Droxia

DROXIA is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises.

• Initial dose: 15 mg/kg once daily. Monitor the patient's blood count every two weeks.
  2.1 Dosing Information

  Table 1:     Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose Modification Criteria	Monitoring Parameters
  Initial Recommended Dosing	15 mg/kg/day as a single dose once daily based on the patient's actual or ideal weight, whichever is less.		Monitor the patient's blood count every 2 weeks [see Warnings and Precautions].
  Dosing Based on Blood Counts
  In an acceptable range	Increase dose 5 mg/kg/day every 12 weeks Maximal dose: 35 mg/kg/day* *Maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks.	Increase dosing only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs.	Blood Counts Acceptable Range neutrophils ≥2500 cells/mm3 platelets ≥95,000/mm3 hemoglobin >5.3 g/dL reticulocytes ≥95,000/mm3if the hemoglobin concentration <9 g/dL
  Between acceptable and toxic range	Do not increase dose.	If blood counts are considered toxic , discontinue DROXIA until hematologic recovery.	Blood Counts Toxic Range neutrophils <2000 cells/mm3 platelets <80,000/mm3 hemoglobin <4.5 g/dL reticulocytes <80,000/mm3if the hemoglobin concentration <9 g/dL
  Dosing After Hematologic Recovery	Reduce dose by 2.5 mg/kg/day.	Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 12 weeks in 2.5 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.

  Swallow DROXIA capsules whole. Do NOT open, break, or chew capsules because DROXIA is a cytotoxic drug. 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 DROXIA 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.

  DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

  DROXIA is a cytotoxic drug. Follow applicable special handling and disposal procedures

  [see References (15)].
• The dose may be increased by 5 mg/kg/day every 12 weeks until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range.
  2.1 Dosing Information

  Table 1:     Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose Modification Criteria	Monitoring Parameters
  Initial Recommended Dosing	15 mg/kg/day as a single dose once daily based on the patient's actual or ideal weight, whichever is less.		Monitor the patient's blood count every 2 weeks [see Warnings and Precautions].
  Dosing Based on Blood Counts
  In an acceptable range	Increase dose 5 mg/kg/day every 12 weeks Maximal dose: 35 mg/kg/day* *Maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks.	Increase dosing only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs.	Blood Counts Acceptable Range neutrophils ≥2500 cells/mm3 platelets ≥95,000/mm3 hemoglobin >5.3 g/dL reticulocytes ≥95,000/mm3if the hemoglobin concentration <9 g/dL
  Between acceptable and toxic range	Do not increase dose.	If blood counts are considered toxic , discontinue DROXIA until hematologic recovery.	Blood Counts Toxic Range neutrophils <2000 cells/mm3 platelets <80,000/mm3 hemoglobin <4.5 g/dL reticulocytes <80,000/mm3if the hemoglobin concentration <9 g/dL
  Dosing After Hematologic Recovery	Reduce dose by 2.5 mg/kg/day.	Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 12 weeks in 2.5 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.

  Swallow DROXIA capsules whole. Do NOT open, break, or chew capsules because DROXIA is a cytotoxic drug. 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 DROXIA 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.

  DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

  DROXIA is a cytotoxic drug. Follow applicable special handling and disposal procedures

  [see References (15)].
• The dose is not increased if blood counts are between the acceptable range and toxic. Discontinue DROXIA until hematologic recovery if blood counts are considered toxic. Treatment may then be resumed after reducing the dose by 2.5 mg/kg/day from the dose associated with hematological toxicity.
  2.1 Dosing Information

  Table 1:     Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose Modification Criteria	Monitoring Parameters
  Initial Recommended Dosing	15 mg/kg/day as a single dose once daily based on the patient's actual or ideal weight, whichever is less.		Monitor the patient's blood count every 2 weeks [see Warnings and Precautions].
  Dosing Based on Blood Counts
  In an acceptable range	Increase dose 5 mg/kg/day every 12 weeks Maximal dose: 35 mg/kg/day* *Maximal dose is the highest dose that does not produce toxic blood counts over 24 consecutive weeks.	Increase dosing only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs.	Blood Counts Acceptable Range neutrophils ≥2500 cells/mm3 platelets ≥95,000/mm3 hemoglobin >5.3 g/dL reticulocytes ≥95,000/mm3if the hemoglobin concentration <9 g/dL
  Between acceptable and toxic range	Do not increase dose.	If blood counts are considered toxic , discontinue DROXIA until hematologic recovery.	Blood Counts Toxic Range neutrophils <2000 cells/mm3 platelets <80,000/mm3 hemoglobin <4.5 g/dL reticulocytes <80,000/mm3if the hemoglobin concentration <9 g/dL
  Dosing After Hematologic Recovery	Reduce dose by 2.5 mg/kg/day.	Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 12 weeks in 2.5 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.

  Swallow DROXIA capsules whole. Do NOT open, break, or chew capsules because DROXIA is a cytotoxic drug. 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 DROXIA 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.

  DROXIA causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.

  DROXIA is a cytotoxic drug. Follow applicable special handling and disposal procedures

  [see References (15)].
• Renal impairment: Reduce the dose of DROXIA by 50% in patients with creatinine clearance less than 60 mL/min.
  2.2 Dose Modifications for Renal Impairment

  Reduce the dose of DROXIA 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)]

  . Creatinine clearance values were obtained using 24-hour urine collections.

  *  On dialysis days, administer DROXIA to patients with ESRD following hemodialysis.
  Creatinine Clearance (mL/min)	Recommended DROXIA Initial Dose (mg/kg once daily)
  ≥60	15
  <60 or ESRD*	7.5

  Monitor the hematologic parameters closely in these patients.
  ,
  8.6 Renal Impairment

  The exposure to hydroxyurea is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely monitor the hematologic parameters when DROXIA is to be administered to these patients

  [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]

  .
  ,
  12.3 Pharmacokinetics

  Absorption

  Following oral administration of DROXIA, hydroxyurea reaches peak plasma concentrations in 1 to 4 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose.

  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.

  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

  In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered dose.

  Specific Populations

  Renal Impairment

  The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell disease 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 DROXIA 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)]

  .

Capsules:

• ​​200 mg opaque blue-green capsules, imprinted with black ink "DROXIA" and "200".
• 300 mg opaque purple capsules, imprinted with black ink "DROXIA" and "300".
• 400 mg opaque reddish-orange capsules, imprinted with black ink "DROXIA" and "400".

Lactation: Advise women not to breastfeed.