Siklos

WARNING: MYELOSUPPRESSION and MALIGNANCIES WARNING: MYELOSUPPRESSION and MALIGNANCIES See full prescribing information for complete boxed warning . Myelosuppression : SIKLOS may cause severe myelosuppression. Do not give if bone marrow function is markedly depressed. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary. ( 5.1 ) Malignancies : Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies. ( 5.2 ) Myelosuppression: SIKLOS may cause severe myelosuppression. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary [see Warnings and Precautions (5.1) ] . Malignancies: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies [see Warnings and Precautions (5.2) ] .

5 WARNINGS AND PRECAUTIONS Embryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.3 , 8.1 , 8.3 ) Cutaneous vasculitic toxicities (incl. leg ulcers): Institute treatment and discontinue SIKLOS and/or reduce dose if this occurs. ( 5.4 ) Risks with concomitant use of antiretroviral drugs: Pancreatitis, hepatotoxicity, and neuropathy have occurred. Monitor for signs and symptoms patients with HIV infection using antiretroviral drugs; discontinue SIKLOS, and implement treatment. ( 5.5 ) Concomitant use with live virus vaccine: increased risk of severe infections. ( 5.6 ) Hemolytic Anemia: Monitor blood counts throughout treatment. If hemolysis persists, discontinue SIKLOS. ( 5.9 ) 5.1 Myelosuppression Hydroxyurea causes severe myelosuppression. Do not initiate treatment with hydroxyurea in patients if bone marrow function is markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common manifestation. Thrombocytopenia and anemia occur less often, and are seldom seen without a preceding leukopenia. Some patients, treated at the recommended initial dose of 15 mg/kg/day in adults or 20 mg/kg/day in children, have experienced severe or life-threatening myelosuppression. Due to the change in body weight requiring modification of daily dose, pediatric patients have an increased risk of myelosuppression at the time of dose adjustment. Evaluate hematologic status prior to and every two weeks during treatment with SIKLOS. Provide supportive care and modify dose or discontinue SIKLOS as needed. Recovery from myelosuppression is usually observed within 15 days when therapy is interrupted. Resume therapy after interruption at a lower dose [see Dosage and Administration (2.1) ] . 5.2 Malignancies Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which Siklos is not approved), secondary leukemia has been reported. Leukemia secondary to long-term hydroxyurea has also been reported in patients with sickle cell disease. Leukemia has also been reported in patients with sickle cell disease and no prior history of treatment with hydroxyurea. Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and monitor for the development of secondary malignancies. 5.3 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, SIKLOS can cause fetal harm when administered to a pregnant woman. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with SIKLOS for at least 6 months after therapy [see Use in Specific Populations (8.1 , 8.3) ] . 5.4 Vasculitic Toxicities (Including Leg Ulcers) Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease (a condition for which SIKLOS is not approved), treatment with SIKLOS should be discontinued and/or its dose reduced if cutaneous vasculitic ulcerations develop. Rarely, ulcers are caused by leukocytoclastic vasculitis. Avoid use of SIKLOS in patients with wounds on the legs (leg ulcers). 5.5 Risks with Concomitant Use of Antiretroviral Drugs Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1) ] . 5.6 Risks with Concomitant Use of Live Virus Vaccine Avoid use of live virus vaccine in patients taking SIKLOS. Concomitant use of hydroxyurea with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus and result in severe infections [see Drug Interactions (7.2) ]. Patient's antibody response to vaccines may be decreased. Consider consultation with a specialist. 