neuropathy peripheral neuropathy, which was severe in some cases, has been reported in patients with hiv infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine. 7.2 concomitant use of live virus vaccine concomitant use of siklos with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus, because normal defense mechanisms may be suppressed by siklos therapy. vaccination with a live vaccine in a patient taking siklos may result in severe infections. generally, the patient's antibody response to vaccines may be decreased. treatment with siklos and concomitant immunization with live virus vaccines should only be performed if benefits clearly outweigh potential risks. consider consultation with a specialist. 7.3 test interference interference with uric acid, urea, or lactic acid assays studies have shown that there is an analytical interference of siklos with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with siklos.

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) ]. 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.

ight, whichever is less. monitor the patient's blood count every 2 weeks [see warnings and precautions (5.1) ] . dosing adjustment based on blood counts in an acceptable range increase dose 5 mg/kg/day every 8 weeks or if a painful crisis occurs. give until mild myelosuppression (absolute neutrophil count 2,000/ul to 4,000/ul) is achieved, up to a maximum of 35 mg/kg/day. increase dosing only if blood counts are in an acceptable range. increase dosing if a painful crisis occurs. do not increase if myelosuppression occurs. blood counts acceptable range: - neutrophils greater than or equal to 2,000 cells/mm 3 - platelets greater than or equal to 80,000/mm 3 - hemoglobin greater than 5.3 g/dl - reticulocytes greater than or equal to 80,000/mm 3 if the hemoglobin concentration less than 9 g/dl dosing adjustment based on blood counts in a toxic range discontinue treatment. if blood counts are considered toxic, discontinue siklos until hematologic recovery. blood counts toxic range: - neutrophils less than 2,000 cells/mm 3 younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1,250/mm 3 . - platelets less than 80,000/mm 3 - hemoglobin less than 4.5 g/dl - reticulocytes less than 80,000/mm 3 if the hemoglobin concentration less than 9 g/dl dosing after hematologic recovery reduce dose by 5 mg/kg/day. reduce the dose from the dose associated with hematologic toxicity. may titrate up or down every 8 weeks in 5 mg/kg/day increments. the patient should be at a stable dose with no hematologic toxicity for 24 weeks. discontinue the treatment permanently if a patient develops hematologic toxicity twice. siklos is available in 100 mg and 1,000 mg tablets. the 100 mg tablets have 1 score line and can be split into 2 parts (each 50 mg). the 1,000 mg tablets have 3 score lines and can be split into 4 parts (each 250 mg). therefore, the two strengths can be used to deliver doses of 1,000 mg, 750 mg, 500 mg, 250 mg, 100 mg, 50 mg and combinations thereof. calculate the rounded doses to the nearest 50 mg or 100 mg strength based on clinical judgment. patients must be able to follow directions regarding drug administration and their monitoring and care. fetal hemoglobin (hbf) levels may be used to evaluate the efficacy of siklos in clinical use. obtain hbf levels every three to four months. monitor for an increase in hbf of at least two-fold over the baseline value. administration: the tablets should be taken once daily, at the same time each day, with a glass of water. for patients who are not able to swallow the tablets, these can be dispersed immediately before use in a small quantity of water in a teaspoon. siklos is a cytotoxic drug. follow applicable special handling and disposal procedures [see references (15) ]. 2.2 dose modifications for renal impairment reduce the dose of siklos by 50% in patients with creatinine clearance of less than 60 ml/min or with end-stage renal disease (esrd) [see use in specific populations (8.6) and clinical pharmacology (12.3) ] . obtain the creatinine clearance using a 24-hour urine collection. creatinine clearance (ml/min) recommended siklos initial dose (mg/kg daily) pediatrics adults greater than or equal to 60 20 15 less than 60 or esrd on dialysis days, administer siklos to patients with esrd following hemodialysis 10 7.5 monitor the hematologic parameters closely in these patients.

ion 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

neuropathy peripheral neuropathy, which was severe in some cases, has been reported in patients with hiv infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine. 7.2 concomitant use of live virus vaccine concomitant use of siklos with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus, because normal defense mechanisms may be suppressed by siklos therapy. vaccination with a live vaccine in a patient taking siklos may result in severe infections. generally, the patient's antibody response to vaccines may be decreased. treatment with siklos and concomitant immunization with live virus vaccines should only be performed if benefits clearly outweigh potential risks. consider consultation with a specialist. 7.3 test interference interference with uric acid, urea, or lactic acid assays studies have shown that there is an analytical interference of siklos with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with siklos.

