Dosing and uses of Exjade, Jadenu (deferasirox)
Dosing Strengths
tablet for oral suspension (Exjade)
- 125mg
- 250mg
- 500mg
oral tablet (Jadenu)
- 90mg
- 180mg
- 360mg
Transfusional Hemosiderosis
Indicated for treatment of chronic iron overload caused by blood transfusion
Exjade: 20 mg/kg PO qDay; may increase by 5-10 mg increments based on serum ferritin; if not controlled on 30 mg/kg/day (ie, serum ferritin persistently >2500 mcg/L), may increase up to 40 mg/kg qDay
Jadenu: 14 mg/kg PO qDay (calculate dose to the nearest whole tablet); adjust dose in 3.5-7 mg/kg according to response and goals; if not adequately controlled with doses of 21mg/kg (serum ferritin levels persistently >2500 mcg/L), doses of up to 28 mg/kg may be considered; do not exceed 28 mg/kg
Dosing considerations
- Before initiating, obtain serum ferritin level, baseline serum creatinine (in duplicate) and determine creatinine clearance, serum transaminases, bilirubin, and baseline auditory and ophthalmic examinations
- Measure serum ferritin qMonth
Nontransfusion-Dependent Thalassemia
Indicated for treatment of chronic iron overload caused by nontransfusion-dependent thalassemia syndromes and with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight (dw) and a serum ferritin >300 mcg/L
This indication is based on achievement of an LIC <5 mg Fe/g dw; improvement in survival or disease-related symptoms has not been established
Exjade: 10 mg/kg PO qDay (calculate dose to nearest tablet size); if LIC >15 mg Fe/g dw after 4 weeks, consider increasing dose to 20 mg/kg/day
Jadenu: 7 mg/kg PO qDay (calculate dose to nearest whole tablet); if LIC >7 mg Fe/g dw after 6 months, increase dose to 14 mg/kg/day; do not exceed 14 mg/kg/day
Dosing considerations
- Before initiating, obtain LIC by liver biopsy or other approved method, serum ferritin level (based on at least 2 measurements 1 month apart), baseline serum creatinine (in duplicate) and determine creatinine clearance, serum transaminases, bilirubin, and baseline auditory and ophthalmic examinations
- Monitor serum ferritin monthly; interrupt treatment if serum ferritin <300 mcg/L and obtain an LIC to determine whether the LIC has fallen to <3 mg Fe/g dw
- Measure LIC q6Months
- If the LIC remains >7 mg Fe/g dw after 6 months, increase dose to a maximum of 20 mg/kg/day; do not exceed 20 mg/kg/day
- If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg/day
- When the LIC is <3 mg Fe/g dw, interrupt treatment and continue to monitor LIC
- Monitor blood counts, hepatic function, and renal function
Dosage modifications
Coadministration with potent UGT1A1 inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir) or cholestyramine: Consider increasing initial dose to 30 mg/kg; these drugs decrease systemic exposure (AUC)
Renal Impairment
Baseline renal impairment
- CrCl 40-60 mL/min: Reduce starting dose by 50%
- Serum Cr >2 xULN or CrCl <40 mL/min: Do not use
While take for transfusional iron overload
- Adults and adolescents (aged 16 yr or older): Reduce daily dose by 10 mg/kg if serum creatinine increases by >33% (on 2 consecutive visits) above pretreatment levels
- Children aged 2-15 yr: Reduce the dose by 10 mg per kg if serum creatinine increases by >33% above the average baseline measurement and greater than the age appropriate upper limit of normal
- Serum creatinine >2 x ULN or CrCl <40 mL/min (all patients): Contraindicated; discontinue if these measurements occur during treatment
While taking for nontransfusion-dependent thalassemia
- Adults and adolescents (aged 16 yr or older): If serum creatinine increases by >33% (on 2 consecutive visits) above pretreatment levels, interrupt therapy if dose is 5 mg/kg, or reduce by 50% if dose is 10-20 mg/kg
- Children aged 10-15 yr: Reduce the dose by 5 mg per kg if serum creatinine increases by >33% above the average baseline measurement and greater than the age appropriate upper limit of normal
- Serum creatinine >2 x ULN or CrCl <40 mL/min (all patients): Contraindicated; discontinue if these measurement occur during treatment
