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  • CLASSES

    Antidotes, Systemic
    Chelating Agents

    BOXED WARNING

    Nephrotoxicity, proteinuria, renal disease, renal failure, renal impairment

    Deferasirox may cause nephrotoxicity and is contraindicated for use in patients with renal failure or severe renal impairment with a creatinine clearance < 40 mL/min or serum creatinine (SCr) > 2 times the age appropriate upper limit of normal (ULN). In patients with moderate renal impairment (creatinine clearance 40—60 mL/min), a reduction in the starting dose is advised. Use with caution in any patient with known renal disease. Prior to initiating treatment in any patient, obtain two SCr assessments and calculate creatinine clearance (CrCl, using Cockcroft-Gault) to establish a reliable pre-treatment baseline. Monitor SCr and CrCl weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor more frequently if creatinine levels are increasing. For any elevations in SCr, dose reductions, treatment interruption, or treatment discontinuation is recommended, depending on the age of the patient, the disease state treated, and the degree of the changes. In clinical trials, deferasirox treated patients experienced dose-dependent increases in serum creatinine; there have been post-marketing reports of renal impairment and acute renal failure leading to death in some patients and requiring dialysis in others. Most reported fatalities occurred in patients with multiple comorbidities and who were in an advanced stage of their hematological disorder. Intermittent proteinuria (urine protein/creatinine ratio > 0.6 mg/mg) occurred in 18.6% of deferasirox treated patients compared to 7.2% of deferoxamine-treated patients in clinical studies. In studies in patients with transfusional iron overload, deferasirox was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is also recommended. The clinical significance and mechanism of the proteinuria are uncertain.

    Hepatic decompensation, hepatic disease, hepatitis, hepatotoxicity

    Deferasirox use has been associated with hepatotoxicity. Hepatic failure, sometimes fatal, has also been reported during post-marketing surveillance. Most of these occurred in patients older than 55 years of age. Many reports have also occurred in patients with significant comorbidities including liver cirrhosis and multi-organ failure. In one study, 4 patients discontinued deferasirox because of hepatic abnormalities (drug-induced hepatitis and increased serum transaminases). Deferasirox be avoided in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic disease may be at higher risk for hepatic toxicity. In one study, 4 patients discontinued deferasirox because of hepatic abnormalities (drug-induced hepatitis and increased serum transaminases). Monitor closely for signs and symptoms of hepatic decompensation. Monitor liver function tests (serum transaminases - AST, ALT, and bilirubin) before the initiation of treatment, every 2 weeks during the first month, and monthly thereafter. If there are unexplained, persistent, or progressive increases in serum transaminase levels, consider dose modifications or interruption of treatment. Hepatic disease may also dramatically alter enterohepatic recirculation of deferasirox, and may lead to a decrease in efficacy.

    Anticoagulant therapy, corticosteroid therapy, GI bleeding, GI perforation, peptic ulcer disease

    Treatment with deferasirox has been associated with serious, sometimes fatal, gastrointestinal (GI) adverse events, including GI bleeding, GI ulceration, and GI perforation. Fatal GI hemorrhages have been most frequently reported in patients 65 years of age or older who had advanced hematologic malignancies and/or low platelet counts. Use with caution in patients with known peptic ulcer disease. Non-fatal upper GI irritation, gastric ulceration, and GI hemorrhage have been reported in patients, including pediatric patients less than 18 years of age, receiving deferasirox. Physicians and patients should remain alert for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. Use caution when administering deferasirox in combination with drugs that have ulcerogenic or hemorrhagic risk potential, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroid therapy, oral bisphosphonates, or anticoagulant therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Tridentate iron chelator for once-daily oral administration
    Used in the treatment of chronic iron overload associated with frequent blood transfusions and non-transfusion dependent thalassemia syndromes
    Product label contains Black Box Warning regarding hepatic failure, renal failure, and GI bleeds

    COMMON BRAND NAMES

    Exjade, Jadenu

    HOW SUPPLIED

    Exjade Oral Tab for Susp: 125mg, 250mg, 500mg
    Jadenu Oral Gran: 90mg, 180mg, 360mg
    Jadenu Oral Tab: 90mg, 180mg, 360mg

    DOSAGE & INDICATIONS

    For the treatment of chronic iron toxicity.
    For the initiation of therapy for chronic iron toxicity secondary to transfusional iron overload (transfusional hemisiderosis).
    Oral dosage (Exjade)
    Adults, Adolescents, and Children >= 2 years