characterized by decreased fetal viability, reduced live litter sizes, and developmental delays (see data ) . advise pregnant women of the potential risk to a fetus (see clinical considerations ). background risk of major birth defects and miscarriage for the indicated population are unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. clinical considerations fetal/neonatal adverse reactions although the data on a limited number of exposed pregnancies indicate no adverse effects on pregnancy or on the health of the fetus/newborn, patients on siklos should be made aware of the potential risks to the fetus. based on the limited amount of available information, in case of an exposure to siklos of pregnant female patients or pregnant partners of male patients, treated by siklos, a careful follow-up with adequate clinical, biological and ultrasonographic examinations should be considered. data human data according to a retrospective analysis of a cohort of 123 adult patients treated with hydroxyurea, twenty-three pregnancies have been reported from 15 women treated with hydroxyurea and partners of 3 men not using barrier contraception treated with hydroxyurea. most (61%) had no adverse developmental outcomes. in the other cases with known evolution, pregnancy had been interrupted either voluntarily or upon medical advice. in retrospective cohorts of 352 children and adolescents with sickle cell disease older than 2 years treated with hydroxyurea for a period of up to 12 years, 3 pregnancies under hydroxyurea were reported with no adverse developmental outcomes. from post-marketing data of siklos, 3 pregnancies have been reported while the father was treated with siklos and 16 pregnancies have been reported in 15 females treated with siklos. among the 13 cases with known evolution, 5 pregnancies had no adverse developmental outcomes, 4 led to premature birth, and 4 were early terminated. animal data hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2 basis. hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 basis) in rabbits. embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. hydroxyurea crosses the placenta. single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m 2 basis) to rats caused growth retardation and impaired learning ability. 8.2 lactation risk summary it is not known whether siklos is excreted in human milk, the effects of siklos on the breastfed child, or the effects of siklos on milk production. because of the potential for serious adverse reactions in a breastfed child from siklos, including carcinogenicity, advise patients not to breastfeed during treatment with siklos. 8.3 females and males of reproductive potential pregnancy testing siklos can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1) ] . verify the pregnancy status of females of reproductive potential prior to initiating siklos therapy. contraception females advise females of reproductive potential to use effective contraception during and after treatment with siklos for at least 6 months after therapy. advise females to immediately report pregnancy. males siklos may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. males with female sexual partners of reproductive potential should use effective contraception during and after treatment with siklos for at least 6 months after therapy [see nonclinical toxicology (13.1) ] . infertility males based on findings in animals and humans, male fertility may be compromised by treatment with siklos. azoospermia or oligospermia, sometimes reversible, has been observed in men. before the start of therapy, inform male patients about the possibility of sperm conservation [see adverse reactions (6) and nonclinical toxicology (13.1) ] . 8.4 pediatric use the safety and effectiveness of siklos have been established in pediatric patients aged 2-18 years with sickle cell anemia with recurrent moderate to severe painful crises. use of siklos in these age groups is supported by evidence from a non-interventional cohort study, the european sickle cell disease prospective cohort study, escort-hu, in which 405 pediatric patients ages 2 to <18 were enrolled. among the 405 pediatric patients treated with siklos, 274 were children (2-11) and 108 were adolescents (12-16) [see clinical studies (14) ] . continuous follow-up of the growth of treated children is recommended. pediatric patients aged 2-16 years had a higher risk of neutropenia than patients more than 16 years old. the safety and effectiveness of siklos have not been established in pediatric patients less than 2 years of age. 8.6 renal impairment the exposure to siklos is higher in patients with creatinine clearance of less than 60 ml/min. reduce dosage and closely monitor the hematologic parameters when siklos is to be administered to these patients [see dosage and administration (2.2) and clinical pharmacology (12.3) ] . 8.7 hepatic impairment monitor hematologic parameters more frequently in patients with hepatic impairment receiving siklos.

) . advise pregnant women of the potential risk to a fetus (see clinical considerations ). background risk of major birth defects and miscarriage for the indicated population are unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. clinical considerations fetal/neonatal adverse reactions although the data on a limited number of exposed pregnancies indicate no adverse effects on pregnancy or on the health of the fetus/newborn, patients on siklos should be made aware of the potential risks to the fetus. based on the limited amount of available information, in case of an exposure to siklos of pregnant female patients or pregnant partners of male patients, treated by siklos, a careful follow-up with adequate clinical, biological and ultrasonographic examinations should be considered. data human data according to a retrospective analysis of a cohort of 123 adult patients treated with hydroxyurea, twenty-three pregnancies have been reported from 15 women treated with hydroxyurea and partners of 3 men not using barrier contraception treated with hydroxyurea. most (61%) had no adverse developmental outcomes. in the other cases with known evolution, pregnancy had been interrupted either voluntarily or upon medical advice. in retrospective cohorts of 352 children and adolescents with sickle cell disease older than 2 years treated with hydroxyurea for a period of up to 12 years, 3 pregnancies under hydroxyurea were reported with no adverse developmental outcomes. from post-marketing data of siklos, 3 pregnancies have been reported while the father was treated with siklos and 16 pregnancies have been reported in 15 females treated with siklos. among the 13 cases with known evolution, 5 pregnancies had no adverse developmental outcomes, 4 led to premature birth, and 4 were early terminated. animal data hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2 basis. hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 basis) in rabbits. embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. hydroxyurea crosses the placenta. single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m 2 basis) to rats caused growth retardation and impaired learning ability.