5.7 Macrocytosis SIKLOS may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of pernicious anemia. Prophylactic administration of folic acid is recommended. 5.8 Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays is possible, rendering falsely elevated results of these in patients treated with hydroxyurea [see Drug Interactions (7.3) ]. Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin. If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods. 5.9 Hemolytic Anemia Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse Reactions (6.1) ] . Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte, unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed diagnosis of hemolytic anemia not related to the disease and in the absence of other causes, discontinue SIKLOS.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1) ] Malignancies [see Warnings and Precautions (5.2) ] Vasculitic toxicities (including Leg Ulcers) [see Warnings and Precautions (5.4) ] Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.5) ] Risk with concomitant use of live virus vaccine [see Warnings and Precautions (5.6) ] Macrocytosis [see Warnings and Precautions (5.7) ] Hemolytic Anemia [see Warnings and Precautions (5.9) ] Most common adverse reactions to SIKLOS (incidence > 10%) include infections and neutropenia in children and infections and headache and dry skin in adults. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact the marketer Medunik at 1 844-884-5520 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 safety of SIKLOS has been assessed in 405 pediatric patients with sickle cell disease from 2-18 years of age and 1077 adults in the European Sickle Cell Disease prospective Cohort study ESCORT-HU. The most frequently reported adverse reactions in ESCORT-HU were infections and myelosuppression, with mild to moderate neutropenia as the most common manifestation. Other adverse reactions include skin and subcutaneous disorders (skin depigmentation/melanonychia, skin rash, alopecia), gastrointestinal disorders, vitamin D deficiency and headache. At least one serious adverse reaction was reported in 33% of the 405 pediatric patients and 32% of the 1077 adults with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%) in children, including serious neutropenia (3.2%), thrombocytopenia (3%) and anemia (3%). Other reported serious adverse reactions were gastrointestinal disorders (3.2 %), fever (2.5 %) and nervous system disorders (4%), including headache (2.7%). Among adults, the most frequent serious adverse reactions were infections (12.9%), respiratory, thoracic and mediastinal disorders (5.8%), blood and lymphatic disorders (4.8%), nervous system disorders (3.6%), and general disorders and administration site disorders (3.1%). Table 2: Most frequent (greater than or equal to 2%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU Global Safety Set (N=405) Total Severity Mild Moderate Severe n % n % n % n % n: number of patients with an adverse reaction At least one adverse reaction 261 64 Infections 161 40 120 30 88 22 18 4.4 Other Infections 92 23 66 16 32 8 3 0.7 Bacterial 65 16 24 6 37 9 10 2.5 Viral 40 10 23 6 14 3.5 3 0.7 Parvovirus B19 15 4 7 1.7 5 1.2 2 0.5 Blood and lymphatic system disorders 85 21 51 13 59 15 14 3.5 Neutropenia 51 13 26 6 31 8 4 1 Thrombocytopenia 30 7 16 4 15 3.7 2 0.5 Anemia 17 4.2 4 1 8 2 7 1.7 Gastrointestinal disorders 53 13 29 7 30 7 4 1 Other Gastrointestinal Disorders 30 7 13 3.2 15 3.7 2 0.5 Constipation 10 2.5 5 1.2 5 1.2 0 0 Nausea 10 2.5 4 1 4 1 2 0.5 Metabolic and nutrition disorders 44 11 24 6 21 5 1 0.2 Deficiency of vitamin D 25 6 19 4.7 7 1.7 1 0.2 Other Metabolic and nutrition disorders 8 2 3 0.7 4 1 1 0.2 Weight gain 8 2 1 0.2 7 1.7 0 0 Nervous system disorders 45 11 19 4.7 19 4.7 8 2 Headache 30 7 15 3.7 7 1.7 4 1 Other Nervous system disorders 11 2.7 2 0.5 4 1 4 1 General disorders 41 10 22 5 17 4.2 4 1 Fever 31 8 20 4.9 12 3 2 0.5 Skin and subcutaneous tissue disorders 38 9 29 7 14 3.5 1 0.2 Skin reactions 15 4 8 2 7 1.7 1 0.2 Other Skin and subcutaneous tissue disorders 13 3.2 8 2 5 1.2 0 0 Other Not SCD-related reactions 