Hepatic Impairment
Mild (Child-Pugh A): No dose adjustment required
Moderate (Child-Pugh B): Decrease initial dose by 50%
Severe (Child-Pugh C): Avoid use
Administration
Do not chew or swallow tablet whole; disperse table in water, apple juice, or orange juice
Disperse doses <1 g in 3.5 oz liquid and doses >1 g in 7 oz liquid; after swallowing the suspension, resuspend any residue in a small volume of liquid and swallow
Take on empty stomach at least 30 minutes prior to food
Pediatric dosage forms and strengths
Dosing Strengths
tablet for oral suspension (Exjade)
- 125mg
- 250mg
- 500mg
oral tablet (Jadenu)
- 90mg
- 180mg
- 360mg
Transfusional Hemosiderosis
Indicated for treatment of chronic iron overload caused by blood transfusion
<2 years: Safety and efficacy not established
Exjade: 20 mg/kg PO qDay; may increase by 5-10 mg increments based on serum ferritin; if not controlled on 30 mg/kg/day (ie, serum ferritin persistently >2500 mcg/L), may increase up to 40 mg/kg qDay
Jadenu: 14 mg/kg PO qDay (calculate dose to the nearest whole tablet); adjust dose in 3.5-7 mg/kg according to response and goals; if not adequately controlled with doses of 21mg/kg (serum ferritin levels persistently >2500 mcg/L), doses of up to 28 mg/kg may be considered; do not exceed 28 mg/kg
Dosing considerations
- Before initiating, obtain serum ferritin level, baseline serum creatinine (in duplicate) and determine creatinine clearance, serum transaminases, bilirubin, and baseline auditory and ophthalmic examinations
- Measure serum ferritin qMonth
Nontransfusion-Dependent Thalassemia
Indicated for treatment of chronic iron overload caused by nontransfusion-dependent thalassemia syndromes and with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight (dw) and a serum ferritin >300 mcg/L
This indication is based on achievement of an LIC <5 mg Fe/g dw; improvement in survival or disease-related symptoms has not been established
<10 years: Safety and efficacy not established
Exjade: 10 mg/kg PO qDay (calculate dose to nearest tablet size); if LIC >15 mg Fe/g dw after 4 weeks, consider increasing dose to 20 mg/kg/day
Jadenu: 7 mg/kg PO qDay (calculate dose to nearest whole tablet); if LIC >7 mg Fe/g dw after 6 months, increase dose to 14 mg/kg/day; do not exceed 14 mg/kg/day
Dosing considerations
- Before initiating, obtain LIC by liver biopsy or other approved method, serum ferritin level (based on at least 2 measurements 1 month apart), baseline serum creatinine (in duplicate) and determine creatinine clearance, serum transaminases, bilirubin, and baseline auditory and ophthalmic examinations
- Monitor serum ferritin monthly; interrupt treatment if serum ferritin <300 mcg/L and obtain an LIC to determine whether the LIC has fallen to <3 mg Fe/g dw
- Measure LIC q6Months
- If the LIC remains >7 mg Fe/g dw after 6 months, increase dose to a maximum of 20 mg/kg/day; do not exceed 20 mg/kg/day
- If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg/day
- When the LIC is <3 mg Fe/g dw, interrupt treatment and continue to monitor LIC
- Monitor blood counts, hepatic function, and renal function
Renal Impairment
Baseline renal impairment
- CrCl 40-60 mL/min: Reduce starting dose by 50%
- Serum Cr >2 xULN or CrCl <40 mL/min: Do not use
While take for transfusional iron overload
- Adults and adolescents (aged 16 yr or older): Reduce daily dose by 10 mg/kg if serum creatinine increases by >33% (on 2 consecutive visits) above pretreatment levels
- Children aged 2-15 yr: Reduce the dose by 10 mg per kg if serum creatinine increases by >33% above the average baseline measurement and greater than the age appropriate upper limit of normal
- Serum creatinine >2 x ULN or CrCl <40 mL/min (all patients): Contraindicated; discontinue if these measurements occur during treatment
While taking for nontransfusion-dependent thalassemia
- Adults and adolescents (aged 16 yr or older): If serum creatinine increases by >33% (on 2 consecutive visits) above pretreatment levels, interrupt therapy if dose is 5 mg/kg, or reduce by 50% if dose is 10-20 mg/kg
