxicities included hyperthyroidism (1.1%), hypothyroidism (1.1%), autoimmune thyroiditis (0.5%), and thyroiditis (0.5%) in BESREMi-treated patients with essential thrombocythemia. Endocrine toxicities included hyperthyroidism (4.5%), hypothyroidism (3.9%), and autoimmune thyroiditis/thyroiditis (2.8%) in BESREMi-treated patients with polycythemia vera. Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease [see Contraindications ( 4 )] . Evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during BESREMi therapy. Discontinue BESREMi in patients who develop endocrine disorders that cannot be adequately managed during treatment with BESREMi. 5.3 Cardiovascular Toxicity Cardiovascular toxicity has occurred in patients receiving interferon alfa products, including BESREMi. Toxicities may include cardiomyopathy, myocardial infarction, atrial fibrillation, coronary artery ischemia, and acute coronary syndrome [see Adverse Reactions ( 6.1 )] . Three thrombotic events of transient ischemic attack (grade 2, 1 patient), pulmonary embolism (grade 3, 1 patient), and peripheral vein thrombosis (grade 2, 1 patient) occurred in the essential thrombocythemia Phase 3 SURPASS ET study. Patients with a history of cardiovascular disorders and/or thrombotic events should be closely monitored for cardiovascular toxicity and/or thrombotic events during BESREMi therapy. Avoid use of BESREMi in patients with severe or unstable cardiovascular disease (e.g., uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction. 5.4 Hematologic and Hemorrhagic Disorders Decreased peripheral blood counts have occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include thrombocytopenia (increasing the risk of bleeding), anemia, and leukopenia (increasing the risk of infection). In BESREMi-treated patients with essential thrombocythemia, anemia of grade 3 or greater occurred in 1% of patients. Leukopenia of grade 3 or greater occurred in 2% of patients. Infection occurred in 45% of patients, while serious infections occurred in 4% of patients. Essential thrombocythemia-related hemorrhagic cases occurred in 6% of patients and included gingival bleeding, tongue hemorrhage, epistaxis, purpura, and retinal hemorrhage. In BESREMi-treated patients with polycythemia vera, thrombocytopenia of grade 3 (platelet counts <50,000 – 25,000/mm 3 ) or greater occurred in 2% of patients. Anemia of grade 3 (Hgb <8 g/dL) or greater occurred in 1% of patients. Leukopenia of grade 3 (WBC counts <2,000 – 1,000/mm 3 ) or greater occurred in 2% of patients. Infection occurred in 48% of patients, while serious infections occurred in 8% of patients. Monitor complete blood counts at baseline, during titration and every 3-6 months during the maintenance phase. Monitor patients for signs and symptoms of infection or bleeding. 5.5 Hypersensitivity Reactions Hypersensitivity reactions have occurred in patients receiving interferon alfa products, including BESREMi. BESREMi is contraindicated in patients with hypersensitivity reactions to interferon products or any of the inactive ingredients in BESREMi [see Contraindications ( 4 )] . Toxicities may include serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis, drug eruption). If such reactions occur, discontinue BESREMi and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment. 5.6 Pancreatitis Pancreatitis has occurred in patients receiving interferon alfa products, including BESREMi. Pancreatitis was reported in 2.2% of patients receiving BESREMi for polycythemia vera. Symptoms may include nausea, vomiting, upper abdominal pain, bloating, and fever. Patients may experience elevated lipase, amylase, white blood cell count, or altered renal/hepatic function. Interrupt BESREMi treatment in patients with possible pancreatitis and evaluate promptly. Consider discontinuation of BESREMi in patients with confirmed pancreatitis. 5.7 Colitis Serious and, in very rare cases potentially life-threatening ulcerative or hemorrhagic/ischemic colitis have occurred in patients receiving interferon alfa products, some cases occurring as early as 12 weeks after start of treatment. Symptoms may include abdominal pain, bloody diarrhea, and fever. Discontinue BESREMi in patients who develop these signs or symptoms. Colitis may resolve within 1 to 3 weeks of stopping treatment. 5.8 Pulmonary Toxicity Pulmonary toxicity has occurred in patients receiving interferon alfa products, including BESREMi. Pulmonary toxicity may manifest as dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, pleural effusion, and sarcoidosis. Some events have resulted in respiratory failure or death. Discontinue BESREMi in patients who develop pulmonary infiltrates or pulmonary function impairment. 