23 6 16 4 3 0.7 1 0.2 Other Not SCD-related reactions 23 6 16 4 3 0.7 1 0.2 Respiratory thoracic and mediastinal disorders 11 3 6 1.5 3 0.7 2 0.5 Renal and urinary disorders 8 2 2 0.5 4 1 0 0 Table 3: Most frequent (greater than or equal to 3%) adverse reactions reported in adult patients enrolled in ESCORT-HU Global adult safety set (N=1077) Total Severity Mild Moderate Severe n % n % n % n % At least one adverse reaction 897 84 586 54 617 57 345 32 Infections 465 43 171 16 240 22 101 9 Viral infection 47 4.4 17 1.6 21 1.9 5 0.5 Bacterial infection 45 4.2 9 0.8 27 2.5 5 0.5 Bronchitis 41 3.8 10 0.9 19 1.8 3 0.3 Influenza 40 3.7 8 0.7 15 1.4 5 0.5 Urinary tract infection 40 3.7 19 1.8 11 1.0 1 0.1 Nasopharyngitis 40 3.7 21 1.9 13 1.2 1 0.1 Nervous system disorders 313 29 131 12 125 12 54 5 Headache 211 20 84 8 74 7 27 2.5 Dizziness 100 9 43 4.0 32 3.0 9 0.8 General disorders and administration site conditions 300 28 111 10 113 10 24 2.2 Asthenia 100 9 30 2.8 18 1.7 10 0.9 Pyrexia 91 8 27 2.5 39 3.6 4 0.4 Fatigue 51 4.7 22 2.0 17 1.6 2 0.2 Edema peripheral 33 3.1 9 0.8 13 1.2 2 0.2 Skin and subcutaneous tissue disorders 297 28 160 15 123 11 23 2.1 Dry skin 128 12 67 6.2 36 3.3 5 0.5 Skin ulcer 80 7 19 1.8 44 4.1 11 1.0 Alopecia 49 4.5 31 2.9 13 1.2 5 0.5 Gastrointestinal disorders 267 25 116 11 110 10 25 2.3 Nausea 69 6 28 2.6 26 2.4 3 0.3 Abdominal pain upper 52 4.8 15 1.4 22 2.0 5 0.5 Diarrhea 37 3.4 10 0.9 13 1.2 Respiratory, thoracic and mediastinal disorders 256 24 70 7 103 10 48 4.5 Cough 59 5.5 23 2.1 21 1.9 3 0.3 Lung disorder 51 4.7 4 0.4 28 2.6 16 1.5 Dyspnea 44 4.1 12 1.1 14 1.3 4 0.4 Blood and lymphatic system disorders 250 23 74 7 121 11.2 61 6 Anemia 103 10 11 1.0 51 4.7 37 3.4 Thrombocytopenia 70 7 29 2.7 30 2.8 13 1.2 Neutropenia 50 4.6 24 2.2 18 1.7 7 0.6 Musculoskeletal and connective tissue disorders 247 23 93 9 101 9 25 2.3 Arthralgia 95 9 26 2.4 31 2.9 7 0.6 Back pain 48 4.5 11 1.0 18 1.7 6 0.6 Pain in extremity 33 3.1 14 1.3 10 0.9 Investigations 198 18 40 3.7 47 4.4 10 0.9 Weight increased 43 4.0 15 1.4 22 2.0 4 0.4 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SIKLOS. 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. Blood and lymphatic system disorders : macrocytosis, hemolytic anemia in patients who are treated with hydroxyurea for myeloproliferative disorders. Gastrointestinal disorders: vomiting, gastrointestinal ulcer, severe hypomagnesemia Hepatobiliary disorders: elevation of hepatic enzymes Skin and subcutaneous tissue disorders: skin reactions (oral, ungula and cutaneous pigmentation), oral mucositis, rash, melanonychia, Reproductive system and breast disorders : oligospermia, azoospermia, amenorrhea

<table width="100%"><caption>Table 2: Most frequent (greater than or equal to 2%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU</caption><col width="40%" align="left" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule">Global Safety Set (N=405)</th><th colspan="2" rowspan="2" styleCode="Rrule">Total</th><th colspan="6" styleCode="Rrule">Severity</th></tr><tr styleCode="Botrule"><th colspan="2" align="center" styleCode="Rrule">Mild</th><th colspan="2" styleCode="Rrule">Moderate</th><th colspan="2" styleCode="Rrule">Severe</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th></tr></thead><tfoot><tr><td align="left" colspan="9">n: number of patients with an adverse reaction</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">At least one adverse reaction</td><td styleCode="Rrule">261</td><td styleCode="Rrule">64</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections</content></td><td styleCode="Rrule">161</td><td styleCode="Rrule">40</td><td styleCode="Rrule">120</td><td styleCode="Rrule">30</td><td styleCode="Rrule">88</td><td styleCode="Rrule">22</td><td styleCode="Rrule">18</td><td styleCode="Rrule">4.