    20 mg/kg PO daily, as an oral suspension; calculate dose to the nearest whole tablet mg strength. In patients taking bile acid sequestrants or potent UGT inducers (e.g., rifampin, phenytoin, phenobarbital, and ritonavir), consider increasing the initial dose to 30 mg/kg PO once daily; further adjust dose based on ferritin concentrations or as clinical response dictates. Start treatment when there is evidence of chronic iron overload (i.e., the transfusion of approximately 100 mL/kg of packed red blood cells and serum ferritin concentrations consistently more than 1,000 mcg/L). Prior to starting therapy, obtain baseline serum ferritin, transaminases, and bilirubin concentrations. Baseline serum creatinine should be obtained in duplicate, and a creatinine clearance calculated using Cockcroft-Gault method. Additionally, it is advised that patients receive auditory and ophthalmic examinations prior to treatment. Once treatment is initiated, monitor serum ferritin concentrations monthly.

    Oral dosage (Jadenu)
    Adults, Adolescents, and Children >= 2 years

    14 mg/kg PO once daily; calculate dose to the nearest whole tablet mg strength. In patients taking bile acid sequestrants or potent UGT inducers (e.g., rifampin, phenytoin, phenobarbital, and ritonavir), consider increasing the initial dose to 21 mg/kg PO once daily; further adjust dose based on ferritin concentrations or as clinical response dictates. Start treatment when there is evidence of chronic iron overload (i.e., transfusion of 100 mL/kg or more of packed red blood cells and serum ferritin concentrations consistently more than 1,000 mcg/L). Prior to starting therapy, obtain baseline serum ferritin, transaminases, and bilirubin concentrations. Baseline serum creatinine should be obtained in duplicate, and a creatinine clearance calculated using Cockcroft-Gault method. Additionally, it is advised patients receive auditory and ophthalmic examinations prior to treatment. Once treatment is initiated, monitor serum ferritin concentrations monthly.

    For maintenance therapy for chronic iron toxicity secondary to transfusional iron overload (transfusional hemosiderosis).
    Oral dosage (Exjade)
    Adults, Adolescents and Children > = 2 years

    Following initial dosing, adjust dose every 3 to 6 months in increments of 5 to 10 mg/kg PO (to the nearest whole tablet mg strength) based on serum ferritin concentrations. For patients not adequately controlled with doses of 30 mg/kg/day PO (e.g., serum ferritin concentrations more than 2,500 mcg/L and not showing a decreasing trend over time), doses up to 40 mg/kg/day PO may be considered. Doses greater than 40 mg/kg are not recommended by the manufacturer; however, a dose of 80 mg/kg/day PO was well tolerated in one study with no noted safety concerns. The risk of toxicity from deferasirox may be increased when inappropriately high doses are given to patients with low iron burden or in patients with serum ferritin levels that are only slightly elevated. If the serum ferritin consistently falls below 500 mcg/L, consider temporarily interrupting therapy.

    Oral dosage (Jadenu)
    Adults, Adolescents and Children > = 2 years

    Following initial dosing, adjust dose based on serum ferritin trends every 3 to 6 months as needed in increments of 3.5 mg/kg or 7 mg/kg (to the nearest whole tablet mg strength). For patients not adequately controlled with doses of 21 mg/kg/day PO (e.g., serum ferritin concentrations more than 2,500 mcg/L and not showing a decreasing trend over time), doses up to 28 mg/kg/day PO may be considered. Doses greater than 28 mg/kg are not recommended. If the serum ferritin consistently falls below 500 mcg/L, consider temporarily interrupting therapy. For patients being converted from chelation therapy with Exjade, the dose of Jadenu should be approximately 30% lower with dose rounded to the nearest whole tablet.

