XROMI

2 DOSAGE AND ADMINISTRATION Initial dose: 15 mg/kg orally once daily. Monitor the patient’s blood count every two weeks. (2.1) 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) 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) Renal impairment: Reduce the dose of XROMI by 50% in patients with creatinine clearance less than 60 mL/min. (2.2 , 8.6 , 12.3) 2.1 Recommended Dosage The recommended XROMI dosage in pediatric patients aged 6 months and older 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 to 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 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 10 9 /L and platelets at least 80 x 10 9 /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 10 9 /L Platelets less than 80 x 10 9 /L Hemoglobin 20% decrease from baseline or hemoglobin less than 4.5 g/dL Reticulocytes less than 80 x 10 9 /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. 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 oral dosing 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) ] . 2.3 Dosage Modifications in Renal Impairment Reduce the dose of XROMI 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 were obtained using 24-hour urine collection. Table 2. Creatinine Clearance Creatinine Clearance (mL/min) Recommended XROMI Initial Dose Greater than or equal to 60 15 mg/kg once daily Less than 60 or ESRD* 7.5 mg/kg once daily * On dialysis days, administer XROMI to patients with ESRD following hemodialysis Monitor the hematologic parameters closely in these patients.

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1 INDICATIONS AND USAGE 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 and older with sickle cell anemia with recurrent moderate to severe painful crises.