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Other Infections</td><td styleCode="Rrule">92</td><td styleCode="Rrule">23</td><td styleCode="Rrule">66</td><td styleCode="Rrule">16</td><td styleCode="Rrule">32</td><td styleCode="Rrule">8</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Bacterial</td><td styleCode="Rrule">65</td><td styleCode="Rrule">16</td><td styleCode="Rrule">24</td><td styleCode="Rrule">6</td><td styleCode="Rrule">37</td><td styleCode="Rrule">9</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Viral</td><td styleCode="Rrule">40</td><td styleCode="Rrule">10</td><td styleCode="Rrule">23</td><td styleCode="Rrule">6</td><td styleCode="Rrule">14</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Parvovirus B19</td><td styleCode="Rrule">15</td><td styleCode="Rrule">4</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Blood and lymphatic system disorders</content></td><td styleCode="Rrule">85</td><td styleCode="Rrule">21</td><td styleCode="Rrule">51</td><td styleCode="Rrule">13</td><td styleCode="Rrule">59</td><td styleCode="Rrule">15</td><td styleCode="Rrule">14</td><td styleCode="Rrule">3.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">51</td><td styleCode="Rrule">13</td><td styleCode="Rrule">26</td><td styleCode="Rrule">6</td><td styleCode="Rrule">31</td><td styleCode="Rrule">8</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Thrombocytopenia</td><td styleCode="Rrule">30</td><td styleCode="Rrule">7</td><td styleCode="Rrule">16</td><td styleCode="Rrule">4</td><td styleCode="Rrule">15</td><td styleCode="Rrule">3.7</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">17</td><td styleCode="Rrule">4.2</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule">53</td><td styleCode="Rrule">13</td><td styleCode="Rrule">29</td><td styleCode="Rrule">7</td><td styleCode="Rrule">30</td><td styleCode="Rrule">7</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Other Gastrointestinal Disorders</td><td styleCode="Rrule">30</td><td styleCode="Rrule">7</td><td styleCode="Rrule">13</td><td styleCode="Rrule">3.2</td><td styleCode="Rrule">15</td><td styleCode="Rrule">3.7</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolic and nutrition disorders</content></td><td styleCode="Rrule">44</td><td styleCode="Rrule">11</td><td styleCode="Rrule">24</td><td styleCode="Rrule">6</td><td styleCode="Rrule">21</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Deficiency of vitamin D</td><td styleCode="Rrule">25</td><td styleCode="Rrule">6</td><td styleCode="Rrule">19</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Other Metabolic and nutrition disorders</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Weight gain</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule">45</td><td styleCode="Rrule">11</td><td styleCode="Rrule">19</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">19</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">30</td><td styleCode="Rrule">7</td><td styleCode="Rrule">15</td><td styleCode="Rrule">3.7</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Other Nervous system disorders</td><td styleCode="Rrule">11</td><td styleCode="Rrule">2.7</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders</content></td><td styleCode="Rrule">41</td><td styleCode="Rrule">10</td><td styleCode="Rrule">22</td><td styleCode="Rrule">5</td><td styleCode="Rrule">17</td><td styleCode="Rrule">4.2</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fever</td><td styleCode="Rrule">31</td><td styleCode="Rrule">8</td><td styleCode="Rrule">20</td><td styleCode="Rrule">4.9</td><td styleCode="Rrule">12</td><td styleCode="Rrule">3</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td><td styleCode="Rrule">38</td><td styleCode="Rrule">9</td><td styleCode="Rrule">29</td><td styleCode="Rrule">7</td><td styleCode="Rrule">14</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Skin reactions</td><td styleCode="Rrule">15</td><td styleCode="Rrule">4</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Other Skin and subcutaneous tissue disorders</td><td styleCode="Rrule">13</td><td styleCode="Rrule">3.2</td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Other Not SCD-related reactions</content></td><td styleCode="Rrule">23</td><td styleCode="Rrule">6</td><td