5.9 Ophthalmologic Toxicity Ophthalmologic toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include severe eye disorders such as retinopathy, retinal hemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness. During BESREMi therapy in patients with essential thrombocythemia, 23% of patients were identified with eye disorders. Eye disorders in ≥5% of patients included vision blurred (8%) and dry eye (7%). During BESREMi therapy in patients with polycythemia vera, 23% of patients were identified with an eye disorder. Eyes disorders ≥5% included cataract (6%) and dry eye (5%). Advise patients to have eye examinations before and during BESREMi therapy, specifically in those patients with a retinopathy-associated disease such as diabetes mellitus or hypertension. Evaluate eye symptoms promptly. Discontinue BESREMi in patients who develop new or worsening eye disorders. 5.10 Hyperlipidemia Hyperlipidemia has occurred in patients treated with interferon alfa products, including BESREMi. Hypertriglyceridemia occurred in 9% of patients, hyperlipidemia occurred in 2% of patients, and dyslipidemia occurred in 0.5% of patients receiving BESREMi for essential thrombocythemia. Hyperlipidemia, hypertriglyceridemia, or dyslipidemia occurred in 3% of patients receiving BESREMi for polycythemia vera. Elevated triglycerides may result in pancreatitis [see Warnings and Precautions ( 5.6 )] . Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. Consider discontinuation of BESREMi in patients with persistently, markedly elevated triglycerides. 5.11 Hepatotoxicity Hepatotoxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include increases in serum ALT, AST, GGT, and bilirubin. BESREMi is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Contraindications ( 4 )] . Increases in serum ALT ≥3 × the upper limit of normal (ULN), AST ≥3 × the ULN, GGT ≥3 × ULN, and bilirubin >2 × ULN have been observed in patients treated with BESREMi. In BESREMi-treated patients with essential thrombocythemia, 4% of patients experienced Grade ≥3 liver enzyme elevations including alanine aminotransferase increased in 2.7% of patients, aspartate aminotransferase increased in 1.1% of patients, and blood bilirubin increased in 0.5% of patients. There were 20% of patients with alanine aminotransferase levels ≥3 × ULN and 9% of patients with aspartate aminotransferase levels ≥3 × ULN. A single Grade 4 adverse reaction of hepatitis was reported in an open-label single arm study of BESREMi in patients with essential thrombocythemia, with a time to recovery of 11 days. In BESREMi-treated patients with polycythemia vera, 36 patients (20%) experienced liver enzyme elevations, 33 of whom had elevations of 1.25-5 × ULN. Patients were able to resume BESREMi upon resolution of liver enzyme elevations. Liver enzyme elevations have also been reported in patients after long-term BESREMi therapy. Monitor liver enzymes and hepatic function at baseline and during BESREMi treatment. For dose modifications see Table 1 for patients with essential thrombocythemia and see Table 3 for patients with polycythemia vera [see Dosage and Administration ( 2.3 )] . Discontinue BESREMi in patients who develop evidence of hepatic decompensation (characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or variceal hemorrhage) during treatment [see Use in Specific Populations ( 8.7 )] . 5.12 Renal Toxicity Renal toxicity has occurred in patients receiving interferon alfa products, including BESREMi. During BESREMi therapy in patients with polycythemia vera, <1% of patients were reported to develop renal impairment and <1% of patients were reported to have toxic nephropathy. Monitor serum creatinine at baseline and during therapy. Avoid use of BESREMi in patients with eGFR <30 mL/min. Discontinue BESREMi if severe renal impairment develops during treatment [see Use in Specific Populations ( 8.6 )]. 5.13 Dental and Periodontal Toxicity Dental and periodontal toxicities may occur in patients receiving interferon alfa products, including BESREMi. These toxicities may include dental and periodontal disorders, which may lead to loss of teeth. In addition, dry mouth could have a damaging effect on teeth and oral mucous membranes during long-term treatment with BESREMi. Patients should have good oral hygiene and regular dental examinations. 5.14 Dermatologic Toxicity Dermatologic toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities have included skin rash, pruritus, alopecia, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, and hyperhidrosis. Consider discontinuation of BESREMi if clinically significant dermatologic toxicity occurs. 