    For initiation of therapy for chronic iron toxicity in non-transfusion dependent thalassemia syndromes with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of liver dry weight and serum ferritin more than 300 mcg/L.
    Oral dosage (Exjade)
    Adults, Adolescents, and Children >= 10 years

    10 mg/kg PO daily, as an oral suspension; calculate dose to the nearest whole tablet mg strength. In patients taking bile acid sequestrants or potent UGT inducers (e.g., rifampin, phenytoin, phenobarbital, and ritonavir), consider increasing the initial dose to 15 mg/kg PO once daily. Prior to starting therapy, obtain LIC by liver biopsy or by an FDA-cleared or approved method, as well as serum ferritin level on at least 2 measurements 1 month apart. Start treatment when the liver iron (Fe) concentration (LIC) is at least 5 mg Fe per gram liver dry weight (mg Fe/g dw) and serum ferritin greater than 300 mcg/L. If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 mg/kg/day after 4 weeks. Obtain baseline transaminases and bilirubin concentrations, as well as baseline serum creatinine in duplicate (due to variations in measurements) and a creatinine clearance calculated using the Cockcroft-Gault method. Additionally, patients should receive auditory and ophthalmic examinations prior to treatment. Once treatment is initiated, monitor serum ferritin concentrations monthly and LIC every 6 months.

    Oral dosage (Jadenu)
    Adults, Adolescents, and Children >= 10 years

    7 mg/kg PO daily; calculate dose to the nearest whole tablet mg strength. In patients taking bile acid sequestrants or potent UGT inducers (e.g., rifampin, phenytoin, phenobarbital, and ritonavir), consider increasing the initial dose to 10.5 mg/kg PO once daily. Prior to starting therapy, obtain LIC by liver biopsy or by an FDA-cleared or approved method, as well as serum ferritin level on at least 2 measurements 1 month apart. Start treatment when the liver iron (Fe) concentration (LIC) is at least 5 mg Fe per gram liver dry weight (mg Fe/g dw) and serum ferritin greater than 300 mcg/L. If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks. Obtain baseline transaminases and bilirubin concentrations, as well as baseline serum creatinine in duplicate (due to variations in measurements) and a creatinine clearance calculated using the Cockcroft-Gault method. Additionally, patients should receive auditory and ophthalmic examinations prior to treatment. Once treatment is initiated, monitor serum ferritin concentrations monthly and LIC every 6 months.

    For maintenance of therapy for chronic iron toxicity in non-transfusion dependent thalassemia syndromes and a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram liver dry weight and serum ferritin more than 300 mcg/L.
    Oral dosage (Exjade)
    Adults, Adolescents, and Children >= 10 years

    Following initial dosing, monitor serum ferritin monthly and liver iron concentration (LIC) every 6 months. If serum ferritin is less than 300 mcg/L, interrupt treatment and obtain an LIC. When the LIC is less than 3 mg Fe/g dw, treatment should be held, and restarted when it rises to more than 5 mg Fe per gram liver dry weight (mg Fe/g dw). After 6 months of therapy, if the LIC remains more than 7 mg Fe/g dw, the dose may be increased to a maximum of 20 mg/kg/day PO. Doses greater than 20 mg/kg/day PO are not recommended by the manufacturer. If after 6 months of therapy the LIC is 3 to 7 mg Fe/g dw, continue treatment with 10 mg/kg PO daily.

    Oral dosage (Jadenu)
    Adults, Adolescents, and Children >= 10 years

    Following initial dosing, monitor serum ferritin monthly and liver iron concentration (LIC) every 6 months. If serum ferritin is less than 300 mcg/L, interrupt treatment and obtain an LIC. When the LIC is less than 3 mg Fe/g dw, treatment should be held, and restarted when it rises to more than 5 mg Fe per gram liver dry weight (mg Fe/g dw). After 6 months of therapy, if the LIC remains more than 7 mg Fe/g dw, increase the dose to a maximum of 14 mg/kg/day PO. Doses greater than 14 mg/kg/day PO are not recommended. If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with 7 mg/kg PO daily. For patients being converted from chelation therapy with Exjade, the dose of Jadenu should be approximately 30% lower with dose rounded to the nearest whole tablet.

    MAXIMUM DOSAGE

    Adults

    28 mg/kg/day PO for Jadenu; 40 mg/kg/day PO for Exjade. Experience with higher doses is limited; 80 mg/kg/day PO of Exjade was well tolerated in one study with no noted safety concerns.

    Geriatric

    28 mg/kg/day PO for Jadenu; 40 mg/kg/day PO for Exjade.

    Adolescents

    28 mg/kg/day PO for Jadenu; 40 mg/kg/day PO for Exjade.

    Children

    > 2 years: 28 mg/kg/day PO for Jadenu; 40 mg/kg/day PO Exjade.
    < 2 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Child-Pugh A: No dosage adjustment necessary.
    Child-Pugh B: Reduce the starting dose by 50%.
    Child-Pugh C: Avoid use.

