Hydroxyureaside effects

The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression Malignancies Vasculitic toxicities (including Leg Ulcers) Risks with concomitant use of antiretroviral drugs Risk with concomitant use of live virus vaccine Macrocytosis Hemolytic Anemia Most common adverse reactions to SIKLOS (incidence > 10%) include infections and neutropenia in children and infections and headache and dry skin in adults. 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