- Children aged 10-15 yr: Reduce the dose by 5 mg per kg if serum creatinine increases by >33% above the average baseline measurement and greater than the age appropriate upper limit of normal
- Serum creatinine >2 x ULN or CrCl <40 mL/min (all patients): Contraindicated; discontinue if these measurement occur during treatment
Hepatic Impairment
Mild (Child-Pugh A): No dose adjustment required
Moderate (Child-Pugh B): Decrease initial dose by 50%
Severe (Child-Pugh C): Avoid use
Administration
Do not chew or swallow tablet whole; disperse table in water, apple juice, or orange juice
Disperse doses <1 g in 3.5 oz liquid and doses >1 g in 7 oz liquid; after swallowing the suspension, resuspend any residue in a small volume of liquid and swallow
Take on empty stomach at least 30 minutes prior to food
Exjade, Jadenu (deferasirox) adverse (side) effects
>10%
Serum creatinine increase (dose related; 7-38%)
Abdominal pain (21-28%)
Nausea (11-23%)
Vomiting (10-21%)
Diarrhea (12-20%)
Proteinuria (19%)
Pyrexia (19%)
Headache (16%)
Cough (14%)
Nasopharyngitis (13%)
Pharyngolaryngeal pain (11%)
Influenza (11%)
Rash (8-11%)
1-10%
Respiratory tract infection (10%)
Bronchitis (9%)
ALT increased (2-8%)
Arthralgia, back pain (6-7%)
Acute tonsillitis (6%)
Rhinitis (6%)
Fatigue (6%)
Ear infection (5%)
Transaminitis (4%)
Urticaria (4%)
<1%
Anaphylaxis
Angioedema
Cytopenias, including agranulocytosis, neutropenia and thrombocytopenia; leukocytoclastic vasculitis
Postmarketing Reports
Skin and subcutaneous tissue disorders: Leukocytoclastic vasculitis, urticaria, alopecia, Stevens-Johnson syndrome
Immune system disorders: Hypersensitivity reactions (including anaphylaxis and angioedema)
Renal and urinary disorders: Acute renal failure, renal tubular necrosis, tubulointerstitial nephritis
Hepatobiliary disorders: Hepatic failure
Gastrointestinal disorders: GI perforation and hemorrhage
Warnings
Black box warnings
Renal failure
- Can cause acute renal failure and death, especially with comorbidities and advanced stages of hematologic disorders
- Measure serum creatinine and determine creatinine clearance in duplicate prior to treatment initiation; monitor renal function at least monthly thereafter
- If baseline renal impairment or increased risk of acute renal failure exist, monitor creatinine weekly for the first month, then at least monthly
- Consider dose reduction, interruption, or discontinuation based on increases in serum creatinine
Hepatic failure
- Can cause hepatic injury including hepatic failure and death
- Obtain serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter
- Avoid with severe (Child-Pugh C) hepatic impairment and reduce the dose with moderate (Child Pugh B) hepatic impairment
Gastrointestinal hemorrhage
- Can cause gastrointestinal (GI) hemorrhages, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts
- Monitor and discontinue for suspected GI ulceration or hemorrhage
Contraindications
Hypersensitivity
CrCl <40 mL/min or serum creatinine >2 x ULn
Poor performance status and high-risk myelodysplastic syndromes or advanced malignancies
Platelet counts <50 x10^9/L
Cautions
Coadministration with aluminum-containing antacids decreases absorption
Concomitant cholestyramine (see Dosage modifications)
Risk of hepatic failure, some with fatal outcome; most occurred with age >55 yr and with comorbid conditions (eg, liver cirrhosis, multiorgan failure) (see Black box warnings)
Avoid use with severe (Child-Pugh C) hepatic impairment; closely monitor with mild or moderate hepatic impairment and decrease initial dose by 50%
Consider discontinuation if auditory/ocular disturbances occur
GI perforation and hemorrhage, including deaths reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts; nonfatal upper GI irritation, ulceration and hemorrhage reported; monitor for signs and symptoms of GI ulceration and hemorrhage during therapy and promptly initiate evaluation and treatment if serious GI adverse event is suspected; risk of gastrointestinal hemorrhage may be increased when administering in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants; there have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome; see Black box warnings)