styleCode="Rrule">16</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Other Not SCD-related reactions</td><td styleCode="Rrule">23</td><td styleCode="Rrule">6</td><td styleCode="Rrule">16</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory thoracic and mediastinal disorders</content></td><td styleCode="Rrule">11</td><td styleCode="Rrule">3</td><td styleCode="Rrule">6</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Renal and urinary disorders</content></td><td styleCode="Rrule">8</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="100%" ID="TABLE3"><caption>Table 3: Most frequent (greater than or equal to 3%) adverse reactions reported in adult patients enrolled in ESCORT-HU</caption><col width="40%" align="left" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="8%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule">Global adult safety set (N=1077)</th><th colspan="2" rowspan="2" styleCode="Rrule">Total</th><th colspan="6" styleCode="Rrule">Severity</th></tr><tr styleCode="Botrule"><th colspan="2" align="center" styleCode="Rrule">Mild</th><th colspan="2" styleCode="Rrule">Moderate</th><th colspan="2" styleCode="Rrule">Severe</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th><th styleCode="Rrule">n</th><th styleCode="Rrule">%</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">At least one adverse reaction</content></td><td styleCode="Rrule">897</td><td styleCode="Rrule">84</td><td styleCode="Rrule">586</td><td styleCode="Rrule">54</td><td styleCode="Rrule">617</td><td styleCode="Rrule">57</td><td styleCode="Rrule">345</td><td styleCode="Rrule">32</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections</content></td><td styleCode="Rrule"><content styleCode="bold">465</content></td><td styleCode="Rrule"><content styleCode="bold">43</content></td><td styleCode="Rrule"><content styleCode="bold">171</content></td><td styleCode="Rrule"><content styleCode="bold">16</content></td><td styleCode="Rrule"><content styleCode="bold">240</content></td><td styleCode="Rrule"><content styleCode="bold">22</content></td><td styleCode="Rrule"><content styleCode="bold">101</content></td><td styleCode="Rrule"><content styleCode="bold">9</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Viral infection</td><td styleCode="Rrule">47</td><td styleCode="Rrule">4.4</td><td styleCode="Rrule">17</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">21</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Bacterial infection</td><td styleCode="Rrule">45</td><td styleCode="Rrule">4.2</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">27</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Bronchitis</td><td styleCode="Rrule">41</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.9</td><td styleCode="Rrule">19</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Influenza</td><td styleCode="Rrule">40</td><td styleCode="Rrule">3.7</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Urinary tract infection</td><td styleCode="Rrule">40</td><td styleCode="Rrule">3.7</td><td styleCode="Rrule">19</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nasopharyngitis</td><td styleCode="Rrule">40</td><td styleCode="Rrule">3.7</td><td styleCode="Rrule">21</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">13</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule"><content styleCode="bold">313</content></td><td styleCode="Rrule"><content styleCode="bold">29</content></td><td styleCode="Rrule"><content styleCode="bold">131</content></td><td styleCode="Rrule"><content styleCode="bold">12</content></td><td styleCode="Rrule"><content styleCode="bold">125</content></td><td styleCode="Rrule"><content styleCode="bold">12</content></td><td styleCode="Rrule"><content styleCode="bold">54</content></td><td styleCode="Rrule"><content styleCode="bold">5</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">211</td><td styleCode="Rrule">20</td><td styleCode="Rrule">84</td><td styleCode="Rrule">8</td><td styleCode="Rrule">74</td><td styleCode="Rrule">7</td><td styleCode="Rrule">27</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">100</td><td