rations and aucs increase more than proportionally with increase of dose. there is no drug accumulation upon once daily dosing of hydroxyurea. absorption following oral administration, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. the oral bioavailability of hydroxyurea was reported to be 85 -100%. effect of food there are no data on the effect of food on the absorption of hydroxyurea. distribution hydroxyurea distributes throughout the body with a volume of distribution approximating total body water. hydroxyurea concentrates in leukocytes and erythrocytes. elimination half-life of hydroxyurea is about 2-4 hours. metabolism up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation by urease found in intestinal bacteria. excretion the percentage of the dose excreted in urine was approximately 40% in pediatric patients with sickle cell anemia. specific populations patients with renal impairment the effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell anemia and renal impairment. patients with normal renal function (creatinine clearance [crcl] >80 ml/min), mild (crcl 50-80 ml/min), moderate (crcl =30-<50 ml/min), or severe (<30 ml/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. creatinine clearance values were obtained using 24-hour urine collections. patients with esrd received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. the exposure to hydroxyurea (mean auc) in patients with crcl <60 ml/min and those with esrd was 64% higher than in patients with normal renal function (crcl >60 ml/min). reduce the dose of siklos when it is administered to patients with creatinine clearance of <60 ml/min or with esrd following hemodialysis [see dosage and administration (2.2) and use in specific populations (8.6) ]. patients with hepatic impairment there are no data that support specific guidance for dose adjustment in patients with hepatic impairment. pediatric patients the pharmacokinetics of hydroxyurea is similar between children (4 to 17 years) and adults.

patients with renal impairment the effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell anemia and renal impairment. patients with normal renal function (creatinine clearance [crcl] >80 ml/min), mild (crcl 50-80 ml/min), moderate (crcl =30-<50 ml/min), or severe (<30 ml/min) renal impairment received a single oral dose of 15 mg/kg hydroxyurea. creatinine clearance values were obtained using 24-hour urine collections. patients with esrd received two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. the exposure to hydroxyurea (mean auc) in patients with crcl <60 ml/min and those with esrd was 64% higher than in patients with normal renal function (crcl >60 ml/min). reduce the dose of siklos when it is administered to patients with creatinine clearance of <60 ml/min or with esrd following hemodialysis [see dosage and administration (2.2) and use in specific populations (8.6) ]. patients with hepatic impairment there are no data that support specific guidance for dose adjustment in patients with hepatic impairment. pediatric patients the pharmacokinetics of hydroxyurea is similar between children (4 to 17 years) and adults.

aily dose on a mg/m 2 basis) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females [see use in specific populations (8.3) ].

s) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females [see use in specific populations (8.3) ].

