Siklos

• 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 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)]

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• Malignancies

  : Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies. (
  
  

  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.

  )
  
  

Initial dose: 15 mg/kg in adults and 20 mg/kg in children once daily. Monitor blood counts every two weeks. (

• The dose may be increased by 5 mg/kg/day every 8 weeks, or sooner if a severe painful crisis occurs, until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range. (
  
  
  2.1 Recommended Dosing

  The recommended SIKLOS dosing is described in Table 1.

  Table 1: Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose Modification Criteria	Monitoring Parameters
  Initial Recommended Dosing	Adults: 15 mg/kg Pediatrics: 20 mg/kg once daily based on patient's actual or ideal weight, 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/mm3 - platelets greater than or equal to 80,000/mm3 - hemoglobin greater than 5.3 g/dL - reticulocytes greater than or equal to 80,000/mm3if 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/mm3 younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1,250/mm3. - platelets less than 80,000/mm3 - hemoglobin less than 4.5 g/dL - reticulocytes less than 80,000/mm3if 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)].
  )
  
• Discontinue SIKLOS until hematologic recovery if blood counts are considered toxic. Resume treatment after reducing the dose by 5 mg/kg/day from the dose associated with hematological toxicity. (
  
  
  2.1 Recommended Dosing

  The recommended SIKLOS dosing is described in Table 1.

  Table 1: Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose Modification Criteria	Monitoring Parameters
  Initial Recommended Dosing	Adults: 15 mg/kg Pediatrics: 20 mg/kg once daily based on patient's actual or ideal weight, 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/mm3 - platelets greater than or equal to 80,000/mm3 - hemoglobin greater than 5.3 g/dL - reticulocytes greater than or equal to 80,000/mm3if 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/mm3 younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1,250/mm3. - platelets less than 80,000/mm3 - hemoglobin less than 4.5 g/dL - reticulocytes less than 80,000/mm3if 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)].
  )
  
• Renal impairment: Reduce the dose of SIKLOS by 50% in patients with creatinine clearance less than 60 mL/min. (
  
  
  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 ESRDOn dialysis days, administer SIKLOS to patients with ESRD following hemodialysis	10	7.5

  Monitor the hematologic parameters closely in these patients.
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  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)]

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  12.3 Pharmacokinetics

  Mean peak plasma concentrations 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.
  )
  

Tablets: functionally scored 100 mg and functionally triple-scored 1,000 mg tablet (

Lactation: Advise women to stop breastfeeding while taking SIKLOS. (