    Renal Impairment

    Use caution when administering to patients with renal disease, or renal impairment of any kind. Elevated serum creatinine (SCr) measurements may occur during treatment, and dose reduction or treatment interruption or discontinuation should be considered.
    Dose modifications for patients with baseline renal impairment:
    Creatinine clearance (CrCl) 40—60 mL/min: decrease starting dose by 50%.
    CrCl < 40 mL/min or SCr > 2 times the age appropriate upper limit of normal: do not use.
    Dose modifications for increases in SCr during treatment:
    Transfusional iron overload
    Adults and adolescents > 15 years old: Decrease daily Exjade dose by 10 mg/kg and daily Jadenu dose by 7 mg/kg if two SCr measurements (separated by < 1 week) are increased >= 33% above average pretreatment levels.
    Adolescents <= 15 years and children: Decrease daily Exjade dose by 10 mg/kg and daily Jandenu dose by 7 mg/kg if SCr increases > 33% above average pretreatment levels and above the age appropriate upper limit of normal.
    All patients (regardless of age): Do not use if CrCl < 40 mL/min or SCr > 2 times the age appropriate upper limit of normal.
    Non-transfusion dependent thalassemia syndromes
    Adults and adolescents > 15 years old: Interrupt therapy (if daily Exjade dose is 5 mg/kg or daily Jadenu dose is 3.5 mg/kg) or reduce dose by 50% (if daily Exjade dose is 10—20 mg/kg or daily Jadenu dose is 7—14 mg/kg) if two SCr measurements (separated by < 1 week) are increased >= 33% above average pretreatment levels.
    Adolescents <= 15 years and children >= 10 years: Decrease daily Exjade dose by 5 mg/kg and daily Jadenu dose by 3.5 mg/kg if SCr increases > 33% above the average pretreatment levels and above the age appropriate upper limit of normal.
    All patients (regardless of age): Do not use if CrCl < 40 mL/min or SCr > 2 times the age appropriate upper limit of normal.

    ADMINISTRATION

    Oral Administration

    Administer at approximately the same time every day. Do not administer with any aluminum-containing antacid products.
    For patients converting from Exjade to Jadenu, the dose of Jadenu should be approximately 30% lower and rounded to the nearest whole tablet or sachet content for granules.

    Oral Solid Formulations

    Jadenu:
    Administer on an empty stomach or with a light meal (less than 250 calories and less than 7% fat).
    Tablets: For those who have difficulty swallowing whole tablets, the dose may be crushed and mixed with soft foods (e.g., yogurt, apple sauce). If crushed, the dose should be completely consumed immediately; DO NOT store for future use. Avoid use of commercial crushers with serrated surfaces when crushing the 90 mg tablet strength.
    Sprinkle granules: Sprinkle granules on soft food (e.g., yogurt, apple sauce) immediately prior to use.

    Oral Liquid Formulations

    Exjade:
    Administer on an empty stomach at least 30 minutes before food.
    Tablets are for dispersion only and should not be chewed or swallowed whole. Completely disperse the tablets by stirring in water, orange juice, or apple juice until a fine suspension results.
    Doses less than 1 g should be dispersed in at least 3.5 ounces of liquid and doses more than 1 g in at least 7 ounces of liquid.
    After swallowing the suspension, any residue should be mixed in a small volume of liquid and swallowed.

    STORAGE

    Exjade:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Jadenu:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Nephrotoxicity, proteinuria, renal disease, renal failure, renal impairment

    Deferasirox may cause nephrotoxicity and is contraindicated for use in patients with renal failure or severe renal impairment with a creatinine clearance < 40 mL/min or serum creatinine (SCr) > 2 times the age appropriate upper limit of normal (ULN). In patients with moderate renal impairment (creatinine clearance 40—60 mL/min), a reduction in the starting dose is advised. Use with caution in any patient with known renal disease. Prior to initiating treatment in any patient, obtain two SCr assessments and calculate creatinine clearance (CrCl, using Cockcroft-Gault) to establish a reliable pre-treatment baseline. Monitor SCr and CrCl weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor more frequently if creatinine levels are increasing. For any elevations in SCr, dose reductions, treatment interruption, or treatment discontinuation is recommended, depending on the age of the patient, the disease state treated, and the degree of the changes. In clinical trials, deferasirox treated patients experienced dose-dependent increases in serum creatinine; there have been post-marketing reports of renal impairment and acute renal failure leading to death in some patients and requiring dialysis in others. Most reported fatalities occurred in patients with multiple comorbidities and who were in an advanced stage of their hematological disorder. Intermittent proteinuria (urine protein/creatinine ratio > 0.6 mg/mg) occurred in 18.6% of deferasirox treated patients compared to 7.2% of deferoxamine-treated patients in clinical studies. In studies in patients with transfusional iron overload, deferasirox was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is also recommended. The clinical significance and mechanism of the proteinuria are uncertain.