5.15 Driving and Operating Machinery BESREMi may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how BESREMi affects their abilities. Patients who experience dizziness, somnolence or hallucination during BESREMi therapy should avoid driving or using machinery. 5.16 Embryo-Fetal Toxicity Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.1 )] . Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.1 , 8.3 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Depression and Suicide [see Warnings and Precautions ( 5.1 )] • Endocrine Toxicity [see Warnings and Precautions ( 5.2 )] • Cardiovascular Toxicity [see Warnings and Precautions ( 5.3 )] • Hematologic and Hemorrhagic Disorders [see Warnings and Precautions ( 5.4 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] • Pancreatitis [see Warnings and Precautions ( 5.6 )] • Colitis [see Warnings and Precautions ( 5.7 )] • Pulmonary Toxicity [see Warnings and Precautions ( 5.8 )] • Ophthalmologic Toxicity [see Warnings and Precautions ( 5.9 )] • Hyperlipidemia [see Warnings and Precautions ( 5.10 )] • Hepatotoxicity [see Warnings and Precautions ( 5.11 )] • Renal Toxicity [see Warnings and Precautions ( 5.12 )] • Dental and Periodontal Toxicity [see Warnings and Precautions ( 5.13 )] • Dermatologic Toxicity [see Warnings and Precautions ( 5.14 )] • Driving and Operating Machinery [see Warnings and Precautions ( 5.15 )] • Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.16 )] • Essential thrombocythemia: The most common adverse reactions reported in >20% of patients were transaminase elevations, anemia, pyrexia, beta 2 microglobulin urine increased, bacterial infection, pruritus, and weight decreased. ( 6 ) • Polycythemia vera: The most common adverse reactions reported in >40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact PharmaEssentia at 1-800-999-2449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Essential Thrombocythemia The pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of essential thrombocythemia dosed every 2 weeks in 182 patients in an open-label trial [P1101 ET, SURPASS ET] and a single-arm trial [A22-301, EXCEED ET]. The mean age was 56 years (range: 21 to 84 years). There were 104 (57%) women, 78 (43%) men, and 93 (51%) Asian, 76 (42%) Caucasian, 5 (2.7%) Black or African American, 5 (2.7%) Other, and 3 (1.6%) Hispanic patients were included in the studies. Among 182 patients who received BESREMi, 70 (39%) patients were exposed for >56 weeks (>14 months). The mean (SD) dose of BESREMi was 394.9 (98.4) mcg during the treatment period. In this pooled safety population, the most common adverse reactions in ≥10% of BESREMi-treated patients were aspartate aminotransferase increased (44%), alanine aminotransferase increased (43%), fatigue (31%), anemia (24%), white blood cell count decreased (23%), neutrophil count decreased (22%), pruritus (17%), gamma-glutamyltransferase increased (16%), alopecia (16%), headache (15%), diarrhea (13%), nausea (13%), beta 2 microglobulin urine increased (12%), influenza like illness (11%), and myalgia (11%). The safety findings described below reflect exposure to BESREMi as monotherapy for the treatment of essential thrombocythemia in 91 patients in the SURPASS ET study [see Clinical Studies ( 14 )] . Among the 91 patients receiving BESREMi, 55% were exposed for 9 to 13 months and 36% were exposed for more than 13 months. Serious adverse reactions were reported in 2.2% of patients treated with BESREMi in the SURPASS ET study and included vascular headache and drug eruption. Adverse reactions requiring permanent discontinuation of patients treated with BESREMi occurred in 1.1% patient each and included aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, pneumonitis, pulmonary hypertension, thyroiditis, dry eye, and erythema. The most common adverse reactions reported in ≥10% of patients in the SURPASS ET study are listed in Table 4 . Table 4 Adverse Reactions in ≥10% of Patients with Essential Thrombocythemia in the SURPASS ET Study Over 13 Months. * Adverse Reactions defined as all treatment-emergent adverse events 1 Transaminase elevations include: Alanine aminotransferase increased, Aspartate aminotransferase increased, Hepatic function abnormal, and Liver function test increased 2 Grouped related terms 3 Rash includes: Rash, Rash maculo-papular, and Rash pruritic Term BESREMi N=91 Anagrelide N=80 All Grade n (%) Grade ≥3 n (%) All Grade n (%) Grade ≥3 n (%) Transaminase elevations 1 49 (54) 3 (3) 11 (14) 0 Anemia 25 (28) 0 24 (30) 3 (4) Pyrexia 24 (26) 0 7 (9) 0 Beta 2 microglobulin urine increased 23 (25) 0 3 (4) 0 Bacterial infection 2 22 (24) 5 (5) 18 (23) 2 (3) Pruritus 20 (22) 1 (1.1) 15 (19) 0 Weight decreased 19 (21) 1 (1) 5 (6) 0 Leukopenia 2 17 (19) 1 (1) 2 (3) 1 (1) Fatigue 16 (18) 0 10 (13) 