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To avoid dosing errors, it is important that prescriptions of deferasirox specify both the type of formulation (dispersible tablets for oral suspension or film-coated tablets) and the prescribed dose in mg/kg/day.
Recommended Dose and Dosage Adjustment: Transfusional iron overload: The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden. The decision to remove accumulated iron should be individualized based on anticipated clinical benefit and risks of chelation therapy.
It is recommended that therapy with JADENU (deferasirox) be started when a patient has evidence of chronic iron overload, such as the transfusion of approximately 100 mL/kg of packed red blood cells (approximately 20 units for a 40 kg patient) and a serum ferritin consistently >1000 mcg/L. Doses should be in mg/kg and must be calculated and rounded to the nearest whole tablet size. Changes in weight of pediatric patients over time must be taken into account when calculating the dose. JADENU is available in three strengths (90, 180 and 360 mg).
Starting Dose: The recommended initial daily dose of JADENU is 7, 14 or 21 mg/kg/day body weight, depending on the patient's transfusion rate and the goal of treatment: Patients requiring maintenance of an acceptable body iron level: An initial daily dose of 7 mg/kg/day is recommended for patients receiving less than 7 mL/kg/month of packed red blood cells (approximately <2 units/month for an adult) and for whom the objective is maintenance of an acceptable body iron level.
An initial daily dose of 14 mg/kg/day is recommended for patients receiving more than 7 mL/kg/month of packed red blood cells (approximately >2 units/month for an adult) and for whom the objective is maintenance of an acceptable body iron level.
Patients requiring reduction of iron overload: An initial daily dose of 14 mg/kg/day is recommended for patients receiving less than 14 mL/kg/month of packed red blood cells (approximately <4 units/month for an adult) and for whom the objective is gradual reduction of iron overload.
An initial daily dose of 21 mg/kg/day is recommended for patients receiving more than 14 mL/kg/month of packed red blood cells (approximately >4 units/month for an adult) and for whom the objective is gradual reduction of iron overload.
With deferasirox dispersible tablets for oral suspension, the dose dependent iron excretion (mg/kg/day) was calculated from the change in LIC over one year, the amount of blood transfused and the weight of the patient. Using two example patients of 20 kg and 50 kg, the amount of iron excreted over one year could be calculated in terms of mg/year and transfusion unit-equivalents/year (assuming that one unit of PRBC contains 200 mg iron). Thus in a 50 kg adult, deferasirox tablets for oral suspension doses of 10, 20 and 30 mg/kg (equivalent to JADENU 7, 14 and 21 mg, respectively) for one year can remove the amount of iron contained in about 20, 36 and 55 units of blood, respectively (i.e. about 1.5, 3 and 4.5 units of blood per month, respectively). In a 20 kg pediatric patient, deferasirox tablets for oral suspension doses of 10, 20 and 30 mg (equivalent to JADENU 7, 14 and 21 mg, respectively) for one year can remove the amount of iron contained in about 8, 14 and 22 units of blood, respectively (i.e. about 0.6, 1.2 and 1.8 units of blood per month; or 6, 12 and 18 mL/kg/month, respectively). (See Table 10.)
Click on icon to see table/diagram/imageDose Adjustment: Use the minimum effective dose to establish and maintain a low iron burden.
It is recommended that serum ferritin be monitored every month and that the dose of JADENU be adjusted if necessary, every 3 to 6 months based on serum ferritin trends to minimize the risk of overchelation (see Precautions). Dose adjustments should be made in steps of 3.5 or 7 mg/kg and are to be tailored to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden). The Liver Iron Concentration (LIC) should be assessed periodically by an appropriate method such as biopsy or MRI in order to verify treatment response. In patients with beta-thalassemia not adequately controlled with daily doses of 21 mg/kg, doses of up to 28 mg/kg may be considered. Doses of JADENU should not exceed 28 mg/kg per day since, with the exception of beta-thalassemia patients, there is limited experience with doses above this level (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
As with other iron chelator treatment, the risk of toxicity of JADENU may be increased when inappropriately high doses are given in patients with a low iron burden or with serum ferritin levels that are only slightly elevated. If the serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the dose is greater than 17.5 mg/kg/day (high doses despite body iron burden being in the target range or consistently below the target range is not recommended). Use the minimum effective dose to maintain iron burden in the target range. Continued administration of JADENU in the 14-28 mg/kg/day range when the body iron burden is approaching or within the normal range has resulted in life threatening adverse events (see Precautions). Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions. If the serum ferritin falls consistently below 500 mcg/L, consideration should be given to temporarily interrupting therapy with JADENU.
Non-transfusion-dependent thalassemia syndromes: Chelation therapy should only be initiated when there is evidence of iron overload (liver iron concentration (LIC) ≥5 mg Fe/g dry weight (dw) or serum ferritin consistently >800 mcg/L). In patients with no LIC assessment, caution should be taken during chelation therapy to minimize the risk of over-chelation. Doses should be in mg/kg and must be calculated and rounded to the nearest whole tablet size. JADENU is available in three strengths (90, 180 and 360 mg).
Starting Dose: The recommended initial daily dose of JADENU is 7 mg/kg body weight.
Dose Adjustment: Use the minimum effective dose to establish and maintain a low iron burden.
It is recommended that serum ferritin be monitored every month to assess the patient's response to therapy and to minimize the risk of overchelation (see Precautions). Every 3 to 6 months of treatment, consider a dose increase in increments of 3.5 to 7 mg/kg if the patient's LIC is ≥7 mg Fe/g dw, or serum ferritin is consistently >2,000 mcg/L and not showing a downward trend, and the patient is tolerating the drug well. The incidence of adverse effects increases with increasing dose. Experience with doses of 14 mg/kg is limited. Doses above 14 mg/kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassemia syndromes.