    Hepatic decompensation, hepatic disease, hepatitis, hepatotoxicity

    Deferasirox use has been associated with hepatotoxicity. Hepatic failure, sometimes fatal, has also been reported during post-marketing surveillance. Most of these occurred in patients older than 55 years of age. Many reports have also occurred in patients with significant comorbidities including liver cirrhosis and multi-organ failure. In one study, 4 patients discontinued deferasirox because of hepatic abnormalities (drug-induced hepatitis and increased serum transaminases). Deferasirox be avoided in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic disease may be at higher risk for hepatic toxicity. In one study, 4 patients discontinued deferasirox because of hepatic abnormalities (drug-induced hepatitis and increased serum transaminases). Monitor closely for signs and symptoms of hepatic decompensation. Monitor liver function tests (serum transaminases - AST, ALT, and bilirubin) before the initiation of treatment, every 2 weeks during the first month, and monthly thereafter. If there are unexplained, persistent, or progressive increases in serum transaminase levels, consider dose modifications or interruption of treatment. Hepatic disease may also dramatically alter enterohepatic recirculation of deferasirox, and may lead to a decrease in efficacy.

    Agranulocytosis, anemia, bone marrow suppression, neutropenia, thrombocytopenia

    Deferasirox is contraindicated for use in patients with thrombocytopenia with platelet counts < 50,000/mm3. Cytopenias, including agranulocytosis, neutropenia, worsening anemia, and thrombocytopenia, sometimes fatal, have been reported during clinical trials and post-marketing with use of deferasirox. Preexisting hematological disease or disorders may increase the risk of bone marrow suppression and these events. The relationship of these cytopenias to treatment with deferasirox is uncertain. Side effects such as renal impairment, hepatic impairment and gastrointestinal hemorrhage were observed more frequently in patients with platelet counts < 50,000/mm3. Regularly monitor complete blood counts (CBC) with differential in patients treated with deferasirox. Interrupt treatment in any patient who develops an unexplained cytopenia until the cause is determined.

    Myelodysplastic syndrome (MDS), neoplastic disease

    Deferasirox is contraindicated for use in patients with certain neoplastic disease (advanced malignancies), high-risk myelodysplastic syndrome (MDS), and other patients with poor performance status. Controlled clinical trials have not been conducted in MDS patients who have chronic iron overload due to blood transfusions; however, 627 patients with MDS across 5 uncontrolled trials were evaluated in a pooled analysis. In this group of patients, 20% of patients experienced an increase in serum creatinine (SCr) above baseline and above the upper limit of normal (ULN) at two consecutive visits, compared with 2% of patients with sickle cell disease (n = 132) and 2% of patients with beta-thalassemia (n = 296). Additionally, diarrhea (47% vs 20% vs 12%), nausea (26% vs 23% vs 11%), and rash (13% vs 11% vs 8%) occurred more frequently in patients with MDS compared with sickle cell disease and beta-thalassemia. Gastrointestinal hemorrhage, including some fatal instances, was observed more frequently in patients with advanced malignancies.

    Anticoagulant therapy, corticosteroid therapy, GI bleeding, GI perforation, peptic ulcer disease

    Treatment with deferasirox has been associated with serious, sometimes fatal, gastrointestinal (GI) adverse events, including GI bleeding, GI ulceration, and GI perforation. Fatal GI hemorrhages have been most frequently reported in patients 65 years of age or older who had advanced hematologic malignancies and/or low platelet counts. Use with caution in patients with known peptic ulcer disease. Non-fatal upper GI irritation, gastric ulceration, and GI hemorrhage have been reported in patients, including pediatric patients less than 18 years of age, receiving deferasirox. Physicians and patients should remain alert for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. Use caution when administering deferasirox in combination with drugs that have ulcerogenic or hemorrhagic risk potential, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroid therapy, oral bisphosphonates, or anticoagulant therapy.

