Deferasirox may be confused with deferoxamine
Deferasirox may be confused with deferiprone [Great Britain]
- Antidote;
- Chelating Agent
Chronic iron overload due to blood transfusion: Oral: Note: Baseline serum ferritin and iron levels should be obtained prior to therapy; toxicity may be increased in patients with low iron burden or with only slightly elevated serum ferritin.
Initial: 20 mg/kg daily (calculate dose to nearest whole tablet)
Maintenance: Adjust dose every 3-6 months based on serum ferritin levels; adjust by 5 or 10 mg/kg/day (calculate dose to nearest whole tablet); titrate. Usual range: 20-30 mg/kg/day; doses up to 40 mg/kg/day may be considered for serum ferritin levels persistently >2500 mcg/L (doses above 40 mg/kg/day are not recommended). In clinical trials, doses were individualized based on iron burden determined by liver iron concentrations (LIC); transfusional iron intake should be considered when individualizing maintenance dose. Note: Consider interrupting therapy for serum ferritin <500 mcg/L and dose reduction or interruption for hearing loss or visual disturbances.
Dosage adjustment with concomitant cholestyramine or potent UGT inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Avoid concomitant use; if coadministration necessary, consider increasing the initial dose of deferasirox dose to 30 mg/kg; monitor serum ferritin and clinical response. Doses above 40 mg/kg are not recommended.
Children ≥2 years: Refer to adult dosing.
Refer to adult dosing.
Clcr ≥40 to <60 mL/minute: Use caution; monitor renal function closely, particularly in patients at increased risk for further renal impairment (eg, concomitant therapy, dehydration, severe infection)
Clcr <40 mL/minute or serum creatinine >2 times age-appropriate ULN: Use is contraindicated
Progressive increase in serum creatinine: Consider dose reduction, interruption, or discontinuation. Interrupt treatment for progressive increase in serum creatinine above the age-appropriate ULN; once serum creatinine recovers to within the normal range, reinitiate treatment at a reduced dose; gradually escalate the dose if the clinical benefit outweighs potential risk.
Children: For increase in serum creatinine above the age-appropriate ULN for 2 consecutive levels, reduce daily dose by 10 mg/kg
Adults: For increase in serum creatinine >33% above the average pretreatment level at 2 consecutive levels (and cannot be attributed to other causes), reduce daily dose by 10 mg/kg
Consider dose adjustment or discontinuation for severe or persistent elevations in liver function tests.
Consider dose reduction or interruption for hearing loss or visual disturbances.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet for suspension, oral:
Exjade®: 125 mg, 250 mg, 500 mg
No
Oral: Do not chew or swallow whole tablets. Disperse tablets in water, orange juice, or apple juice (use 3.5 ounces for total doses <1 g; 7 ounces for doses ≥1 g); stir to form suspension and drink entire contents. Rinse remaining residue with more fluid; drink. Administer at same time each day on an empty stomach, 30 minutes before food. Do not take simultaneously with aluminum-containing antacids.
Treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis)
>10%:
Central nervous system: Fever (19%), headache (16%)
Dermatologic: Rash (dose related; 8% to 11%)
Gastrointestinal: Abdominal pain (dose related; 21% to 28%), diarrhea (dose related; 12% to 20%), nausea (dose related; 11% to 23%), vomiting (dose related; 10% to 21%)
Renal: Serum creatinine increased (dose related; 7% to 38%), proteinuria (19%)
Respiratory: Cough (14%), nasopharyngitis (13%), pharyngolaryngeal pain (11%)
Miscellaneous: Influenza (11%)
1% to 10%:
Central nervous system: Fatigue (6%)
Dermatologic: Urticaria (4%)
Hepatic: ALT increased (2% to 8%), transaminitis (4%)
Neuromuscular & skeletal: Arthralgia (7%), back pain (6%)
Otic: Ear infection (5%)
Respiratory: Respiratory tract infection (10%), bronchitis (9%), pharyngitis (8%), acute tonsillitis (6%), rhinitis (6%)
<1% (Limited to important or life-threatening): Acute renal failure, agranulocytosis, anaphylaxis, angioedema, anxiety, ascites, bilirubin increased, cataract, cholecystitis, cholelithiasis, constipation, cytopenias, dizziness, drug fever, duodenal ulcer, edema, erythema multiforme, esophagitis, gastric ulcer, gastritis, gastrointestinal bleeding, gastrointestinal hemorrhage, glomerulonephritis, glucosuria, hearing loss (including high frequency), hematuria, Henoch-Schönlein purpura, hepatic dysfunction, hepatic encephalopathy, hepatic failure, hepatic transaminases increased, hepatitis, hyperactivity, hypersensitivity reaction, hypocalcemia, insomnia, interstitial nephritis, intraocular pressure increased, jaundice, lens opacities, leukocytoclastic vasculitis, maculopathy, neutropenia, optic neuritis, pigment disorder, purpura, renal tubular necrosis, renal tubulopathy, retinal disorder, sleep disorder, thrombocytopenia, visual disturbance
Hypersensitivity to deferasirox or any component of the formulation; platelet counts (<50,000/mm3); poor performance status and high-risk myelodysplastic syndromes or advanced malignancies; creatinine clearance <40 mL/minute or serum creatinine >2 x age-appropriate ULN
Canadian labeling: Additional contraindications (not in U.S. labeling): Clcr <60 mL/minute
Boxed warnings:
• Gastrointestinal effects: See “Concerns related to adverse effects” below.
• Hepatotoxicity: See “Concerns related to adverse effects” below.
• Renal toxicity: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Auditory disturbances: Decreased hearing and high frequency hearing loss have been reported with use; monitor and consider dose reduction or treatment interruption.
• Cytopenias: Cytopenias (including agranulocytosis, neutropenia, and thrombocytopenia) have been reported, predominately in patients with preexisting hematologic disorders; monitor closely. Interrupt treatment for unexplained cytopenias.
• Gastrointestinal effects: [U.S. Boxed Warning]: Gastrointestinal (GI) hemorrhage, including fatalities, has occurred with use, predominately in elderly patients with advanced hematologic malignancies and/or low platelet counts. Other GI effects including irritation and ulceration have been reported. Use caution with concurrent medications that may increase risk of adverse GI effects (eg, NSAIDs, corticosteroids, anticoagulants, oral bisphosphonates). Monitor patients closely for signs/symptoms of GI ulceration/bleeding.
• Hepatotoxicity: [U.S. Boxed Warning]: Severe hepatic dysfunction or failure (including fatalities) have occurred (postmarketing reports), mostly in patients >55 years of age with underlying comorbidities (including hepatic cirrhosis and multiorgan failure). Hepatitis and elevated transaminases have also been reported; monitor transaminases and bilirubin closely and consider dose modification or interruption of therapy with severe or persistent hepatic function test abnormalities. Use with caution in patients with underlying hepatic disease.
• Hypersensitivity: Hypersensitivity reactions, including severe reactions (anaphylaxis and angioedema) have been reported, usually within the first month of treatment. Discontinuation of therapy may be necessary.
• Ocular disturbances: Lens opacities, cataracts, intraocular pressure elevation, and retinal disorders have been reported with use; monitor and consider dose reduction or treatment interruption.
• Rash: May cause skin rash (dose-related) including erythema multiforme; mild-to-moderate rashes may resolve without treatment interruption; for severe rash, interrupt and consider restarting at a lower dose with dose escalation and oral steroids.
• Renal toxicity: [U.S. Boxed Warning]: Acute renal failure (some fatal) and dose-related elevations in serum creatinine have been reported; fatalities generally observed more in patients with multiple comorbidities or advanced hematologic disorders. Monitor serum creatinine and/or creatinine clearance in all patients; monitor patients at risk for renal complications (eg, pre-existing renal conditions, elderly, comorbid conditions, and/or with concurrent medications that may affect renal function) more closely; dose reduction, interruption, or discontinuation may be required for serum creatinine elevations. May cause proteinuria; monitor closely. Renal tubulopathy has also been reported, primarily in pediatric patients with β-thalassemia and serum ferritin levels <1500 mcg/L.
Concurrent drug therapy issues:
• Other iron chelation drugs: Do not combine with other iron chelation therapies; safety of combinations has not been established.