styleCode="Rrule">9</td><td styleCode="Rrule">43</td><td styleCode="Rrule">4.0</td><td styleCode="Rrule">32</td><td styleCode="Rrule">3.0</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule"><content styleCode="bold">300</content></td><td styleCode="Rrule"><content styleCode="bold">28</content></td><td styleCode="Rrule"><content styleCode="bold">111</content></td><td styleCode="Rrule"><content styleCode="bold">10</content></td><td styleCode="Rrule"><content styleCode="bold">113</content></td><td styleCode="Rrule"><content styleCode="bold">10</content></td><td styleCode="Rrule"><content styleCode="bold">24</content></td><td styleCode="Rrule"><content styleCode="bold">2.2</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">100</td><td styleCode="Rrule">9</td><td styleCode="Rrule">30</td><td styleCode="Rrule">2.8</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">91</td><td styleCode="Rrule">8</td><td styleCode="Rrule">27</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">39</td><td styleCode="Rrule">3.6</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">51</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">22</td><td styleCode="Rrule">2.0</td><td styleCode="Rrule">17</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema peripheral</td><td styleCode="Rrule">33</td><td styleCode="Rrule">3.1</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">13</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td><td styleCode="Rrule"><content styleCode="bold">297</content></td><td styleCode="Rrule"><content styleCode="bold">28</content></td><td styleCode="Rrule"><content styleCode="bold">160</content></td><td styleCode="Rrule"><content styleCode="bold">15</content></td><td styleCode="Rrule"><content styleCode="bold">123</content></td><td styleCode="Rrule"><content styleCode="bold">11</content></td><td styleCode="Rrule"><content styleCode="bold">23</content></td><td styleCode="Rrule"><content styleCode="bold">2.1</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry skin</td><td styleCode="Rrule">128</td><td styleCode="Rrule">12</td><td styleCode="Rrule">67</td><td styleCode="Rrule">6.2</td><td styleCode="Rrule">36</td><td styleCode="Rrule">3.3</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Skin ulcer</td><td styleCode="Rrule">80</td><td styleCode="Rrule">7</td><td styleCode="Rrule">19</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">44</td><td styleCode="Rrule">4.1</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alopecia</td><td styleCode="Rrule">49</td><td styleCode="Rrule">4.5</td><td styleCode="Rrule">31</td><td styleCode="Rrule">2.9</td><td styleCode="Rrule">13</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"><content styleCode="bold">267</content></td><td styleCode="Rrule"><content styleCode="bold">25</content></td><td styleCode="Rrule"><content styleCode="bold">116</content></td><td styleCode="Rrule"><content styleCode="bold">11</content></td><td styleCode="Rrule"><content styleCode="bold">110</content></td><td styleCode="Rrule"><content styleCode="bold">10</content></td><td styleCode="Rrule"><content styleCode="bold">25</content></td><td styleCode="Rrule"><content styleCode="bold">2.3</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">69</td><td styleCode="Rrule">6</td><td styleCode="Rrule">28</td><td styleCode="Rrule">2.6</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain upper</td><td styleCode="Rrule">52</td><td styleCode="Rrule">4.8</td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">22</td><td styleCode="Rrule">2.0</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">37</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.9</td><td styleCode="Rrule">13</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode="Rrule"><content styleCode="bold">256</content></td><td styleCode="Rrule"><content styleCode="bold">24</content></td><td styleCode="Rrule"><content styleCode="bold">70</content></td><td styleCode="Rrule"><content styleCode="bold">7</content></td><td styleCode="Rrule"><content