0 Hemorrhage 2 15 (17) 0 30 (38) 3 (4) Alopecia 14 (15) 0 1 (1) 0 Headache 14 (15) 0 25 (31) 0 Diarrhea 13 (14) 0 19 (24) 0 Gamma-glutamyl transferase increased 12 (13) 0 9 (11) 0 Nasopharyngitis 2 12 (13) 0 14 (18) 0 Abdominal pain 2 11 (12) 0 11 (14) 0 Neutrophil count decreased 11 (12) 1 (1) 0 0 Arthralgia 10 (11) 0 7 (9) 0 Cough 10 (11) 0 5 (6) 0 Rash 3 10 (11) 0 4 (5) 0 Dizziness 10 (11) 0 16 (20) 1 (1) Malaise 10 (11) 0 3 (4) 0 Myalgia 10 (11) 0 7 (9) 0 Back pain 2 10 (11) 0 5 (6) 0 Polycythemia Vera The pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of polycythemia vera dosed every two to four weeks in 178 patients in two open-label trials [PEGINVERA, PROUD-PV/CONTINUATION-PV]. The mean age at baseline was 58.6 years (range 30-85 years), 88 (49%) women, 90 (51%) men, 177 (99%) Caucasian and 1 (1%) Asian. Among 178 patients who received BESREMi, 80% were exposed for 12 months or longer. The mean dose of BESREMi was 334 mcg SD ± 121 during the treatment period. In this pooled safety population, the most common adverse reactions greater than 10%, were liver enzyme elevations (20%), leukopenia (20%), thrombocytopenia (19%), arthralgia (13%), fatigue (12%), myalgia (11%), and influenza-like illness (11%). The safety findings described below reflect exposure to BESREMi as monotherapy for the treatment of polycythemia vera in 51 patients in the PEGINVERA study [see Clinical Studies ( 14 )] . Among the 51 patients receiving BESREMi, 71% were exposed for 12 months or longer, 63% were exposed for three years or longer, and 53% were exposed for greater than five years. Serious adverse reactions were reported in 16% of patients in the PEGINVERA study. The most common serious adverse reactions observed during the study ( > 4%) included urinary tract infection (8%), transient ischemic attack (6%) and depression (4%). Adverse reactions requiring permanent discontinuation in >2% of patients who received BESREMi included depression (8%), arthralgia (4%), fatigue (4%), and general physical health deterioration (4%). In the PEGINVERA study, patients were not pre-screened for depression or anxiety disorders. The most common adverse reactions reported in ≥10% of patients in the PEGINVERA study are listed in Table 5 . Table 5 Adverse Reactions in >10% of Patients with Polycythemia Vera in the PEGINVERA Study Over 7.5 Years. *Adverse Reactions defined as all treatment emergent adverse events Grouped Term Definitions a Includes pyrexia, chills, and influenza-like illness. b Includes asthenia, malaise, and fatigue. c Includes pharyngitis and nasopharyngitis. d Includes musculoskeletal pain, back pain, pain in extremity, bone pain, flank pain, and spinal pain. e Includes headache, migraine, and head pain. f Includes night sweats and hyperhidrosis. g Includes upper respiratory tract infection, rhinitis, bronchitis, and respiratory tract infection. h Includes abdominal pain upper, abdominal pain lower, and abdominal pain. i Includes insomnia, sleep disorder, and abnormal dreams. j Includes peripheral edema and generalized edema. k Includes hypertension and hypertensive crisis. l Includes rash, maculopapular rash, and pruritic rash. m Includes transaminase increase, hepatic enzyme increase, GGT increase, AST increase, and ALT increase. Clinically relevant adverse reactions in <10% of patients include: Cardiovascular System: Atrial fibrillation Adverse Reactions* BESREMi N=51 % Influenza-like illness a 59 Arthralgia 47 Fatigue b 47 Pruritus 45 Nasopharyngitis c 43 Musculoskeletal pain d 41 Headache e 39 Diarrhea 33 Hyperhidrosis f 29 Nausea 28 Upper respiratory tract infection g 27 Local administration site reactions 26 Dizziness 22 Abdominal pain h 20 Depression 20 Sleep disorder i 20 Leukopenia 18 Decreased appetite 18 Alopecia 16 Edema j 16 Hypertension k 16 Muscle spasms 16 Neutropenia 16 Rash l 16 Transaminase elevations m 16 Urinary tract infection 16 Thrombocytopenia 12 Vertigo 12

<table ID="_Ref239235490" width="100%"><caption>Table 4 Adverse Reactions in &#x2265;10% of Patients with Essential Thrombocythemia in the SURPASS ET Study Over 13 Months.