n 10 and 14 months) after initiation of siklos treatment. the median (range) change was 0.5 g/dl (-4.6, 6.1) in 63 patients at 6 months (the post-baseline value closest to 6 months collected between 5 and 7 months) and 0.7 g/dl (-6.4, 6.0) in 83 patients at 12 months (the post-baseline value closest to 12 months collected between 10 and 14 months) after initiation of siklos treatment. among pediatric patients not previously treated with hydroxyurea prior to enrollment and analyzable for efficacy (n=141), the percentage of patients with at least one vaso-occlusive episode, one episode of acute chest syndrome, one hospitalization due to scd or one blood transfusion decreased after 12 months of siklos treatment (table 4). table 4: comparison of scd events in the first year of treatment with siklos with scd events in the 12 months prior to enrollment – escort hu trial (n=141) in pediatric patients scd events patients under 18 years old previously not treated with hydroxyurea with at least 12 months follow-up data available for clinical efficacy (n=141) in the 12 months prior to enrolment after 12 months of siklos ® treatment change number of patients with at least one vaso-occlusive episode (in 120 evaluable patients) no 37 (31%) 69 (57.5%) yes 83 (69%) 51 (42.5%) number of vasoocclusive episodes over 12 months (in 113 evaluable patients) median (range) 2 (0, 1) 0 (0.0, 7.0) -1 (-10.0, 5.0) number of patients with at least one episode of acute chest syndrome (in 123 evaluable patients) no 94 (76%) 116 (94%) yes 29 (24%) 7 (6%) number of episodes of acute chest syndrome over 12 months (in 123 evaluable patients) median (range) 0 (0.0, 2.0) 0 (0.0, 1.0) 0 (-2.0, 1.0) number of patients with at least one hospitalization related to scd (in 110 evaluable patients) no 27 (25%) 64 (58%) yes 83 (75%) 46 (42%) number of hospitalizations related to scd over 12 months (in 106 evaluable patients) median (range) 2 (0.0, 6.0) 0 (0.0, 7.0) -1 (-6.0, 6.0) number of days of hospitalizations related to scd over 12 months (in 100 evaluable patients) median (range) 8 (0.0, 58.0) 0 (0.0, 100.0) -3 (-58.0, 86.0) number of patients with at least one blood transfusion (in 122 evaluable patients) no 66 (54%) 94 (77%) yes 56 (46%) 28 (23%) adult patients with sickle cell disease in escort-hu 1077 adult patients were included of which 436 patients were naïve to hu treatment. there were 370 evaluable patients who had at least 12 months follow-up (median [range] 41 months [29, 54]. median (range) hemoglobin f percentages were 5.2% (0.2, 30.9) at baseline and 14.2% (0.5, 41.5) at least 6 months (the value closest to 6 months collected between 5 and 14 months) after initiation of siklos treatment, with a median (range) change of 8% (-8.0, 33.3) in 181 patients. among adult patients previously not treated with hydroxyurea prior to enrollment and analyzable for efficacy (n=370), the incidence and number of vaso-occlusive events, hospitalizations, acute chest syndrome and blood transfusions in the 12 month period before treatment and after initiation of treatment decreased after 12 months of siklos treatment. table 5 provides the efficacy results for escort-hu. table 5: comparison of scd events in the first year of treatment with siklos with scd events in the 12 months prior to enrollment – escort hu trial (n=370) in adult patients scd events adult patients previously not treated with hydroxyurea with at least 12 months follow-up data available for clinical efficacy (n=369) in the 12 months prior to enrolment after 12 months of siklos ® treatment change number of patients with at least one vaso-occlusive episode (in 367 evaluable patients) no 133 (36.2%) 226 (61.6%) yes 234 (63.8%) 141 (38.4%) number of vasoocclusive episodes over 12 months (in 343 evaluable patients) median (range) 1.0 (0.0, 20.0) 0.0 (0.0, 30.0) 0.0 (-20.0, 24.0) number of patients with at least one episode of acute chest syndrome (in 365 evaluable patients) no 273 (74.8%) 338 (92.6%) yes 92 (25.2%) 27 (7.4%) number of episodes of acute chest syndrome over 12 months (in 364 evaluable patients) median (range) 1.0 (0.0, 5.0) 0.0 (0.0, 3.0) 0.0 (-5.0 ; 2.0) number of patients with at least one hospitalization related to scd (in 366 evaluable patients) no 152 (41.5%) 252 (68.9%) yes 214 (58.5%) 114 (31.1%) number of hospitalizations related to scd over 12 months (in 360 evaluable patients) median (range) 1 (0.0, 15.0) 0 (0.0, 10.0) 0 (-15.0, 8.0) number of days of hospitalizations related to scd over 12 months (in 313 evaluable patients) median (range) 2 (0.0, 90.0) 0 (0.0, 77.0) 0 (-90.0, 57.0) number of patients with at least one blood transfusion (in 365 evaluable patients) no 207 (56.7%) 296 (81.1%) yes 158 (43.3%) 69 (18.9%)

�°c and 30°c (59°f and 86°f) [see usp controlled room temperature]. keep tightly closed. broken tablets must be stored in the bottle and must be used within three months. 16.3 handling and disposal siklos is a cytotoxic drug. follow applicable special handling and disposal procedures [see references (15) ] . to decrease the risk of contact, advise caregivers to wear disposable gloves when handling siklos or bottles containing siklos. wash hands with soap and water before and after contact with the bottle or tablets when handling siklos. avoid exposure to crushed tablets. if contact with crushed tablets occurs on the skin, wash affected area immediately and thoroughly with soap and water. if contact with crushed tablets occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown away in a closed container such as a plastic bag to avoid ingestion of powder by other people. the spill areas should then be cleaned using a detergent solution followed by clean water.

ecific populations (8.1 , 8.3) ] . advise females to discontinue breastfeeding during treatment with siklos [see use in specific populations (8.2) ] . advise male patients of potential risk to fertility [see use in specific populations (8.3) ] . advise patients with hiv infection to contact their physician for signs and symptoms of pancreatitis, hepatic events, and peripheral neuropathy [see warnings and precautions (5.5) ] . advise patients of the risk of hemolytic anemia. advise patients that they will have blood tests to evaluate for this if they develop persistent anemia not related to sickle cell anemia [see warnings and precautions (5.9) ] . because siklos tablets are scored, advise patients on how to take siklos properly.