Neutropenia, agranulocytosis, and thrombocytopenia, including fatal events, reported; preexisting hematologic disorders may increase this risk
Elderly: Monitor closely for toxicity due to the greater frequency of decreased hepatic, renal, and/or cardiac function
Serious hypersensitivity reactions (eg, anaphylaxis, angioedema) and erythema multiforme reported
Rashes may occur during treatment; for rashes of mild to moderate severity, therapy may be continued without dose adjustment; rash often resolves spontaneously; in severe cases, interrupt treatment; may consider reintroduction at lower dose after resolution of rash
Severe skin reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme reported; if SJS or erythema multiforme suspected, discontinue therapy immediately and do not reintroduce therapy
Auditory disturbances (eg, high frequency hearing loss, decreased hearing) and ocular disturbances (lens opacities, cataracts, increased IOP, retinal disorders) reported
Avoid overchelation of iron by monitoring serum ferritin levels monthly; when used for nontransfusion-dependent thalassemia, also measure LIC q6Months
Renal failure (see Black box warnings)
- Risk of acute renal failure, fatal is some patients and requiring dialysis in others
- Most fatalities reported with advanced stage hematologic disorder
- Monitor serum Cr level and CBC
- Closely monitor renal function if CrCl 40-60 mL/min, particularly in cases where there are additional risk factors that may impair renal function (eg, concomitant medications, dehydration, severe infections)
- Renal tubulopathy reported; majority of reports were in children and adolescents with beta-thalassemia and serum ferritin levels <1500 mcg/L
Pregnancy and lactation
Pregnancy category: B
Lactation: not known whether excreted in breast milk, use caution
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Exjade, Jadenu (deferasirox)
Mechanism of action
Selective chelator of trivalent iron; reduces liver iron concentration and serum ferritin levels
Absorption
Bioavailability: 70%
Peak Plasma Time: 1.5-4 hr
Peak plasma concentration and AUC increase in a linear fashion (accumulation factor ~1.3-2.3 following multiple doses)
Distribution
Protein Bound: 99% (mostly to albumin)
Vd: 14.37 L (adults)
Metabolism
Glucuronidation, mainly by UGT1A1 and to a lesser extent by UGT1A3
Inhibits CYP1A2, CYP2C8
Induces CYP3A4
Elimination
Half-life: 8-16 hr
Excretion: 84% feces; 8% urine
Administration
Exjade
Do not chew tablets or swallow tablet whole (disperse in water/liquid)
Take once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day
Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained
Disperse doses of <1 g in 3.5 ounces of liquid and doses ≥1 g in 7 ounces of liquid
After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow
Do not take with aluminum-containing antacid products
Jadenu
Swallow tablets whole once daily with water or other liquids, preferably at the same time each day
Do not take with aluminum-containing antacid products
May be taken on an empty stomach or with a light meal (<7% fat content and approximately 250 calories)
Light meal examples
- 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces)
- Turkey sandwich (2 oz. turkey on whole wheat bread with lettuce, tomato, and 1 packet mustard)
Converting from Exjade to Jadenu
The dose of Jadenu should be about 30% lower, rounded to the nearest whole tablet
Dosage comparisons between Exjade and Jadenu are listed below
Transfusion-dependent iron overload
- Starting dose: 20 mg/kg/day (Exjade); 14 mg/kg/day (Jadenu)
- Titration increments: 5-10 mg/kg (Exjade); 3.5-7 mg/kg (Jadenu)
- Maximum dose: 40 mg/kg/day (Exjade); 28 mg/kg/day (Jadenu)
Non-transfusion-dependent thalassemia
- Starting dose: 10 mg/kg/day (Exjade); 7 mg/kg/day (Jadenu)
- Titration increments: 5-10 mg/kg (Exjade); 3.5-7 mg/kg (Jadenu)
- Maximum dose: 20 mg/kg/day (Exjade); 14 mg/kg/day (Jadenu)