In patients in whom LIC was not assessed and serum ferritin is ≤2,000 mcg/L, dosing should not exceed 7 mg/kg.
For patients in whom the dose was increased to >10 mg/kg, dose reduction is recommended to 7 mg/kg or less when LIC is <7 mg Fe/g dw or serum ferritin is ≤2,000 mcg/L.
Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300 mcg/L), treatment should be interrupted. Treatment should be re-initiated when there is evidence from clinical monitoring that chronic iron overload is present.
Transfusional iron overload and non-transfusion-dependent thalassemia syndromes: Dosing Considerations: Conversion from EXJADE dispersible tablets to JADENU film-coated tablets: For patients who are currently on chelation therapy with deferasirox dispersible tablets and converting to deferasirox film-coated tablets, the dose of deferasirox film-coated tablets should be about 30% lower, rounded to the nearest whole tablet. The table as follows provides additional information on dosing conversion to deferasirox film-coated tablets. (See Table 11.)
Click on icon to see table/diagram/imageGeriatrics (≥65 years of age): The pharmacokinetics of deferasirox have not been studied in geriatric patients. The dosing recommendations for elderly patients are the same as described previously. In clinical trials, elderly patients experienced a higher frequency of adverse reactions than younger patients and should be monitored closely for adverse reactions that may require a dose adjustment.
Pediatrics (2 to 16 years of age): The dosing recommendations for pediatric patients are the same as for adult patients. It is recommended that serum ferritin be monitored every month to assess the patient's response to therapy and to minimize the risk of overchelation (see Precautions). In children <6 years of age, exposure was about 50% lower than adults. Since dosing is individually adjusted according to response this difference in exposure is not expected to have clinical consequences. Changes in weight of pediatric patients over time must also be taken into account when calculating the dose.
JADENU has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting (see Precautions). These events were frequently associated with volume depletion or with continued deferasirox dispersible tablets doses in the 20-40 mg/kg/day range, equivalent to 14-28 mg/kg/day JADENU when body iron burden was approaching or in the normal range (patients received high doses despite body iron burden being in the target range or consistently below the target range which is not recommended). The risk of toxicity of JADENU may be increased when inappropriately high doses are given in patients with a low iron burden or with serum ferritin levels that are only slightly elevated. Use the minimum effective dose to maintain iron burden in the target range.
Monitor renal and liver function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. Use the minimum effective dose. Interrupt JADENU in pediatric patients with transfusional iron overload and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, for acute illnesses which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. Evaluate the risk benefit profile of continued JADENU use in the setting of decreased renal function. Avoid use of other nephrotoxic drugs.
Patients with renal impairment: Deferasirox has not been studied in patients with renal impairment (see Contraindications). In the setting of decreased renal function, evaluate the risk benefit profile of continued JADENU use. Use the minimum effective JADENU dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt JADENU to prevent severe and irreversible renal injury.
For adult patients, the daily dose of JADENU should be reduced by 7 mg/kg if a non-progressive rise in serum creatinine by >33% above the average of the pre-treatment measurements is seen at two consecutive visits, and cannot be attributed to other causes. In clinical trials with deferasirox, from those patients who underwent dose reduction, creatinine levels returned to baseline in only 25% of patients and in 60% of them, creatinine levels remained elevated >33% of the average pre-treatment levels. For pediatric patients, the dose should be reduced by 7 mg/kg if serum creatinine levels rise above the age-appropriate upper limit of normal at two consecutive visits. A total of 6 patients <16 years developed creatinine levels >ULN during the core phase of the registration studies. Dose reductions were performed in 5 patients, in 4 of whom the levels returned to baseline. Creatinine levels fell to < ULN in the fifth patient but remained higher than baseline.
If there is a progressive increase in serum creatinine beyond the upper limit of normal, JADENU therapy should be interrupted (see Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data under Adverse Reactions).
Patients with hepatic impairment: Deferasirox has been studied in a clinical trial in patients with hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh B), the starting dose should be reduced by approximately 50%. JADENU should not be used in patients with severe hepatic impairment (Child-Pugh C) (see Precautions and Pharmacology: Pharmacokinetics: Special Populations and Conditions under Actions). Deferasirox treatment has been initiated only in patients with baseline liver transaminase levels up to 5 times the upper limit of normal range. The pharmacokinetics of deferasirox were not influenced by such transaminase levels. The treating physician should initiate treatment with a dose taking into account general dosing instructions together with the extent of hepatic impairment. Close monitoring of efficacy and safety parameters is recommended. It is recommended that serum transaminase, bilirubin and alkaline phosphatase be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is an unexplained, persistent, and progressive increase in serum transaminase levels JADENU treatment should be interrupted.
Patients with skin rash: Skin rashes may occur during JADENU treatment. Severe skin rashes may require interruption of JADENU treatment.
Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this difference in clearance is not expected to have clinical consequences.
Administration: JADENU tablets should be swallowed whole once daily with water or other liquids, preferably at the same time each day. JADENU should be taken on an empty stomach or with a light meal (containing less than 7% fat content and approximately 250 calories). Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread with lettuce, tomato, and 1 packet mustard). (See Pharmacology under Actions).
For patients who are unable to swallow whole tablets, JADENU tablets may be crushed and administered by sprinkling the full dose on a soft food (e.g, yogurt or applesauce). Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be immediately and completely consumed, and followed with a glass of water. The dose should not be stored for future use.
Missed Dose: If a dose is missed it should be taken as soon as remembered on that day, and the next dose should be taken as planned. Doses should not be doubled to make up for a missed dose.
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