• UGT inducers or cholestyramine: Potent UGT inducers (eg, rifampin) or cholestyramine may decrease the efficacy of deferasirox; avoid concomitant use. If coadministration necessary, dosage modifications may be needed; monitor serum ferritin and clinical response.
Special populations:
• Elderly: Use with caution due to the higher incidence of hepatic, renal and cardiac dysfunction in elderly patients.
Other warnings/precautions:
• Appropriate use: Treatment should be initiated with evidence of chronic iron overload (eg, transfusion of ~100 mL/kg of packed RBCs [~20 units for a 40 kg individual] and serum ferritin consistently >1000 mcg/L). Prior to use, consider risk versus anticipated benefit with respect to individual patient’s life expectancy and prognosis. Postmarketing experience indicates serious reactions, including fatalities, has occurred with deferasirox use, particularly when used in older patients with comorbidities or advanced disease.
Deferasirox (Exjade®) is only available through a restricted distribution program called EPASS™ Complete Care. Prescribers must enroll patients in this program in order to obtain the medication. For patient enrollment, contact 1-888-90-EPASS (1-888-903-7277).
Substrate of UGT1A1 (major), 1A3; Inhibits CYP2C8 (moderate); Induces 3A4 (weak)
Aluminum Hydroxide: May diminish the therapeutic effect of Deferasirox.Risk X: Avoid combination
Anticoagulants: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapy
Bisphosphonate Derivatives: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapy
Cholestyramine Resin: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider an increase in initial deferasirox dose to 30 mg/kg, and monitor serum ferritin concentrations/clinical responses to guide further dosing.Risk D: Consider therapy modification
Corticosteroids: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapy
CYP1A2 Substrates: Deferasirox may increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
CYP2C8 Substrates (High risk): Deferasirox may increase the serum concentration of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP3A4 Substrates: Deferasirox may decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Fosphenytoin: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider an increase in initial deferasirox dose to 30 mg/kg, and monitor serum ferritin concentrations/clinical responses to guide further dosing.Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapy
PHENobarbital: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider an increase in initial deferasirox dose to 30 mg/kg, and monitor serum ferritin concentrations/clinical responses to guide further dosing.Risk D: Consider therapy modification
Phenytoin: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider an increase in initial deferasirox dose to 30 mg/kg, and monitor serum ferritin concentrations/clinical responses to guide further dosing.Risk D: Consider therapy modification
Rifampin: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider an increase in initial deferasirox dose to 30 mg/kg, and monitor serum ferritin concentrations/clinical responses to guide further dosing.Risk D: Consider therapy modification
Ritonavir: May decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider an increase in initial deferasirox dose to 30 mg/kg, and monitor serum ferritin concentrations/clinical responses to guide further dosing.Risk D: Consider therapy modification
Theophylline: Deferasirox may increase the serum concentration of Theophylline. Risk X: Avoid combination
C (show table)
Teratogenic effects were observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed.
Excretion in breast milk unknown/not recommended
Bioavailability increased variably when taken with food; take on empty stomach 30 minutes before a meal.
Serum ferritin (baseline, monthly thereafter), iron levels (baseline), CBC with differential, serum creatinine and/or creatinine clearance (2 baseline assessments then monthly thereafter; in patients who are at increased risk of complications [eg, pre-existing renal conditions, elderly, comorbid conditions, or receiving other potentially nephrotoxic medications]: weekly for the first month then monthly thereafter); urine protein (monthly); serum transaminases and bilirubin (baseline and annual auditory and ophthalmic function (including slit lamp examinations and dilated fundoscopy); number of RBC units received
- Exjade®
- Exjade (AR, AT, AU, BE, BG, BR, CH, CN, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HN, ID, IE, IL, IT, KP, MX, MY, NL, NO, NZ, PE, PH, PT, RU, SE, TH, TR, TW, UY)
Selectively binds iron, forming a complex which is excreted primarily through the feces.
Distribution: Adults: 11.7-17.1 L
Protein binding: ~99% to serum albumin
Metabolism: Hepatic via glucuronidation by UGT1A1(primarily) and UGT1A3; minor oxidation by CYP450; undergoes enterohepatic recirculation
Bioavailability: 70%
Half-life elimination: 8-16 hours
Time to peak, plasma: ~1.5-4 hours
Excretion: Feces (84%); urine (8%)