    Angioedema, risk of serious hypersensitivity reactions or anaphylaxis, serious rash

    Deferasirox is contraindicated in patients with hypersensitivity to deferasirox or any of its components. There is a risk of serious hypersensitivity reactions or anaphylaxis, including angioedema, with deferasirox treatment. A majority of serious allergic reactions occurred within the first month of treatment. Discontinue deferasirox, and institute appropriate medical interventions, for severe reactions. Deferasirox should not be restarted in patients experiencing a hypersensitivity reaction. Serious rash events, such as Stevens-Johnson syndrome (SJS), erythema multiforme, and toxic epidermal necrolysis, have been reported with deferasirox therapy. The risk for other serious skin reactions, such as drug reaction with eosinophilia and systemic systems (DRESS), cannot be ruled out. Patients experiencing severe skin reactions while receiving deferasirox should discontinue treatment. If the reaction is determined to be Stevens-Johnson syndrome (SJS), erythema multiforme, or toxic epidermal necrolysis (TEN), use of the drug must not be reinitiated. In cases of other serious rash, the drug may be restarted at a lower dose after resolution of the rash. Patients who experience mild to moderate rashes do not require treatment interruptions or dose adjustments, as these rashes often resolve spontaneously.

    Cataracts, glaucoma, hearing impairment, visual disturbance

    Use caution when administering deferasirox to patients with hearing impairment, visual disturbance, or glaucoma. Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) have been reported rarely with deferasirox therapy during clinical studies. Patients taking deferasirox should undergo auditory and ophthalmologic testing (including slit lamp examinations and dilated funduscopy) before initiation of therapy and annually (every 12 months) thereafter. If changes in hearing or vision are noted, dose reduction or interruption should be considered.

    Children, infants, neonates

    The safety and efficacy of deferasirox has not been established in neonates, infants or children < 2 years. Of the patients receiving deferasirox in clinical trial, 292 were pediatric patients between the ages of 2 and 16 years of age. The safety and efficacy of deferasirox was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modifications are the same for children and adults.

    Geriatric

    During clinical trials, geriatric patients experienced a higher frequency of a variety of adverse reactions compared to younger adult patients. Geriatric patients may be at greater risk of developing deferasirox-related renal impairment, hepatic decompensation, and cytopenias. In addition, fatal GI hemorrhages were more common in elderly patients. In post-marketing reports, serious adverse events and fatalities occurred more frequently in patients with advanced age, complications from underlying conditions, or very advanced disease. Most deaths occurred within 6 months of deferasirox initiation and generally involved worsening of the underlying condition. Four hundred thirty-one patients 65 years of age and older were studied in clinical trials of deferasirox in the transfusional iron overload setting. Two hundred twenty-five of these patients were between 65 and 75 years of age while 206 were 75 years of age and older. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). Geriatric patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range. Health care providers are advised to closely monitor geriatric patients for signs of drug toxicity, especially toxicities that may require dose adjustment or treatment discontinuation.

    Pregnancy

    There are no adequate and well-controlled studies with the use of deferasirox in pregnant women to inform about drug-associated risks. In animal studies, the administration of deferasirox resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses less than the recommended human doses. Deferasirox should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

    Driving or operating machinery

    Deferasirox has been associated with dizziness and patients should be warned to use caution when driving or operating machinery.