</caption><col width="38%"/><col width="15%"/><col width="15%"/><col width="15%"/><col width="15%"/><tfoot><tr><td align="left" colspan="5" valign="top">^*Adverse Reactions defined as all treatment-emergent adverse events</td></tr><tr><td align="left" colspan="5" valign="top">¹ Transaminase elevations include: Alanine aminotransferase increased, Aspartate aminotransferase increased, Hepatic function abnormal, and Liver function test increased</td></tr><tr><td align="left" colspan="5" valign="top">² Grouped related terms</td></tr><tr><td align="left" colspan="5" valign="top">³ Rash includes: Rash, Rash maculo-papular, and Rash pruritic</td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold"><content styleCode="italics">Term</content></content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">BESREMi</content></paragraph><paragraph><content styleCode="bold">N=91</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Anagrelide</content></paragraph><paragraph><content styleCode="bold">N=80</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold"><content styleCode="italics">All Grade</content></content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold"><content styleCode="italics">Grade &#x2265;3</content></content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold"><content styleCode="italics">All Grade</content></content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold"><content styleCode="italics">Grade &#x2265;3</content></content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Transaminase elevations¹</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>49 (54)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (3)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11 (14)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25 (28)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>24 (30)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>24 (26)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7 (9)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Beta 2 microglobulin urine increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>23 (25)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (4)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Bacterial infection²</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>22 (24)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 (5)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>18 (23)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 (3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Pruritus</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20 (22)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (1.1)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15 (19)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Weight decreased</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>19 (21)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>5 (6)</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Leukopenia²</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>17 (19)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2 (3)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Fatigue</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16 (18)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (13)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Hemorrhage²</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15 (17)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>30 (38)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Alopecia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 (15)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 (15)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>25 (31)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13 (14)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>19 (24)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Gamma-glutamyl transferase increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 (13)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>9 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Nasopharyngitis²</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>12 (13)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>14 (18)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Abdominal pain²</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11 (12)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11 (14)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Neutrophil count decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11 (12)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Arthralgia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7 (9)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Cough</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 (6)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Rash³</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4 (5)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16 (20)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Malaise</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3 (4)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Myalgia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7 (9)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Back pain²</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10 (11)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5 (6)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr></tbody></table>