styleCode="bold">103</content></td><td styleCode="Rrule"><content styleCode="bold">10</content></td><td styleCode="Rrule"><content styleCode="bold">48</content></td><td styleCode="Rrule"><content styleCode="bold">4.5</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough</td><td styleCode="Rrule">59</td><td styleCode="Rrule">5.5</td><td styleCode="Rrule">23</td><td styleCode="Rrule">2.1</td><td styleCode="Rrule">21</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lung disorder</td><td styleCode="Rrule">51</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">28</td><td styleCode="Rrule">2.6</td><td styleCode="Rrule">16</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">44</td><td styleCode="Rrule">4.1</td><td styleCode="Rrule">12</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">14</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Blood and lymphatic system disorders</content></td><td styleCode="Rrule"><content styleCode="bold">250</content></td><td styleCode="Rrule"><content styleCode="bold">23</content></td><td styleCode="Rrule"><content styleCode="bold">74</content></td><td styleCode="Rrule"><content styleCode="bold">7</content></td><td styleCode="Rrule"><content styleCode="bold">121</content></td><td styleCode="Rrule"><content styleCode="bold">11.2</content></td><td styleCode="Rrule"><content styleCode="bold">61</content></td><td styleCode="Rrule"><content styleCode="bold">6</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">103</td><td styleCode="Rrule">10</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">51</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">37</td><td styleCode="Rrule">3.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Thrombocytopenia</td><td styleCode="Rrule">70</td><td styleCode="Rrule">7</td><td styleCode="Rrule">29</td><td styleCode="Rrule">2.7</td><td styleCode="Rrule">30</td><td styleCode="Rrule">2.8</td><td styleCode="Rrule">13</td><td styleCode="Rrule">1.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">50</td><td styleCode="Rrule">4.6</td><td styleCode="Rrule">24</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"><content styleCode="bold">247</content></td><td styleCode="Rrule"><content styleCode="bold">23</content></td><td styleCode="Rrule"><content styleCode="bold">93</content></td><td styleCode="Rrule"><content styleCode="bold">9</content></td><td styleCode="Rrule"><content styleCode="bold">101</content></td><td styleCode="Rrule"><content styleCode="bold">9</content></td><td styleCode="Rrule"><content styleCode="bold">25</content></td><td styleCode="Rrule"><content styleCode="bold">2.3</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">95</td><td styleCode="Rrule">9</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">31</td><td styleCode="Rrule">2.9</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Back pain</td><td styleCode="Rrule">48</td><td styleCode="Rrule">4.5</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.7</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain in extremity</td><td styleCode="Rrule">33</td><td styleCode="Rrule">3.1</td><td styleCode="Rrule">14</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.9</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Investigations</content></td><td styleCode="Rrule"><content styleCode="bold">198</content></td><td styleCode="Rrule"><content styleCode="bold">18</content></td><td styleCode="Rrule"><content styleCode="bold">40</content></td><td styleCode="Rrule"><content styleCode="bold">3.7</content></td><td styleCode="Rrule"><content styleCode="bold">47</content></td><td styleCode="Rrule"><content styleCode="bold">4.4</content></td><td styleCode="Rrule"><content styleCode="bold">10</content></td><td styleCode="Rrule"><content styleCode="bold">0.9</content></td></tr><tr><td styleCode="Lrule Rrule"> Weight increased</td><td styleCode="Rrule">43</td><td styleCode="Rrule">4.0</td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">22</td><td styleCode="Rrule">2.0</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0.4</td></tr></tbody></table>