Xromi

• Myelosuppression:

  XROMI 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

  [see

  5.1 Myelosuppression

  Hydroxyurea causes severe myelosuppression. Do not initiate treatment with XROMI 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, have experienced severe or life-threatening myelosuppression.

  Evaluate hematologic status (CBC, reticulocyte count) prior to and every 2 weeks during dose-escalation period of XROMI treatment. Once a stable dose of XROMI is achieved, monitor every 4 weeks. Provide supportive care and modify dose or discontinue XROMI as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted.

  [see Dosage and Administration (2.1)]

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• Malignancies:

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

  [see

  5.3 Malignancies

  Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a condition for which XROMI is not approved), secondary leukemia has been reported.

  Secondary leukemia has also been reported in patients treated with long-term hydroxyurea for sickle cell anemia. Leukemia has also been reported in patients with sickle cell anemia and no prior history of treatment with hydroxyurea.

  All patients using XROMI should be followed up on a long-term basis with regular blood counts to detect development of leukemia.

  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.

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XROMI is indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients aged 6 months of age to less than 2 years, with sickle cell anemia with recurrent moderate to severe painful crises.

• Initial dose: 15 mg/kg orally once daily. Monitor the patient’s blood count every two weeks.
  2.1 Recommended Dosage

  The recommended XROMI dosage in pediatric patients aged 6 months to less than 2 years is described in Table 1.

  Table 1. Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose modification criteria	Monitoring parameters
  Initial Recommended dosing	15 mg/kg/day (rounded to nearest 10 mg) orally as a single dose once daily based on the patient’s actual body weight.		Monitor the patient’s complete blood count (CBC) with differential and reticulocyte count every 2 weeks while adjusting dosage [see Warnings and Precautions (5.1)] .
  Dosing Adjustment Based on Blood Counts in the acceptable range	Increase dose 5 mg/kg/day every 8 to12 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 dose only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs.	Target Blood Counts Absolute neutrophil count (ANC) 1 to 3 x 109/L and platelets at least 80 x 109/L
  Dosing Adjustment Based on Blood Counts below acceptable range	Do not increase dose.	If blood counts are considered toxic, discontinue XROMI until hematologic recovery.	Blood Counts Toxic Range ANC less than 1 x 109/L Platelets less than 80 x 109/L Hemoglobin 20% decrease from baseline or hemoglobin less than 4.5 g/dL Reticulocytes less than 80 x109/L if the hemoglobin concentration is less than 9 g/dL.
  Dosing after Hematologic Recovery	If hematologic toxicity resolved within 1 week, restart at the same XROMI dose. If hematologic toxicity persisted for more than 1 week or occurred twice in a 3 month period, reduce dose by 5 mg/kg/day.		Once a stable dose is established, monitor CBC with differential and reticulocyte count every 4 weeks for 2 months and then as clinically indicated.

  Caregivers must be able to follow directions regarding drug administration and their monitoring and care.

  If a dose of XROMI is missed at the scheduled time, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed.

  The patient should not take two doses to make up for a missed dose.

  Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of XROMI 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.

  XROMI causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.
• The dose may be increased by 5 mg/kg/day every 8 to 12 weeks until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range.
  2.1 Recommended Dosage

  The recommended XROMI dosage in pediatric patients aged 6 months to less than 2 years is described in Table 1.

  Table 1. Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose modification criteria	Monitoring parameters
  Initial Recommended dosing	15 mg/kg/day (rounded to nearest 10 mg) orally as a single dose once daily based on the patient’s actual body weight.		Monitor the patient’s complete blood count (CBC) with differential and reticulocyte count every 2 weeks while adjusting dosage [see Warnings and Precautions (5.1)] .
  Dosing Adjustment Based on Blood Counts in the acceptable range	Increase dose 5 mg/kg/day every 8 to12 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 dose only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs.	Target Blood Counts Absolute neutrophil count (ANC) 1 to 3 x 109/L and platelets at least 80 x 109/L
  Dosing Adjustment Based on Blood Counts below acceptable range	Do not increase dose.	If blood counts are considered toxic, discontinue XROMI until hematologic recovery.	Blood Counts Toxic Range ANC less than 1 x 109/L Platelets less than 80 x 109/L Hemoglobin 20% decrease from baseline or hemoglobin less than 4.5 g/dL Reticulocytes less than 80 x109/L if the hemoglobin concentration is less than 9 g/dL.
  Dosing after Hematologic Recovery	If hematologic toxicity resolved within 1 week, restart at the same XROMI dose. If hematologic toxicity persisted for more than 1 week or occurred twice in a 3 month period, reduce dose by 5 mg/kg/day.		Once a stable dose is established, monitor CBC with differential and reticulocyte count every 4 weeks for 2 months and then as clinically indicated.