<table ID="_Ref239235579" cellpadding="0pt" width="100%"><caption>Table 5 Adverse Reactions in &gt;10% of Patients with Polycythemia Vera in the PEGINVERA Study Over 7.5 Years.</caption><col width="45%"/><col width="33%"/><tfoot><tr><td align="left" colspan="2" valign="top">*Adverse Reactions defined as all treatment emergent adverse events</td></tr><tr><td align="left" colspan="2" valign="top"> </td></tr><tr><td align="left" colspan="2" valign="top"><content styleCode="underline">Grouped Term Definitions</content></td></tr><tr><td align="left" colspan="2" valign="top">^a Includes pyrexia, chills, and influenza-like illness.</td></tr><tr><td align="left" colspan="2" valign="top">^b Includes asthenia, malaise, and fatigue.</td></tr><tr><td align="left" colspan="2" valign="top">^c Includes pharyngitis and nasopharyngitis.</td></tr><tr><td align="left" colspan="2" valign="top">^d Includes musculoskeletal pain, back pain, pain in extremity, bone pain, flank pain, and spinal pain.</td></tr><tr><td align="left" colspan="2" valign="top">^e Includes headache, migraine, and head pain.</td></tr><tr><td align="left" colspan="2" valign="top">^f Includes night sweats and hyperhidrosis.</td></tr><tr><td align="left" colspan="2" valign="top">^g Includes upper respiratory tract infection, rhinitis, bronchitis, and respiratory tract infection.</td></tr><tr><td align="left" colspan="2" valign="top">^h Includes abdominal pain upper, abdominal pain lower, and abdominal pain.</td></tr><tr><td align="left" colspan="2" valign="top">ⁱ Includes insomnia, sleep disorder, and abnormal dreams.</td></tr><tr><td align="left" colspan="2" valign="top">^j Includes peripheral edema and generalized edema.</td></tr><tr><td align="left" colspan="2" valign="top">^k Includes hypertension and hypertensive crisis.</td></tr><tr><td align="left" colspan="2" valign="top">^l Includes rash, maculopapular rash, and pruritic rash.</td></tr><tr><td align="left" colspan="2" valign="top">^m Includes transaminase increase, hepatic enzyme increase, GGT increase, AST increase, and ALT increase.</td></tr><tr><td align="left" colspan="2" valign="top"> </td></tr><tr><td align="left" colspan="2" valign="top">Clinically relevant adverse reactions in &lt;10% of patients include:</td></tr><tr><td align="left" colspan="2" valign="top">Cardiovascular System: Atrial fibrillation</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reactions*</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">BESREMi N=51</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Influenza-like illness ^a</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>59</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Arthralgia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>47</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue ^b</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>47</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pruritus</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>45</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nasopharyngitis ^c</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>43</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Musculoskeletal pain ^d</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>41</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache ^e</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>39</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>33</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hyperhidrosis ^f</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>29</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper respiratory tract infection ^g</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Local administration site reactions</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abdominal pain ^h</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Depression</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Sleep disorder ⁱ</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Alopecia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Edema ^j</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypertension ^k</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Muscle spasms</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash ^l</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Transaminase elevations ^m</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urinary tract infection</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Thrombocytopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Vertigo</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td></tr></tbody></table>