    Breast-feeding

    There are no data available on the presence of deferasirox or its metabolites in human milk, the effects on the breast-fed infant, or the effects on milk production. In animal studies, deferasirox and its metabolites were excreted in rat milk. Due to the potential for serious adverse reactions in the nursing infant from deferasirox, a decision should be made whether to discontinue breast-feeding or discontinue deferasirox, taking into account the mother's clinical need for deferasirox.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 0.1-1.0
    peptic ulcer / Delayed / 0.1-1.0
    pancreatitis / Delayed / 0.1-1.0
    Fanconi syndrome / Delayed / 0.1-1.0
    visual impairment / Early / 0.1-1.0
    hearing loss / Delayed / 0.1-1.0
    erythema multiforme / Delayed / 0-0.1
    optic neuritis / Delayed / 0-0.1
    GI perforation / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    proteinuria / Delayed / 18.3-18.3
    elevated hepatic enzymes / Delayed / 1.0-8.4
    gastritis / Delayed / 0.1-1.0
    cataracts / Delayed / 0.1-1.0
    edema / Delayed / 0.1-1.0
    esophagitis / Delayed / 0-0.1
    cholelithiasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 11.8-47.0
    abdominal pain / Early / 21.3-28.0
    nausea / Early / 10.5-26.0
    vomiting / Early / 10.1-21.2
    rash (unspecified) / Early / 8.0-13.0
    fever / Early / 0.1-1.0
    insomnia / Early / 0.1-1.0
    fatigue / Early / 0.1-1.0
    anxiety / Delayed / 0.1-1.0
    dizziness / Early / 0.1-1.0
    alopecia / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    purpura / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Alclometasone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Alendronate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including alendronate.
    Alendronate; Cholecalciferol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including alendronate.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aluminum Hydroxide: (Moderate) Although deferasirox has a lower affinity for aluminum than for iron, deferasirox may also increase the excretion of aluminum. Because deferasirox may bind to aluminum instead of iron, aluminum containing antacids should not be administered concurrently in order to avoid a possible decreased efficacy of either therapy.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Although deferasirox has a lower affinity for aluminum than for iron, deferasirox may also increase the excretion of aluminum. Because deferasirox may bind to aluminum instead of iron, aluminum containing antacids should not be administered concurrently in order to avoid a possible decreased efficacy of either therapy.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Although deferasirox has a lower affinity for aluminum than for iron, deferasirox may also increase the excretion of aluminum. Because deferasirox may bind to aluminum instead of iron, aluminum containing antacids should not be administered concurrently in order to avoid a possible decreased efficacy of either therapy.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Although deferasirox has a lower affinity for aluminum than for iron, deferasirox may also increase the excretion of aluminum. Because deferasirox may bind to aluminum instead of iron, aluminum containing antacids should not be administered concurrently in order to avoid a possible decreased efficacy of either therapy.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Although deferasirox has a lower affinity for aluminum than for iron, deferasirox may also increase the excretion of aluminum. Because deferasirox may bind to aluminum instead of iron, aluminum containing antacids should not be administered concurrently in order to avoid a possible decreased efficacy of either therapy.
    Amikacin: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Aminoglycosides: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Amiodarone: (Moderate) Deferasirox inhibits CYP2C8. Amiodarone is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and amiodarone are not available, a similar interaction may occur. The dose of amiodarone may need to be decreased if coadministered with deferasirox.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Telmisartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Antithrombin III: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Aprepitant, Fosaprepitant: (Major) Use caution if deferasirox and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Deferasirox is a moderate CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
    Argatroban: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Aspirin, ASA: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Carisoprodol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Dipyridamole: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Omeprazole: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Oxycodone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Aspirin, ASA; Pravastatin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Deferasirox undergoes UGT metabolism, and phenobarbital is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and phenobarbital are not available, a similar interaction may occur. Avoid the concomitant use of phenobarbital and deferasirox if possible. If phenobarbital and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Axitinib: (Major) Avoid coadministration of axitinib with deferasirox if possible, due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Deferasirox is a moderate CYP3A4 inducer. In healthy subjects, deferasirox decreased Cmax and AUC of another CYP3A4 substrate, midazolam, by 23% and 17%, respectively; in the clinical setting, this effect may be more pronounced. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers. Deferasirox is also a CYP1A2 inhibitor, which theoretically could increase exposure to axitinib; however, the effects of deferasirox on CYP1A2 are not expected to overcome its effects on CYP3A4, as CYP3A4 is the major route of metabolism for axitinib.
    Azelastine; Fluticasone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Bedaquiline: (Major) Avoid concurrent use of deferasirox with bedaquiline. Deferasirox is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Deferasirox undergoes UGT metabolism, and phenobarbital is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and phenobarbital are not available, a similar interaction may occur. Avoid the concomitant use of phenobarbital and deferasirox if possible. If phenobarbital and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Bismuth Subsalicylate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Bivalirudin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and deferasirox are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; deferasirox is a moderate inducer of CYP3A4.
    Budesonide: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Budesonide; Formoterol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Bupivacaine; Lidocaine: (Major) Concomitant use of systemic lidocaine and deferasirox may alter lidocaine plasma concentrations; avoid concurrent use. If use together is necessary, monitor patients closely for lidocaine toxicity and therapeutic efficacy. Lidocaine is a CYP3A4 and CYP1A2 substrate; deferasirox inhibits CYP1A2 and induces CYP3A4.
    Cabozantinib: (Moderate) Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and deferasirox is necessary. Cabozantinib is primarily metabolized by CYP3A4 and deferasirox is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