  Caregivers must be able to follow directions regarding drug administration and their monitoring and care.

  If a dose of XROMI is missed at the scheduled time, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed.

  The patient should not take two doses to make up for a missed dose.

  Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of XROMI 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.

  XROMI causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.
• The dose is not increased if blood counts are below the acceptable range and toxic. Discontinue XROMI until hematologic recovery if blood counts are considered toxic. Treatment may be resumed after reducing the dose by 2.5mg/kg/day to 5mg/kg/day from the dose associated with hematological toxicity.
  2.1 Recommended Dosage

  The recommended XROMI dosage in pediatric patients aged 6 months to less than 2 years is described in Table 1.

  Table 1. Dosing Recommendation Based on Blood Count

  Dosing Regimen	Dose	Dose modification criteria	Monitoring parameters
  Initial Recommended dosing	15 mg/kg/day (rounded to nearest 10 mg) orally as a single dose once daily based on the patient’s actual body weight.		Monitor the patient’s complete blood count (CBC) with differential and reticulocyte count every 2 weeks while adjusting dosage [see Warnings and Precautions (5.1)] .
  Dosing Adjustment Based on Blood Counts in the acceptable range	Increase dose 5 mg/kg/day every 8 to12 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 dose only if blood counts are in an acceptable range. Do not increase if myelosuppression occurs.	Target Blood Counts Absolute neutrophil count (ANC) 1 to 3 x 109/L and platelets at least 80 x 109/L
  Dosing Adjustment Based on Blood Counts below acceptable range	Do not increase dose.	If blood counts are considered toxic, discontinue XROMI until hematologic recovery.	Blood Counts Toxic Range ANC less than 1 x 109/L Platelets less than 80 x 109/L Hemoglobin 20% decrease from baseline or hemoglobin less than 4.5 g/dL Reticulocytes less than 80 x109/L if the hemoglobin concentration is less than 9 g/dL.
  Dosing after Hematologic Recovery	If hematologic toxicity resolved within 1 week, restart at the same XROMI dose. If hematologic toxicity persisted for more than 1 week or occurred twice in a 3 month period, reduce dose by 5 mg/kg/day.		Once a stable dose is established, monitor CBC with differential and reticulocyte count every 4 weeks for 2 months and then as clinically indicated.

  Caregivers must be able to follow directions regarding drug administration and their monitoring and care.

  If a dose of XROMI is missed at the scheduled time, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed.

  The patient should not take two doses to make up for a missed dose.

  Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of XROMI 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.

  XROMI causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended.
• Renal impairment: Reduce the dose of XROMI by 50% in patients with creatinine clearance less than 60 mL/min.
  2.2 Administration Instructions

  XROMI is for oral use. See Instructions for Use for details on preparation and administration of XROMI for oral solution.
  
  
  
  Do not shake.
  
  
  
  Two dosing oral syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 mL) are provided for accurate measurement of the prescribed dose of the oral solution. It is recommended that the healthcare professional advises the caregiver which oral dosing syringe to use to ensure that the correct volume is administered.
  
  
  
  The smaller 3 mL oral dosing syringe, marked from 0.5 mL to 3 mL, is for measuring doses of less than or equal to 3 mL. This oral dosing syringe should be recommended for doses less than or equal to 3 mL (each graduation of 0.1 mL contains 10 mg of hydroxyurea).
  
  
  
  The larger 10 mL oral dosing syringe, marked 1 mL to 10 mL, is for measuring doses of more than 3 mL. This oral dosing syringe should be recommended for doses greater than 3 mL (each graduation of 0.25 mL contains 25 mg of hydroxyurea).
  
  
  
  XROMI may be taken with or after meals at any time of the day but caregivers should standardize the method of administration and time of day.
  
  
  
  XROMI is a hazardous drug. Follow applicable special handling and disposal procedures

  [see Reference (15)]

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  8.6 Renal Impairment

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

  Absorption

  
  
  Following oral administration of XROMI, hydroxyurea reaches peak plasma concentrations in 0 to 2 hours. Mean peak plasma concentrations and AUCs increase more than proportionally with increase of dose.

  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

  
  
  

  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).

  [see Dosage and Administration (2.2)and Use in Specific Populations (8.6)].

  Pediatric Patients

  
  
  The model estimated steady state exposures (AUC) in pediatric patients receiving a daily dose of 15 mg/kg is lower in patients aged 6 months to <2 years by 40% compared to adults receiving the same dose (XROMI is not approved for use in adults).

Oral solution: 100 mg/mL clear colorless to pale yellow liquid in a multiple-dose amber bottle.

XROMI is not approved in males or females of reproductive potential.