    Calcium Carbonate; Risedronate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including risedronate.
    Celecoxib: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Cholestyramine: (Major) The concomitant administration of deferasirox and cholestyramine may result in decreased systemic exposure to deferasirox. In healthy volunteers, the administration of cholesytramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). Avoid the concomitant use of cholestyramine with deferasirox if possible. If cholestyramine and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin levels and clinical responses for further dose modification.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Clindamycin: (Moderate) Concomitant use of clindamycin and deferasirox may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; deferasirox is a moderate inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clobetasol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with deferasirox due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and deferasirox is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
    Colesevelam: (Major) The concomitant administration of deferasirox and colesevelam may result in decreased systemic exposure to deferasirox. Avoid the concomitant use if possible. If colesevelam and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox to 30 mg/kg. Monitor serum ferritin levels and clinical responses for further dose modification.
    Colestipol: (Major) The concomitant administration of deferasirox and colestipol may result in decreased systemic exposure to deferasirox. Avoid the concomitant use if possible. If colestipol and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox to 30 mg/kg. Monitor serum ferritin levels and clinical responses for further dose modification.
    Cyclosporine: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as cyclosporine. If these drugs are used together, monitor patients for a decrease in the effects of cyclosporine.
    Dabigatran: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as deferasirox. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dalteparin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Danaparoid: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Dapsone: (Moderate) The metabolism of dapsone may be accelerated when administered concurrently with deferasirox, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of deferasirox with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in altered deferasirox plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Deferasirox is an inducer of CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, deferasirox is a substrate for uridine glucuronyltransferase (UGT); dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. In addition, ritonavir may induce UGT. (Major) Concurrent administration of deferasirox with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered deferasirox plasma concentrations. Deferasirox is a substrate for uridine glucuronyltransferase (UGT); dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. In addition, ritonavir may induce UGT. Caution and close monitoring are advised if these drugs are administered together. (Major) Deferasirox undergoes UGT metabolism, and ritonavir is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and ritonavir are not available, a similar interaction may occur. Avoid the concomitant use of ritonavir and deferasirox if possible. If ritonavir and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Deferiprone: (Major) Although the potential benefits of combination iron chelation therapy have been mentioned in the literature, deferasirox should not be combined with other iron chelator therapies (e.g., deferiprone) as the safety of such combinations has not been established.
    Deferoxamine: (Major) Although the potential benefits of combination iron chelation therapy have been mentioned in the literature, deferasirox should not be combined with deferoxamine as the safety of such combinations has not been established.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and deferasirox. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; deferasirox is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone. Additionally, coadministration may increase the risk of GI toxicity. Gastric ulceration and GI bleeding have been reported in patients taking deferasirox; corticosteroids increase the risk of peptic ulcers or gastric hemorrhage.
    Desirudin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Dexamethasone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Diclofenac: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Diclofenac; Misoprostol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Diflunisal: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Diphenhydramine; Ibuprofen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Diphenhydramine; Naproxen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with deferasirox is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; deferasirox is a moderate inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Drospirenone; Estradiol: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Drospirenone; Ethinyl Estradiol: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Edoxaban: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Elbasvir; Grazoprevir: (Major) If possible, avoid concurrent administration of elbasvir with deferasirox. Deferasirox is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response.
    Enoxaparin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with deferasirox due to an unpredictable effect on the efficacy and toxicity of erlotinib. Deferasirox is a moderate CYP3A4 inducer and a CYP1A2 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Deferasirox decreased the AUC and Cmax of another CYP3A4 substrate, midazolam, by 17% and 23%, respectively; in the clinical setting, this effect may be more pronounced. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. The AUC and elimination half-life of the CYP1A2 substrate, theophylline, approximately doubled when administered with deferasirox. Data are not available on the effect of CYP1A2 inhibition on erlotinib exposure; however, coadministration with ciprofloxacin, a moderate inhibitor of both CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%.
    Esomeprazole; Naproxen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Estradiol; Levonorgestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Estradiol; Norethindrone: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Estradiol; Norgestimate: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Desogestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Etonogestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Levonorgestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Norelgestromin: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Severe) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It is illogical for a patient to receive both iron supplementation and deferasirox simultaneously. Do not give iron supplementation during Deferasirox treatment. (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Norethindrone: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Severe) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It is illogical for a patient to receive both iron supplementation and deferasirox simultaneously. Do not give iron supplementation during Deferasirox treatment. (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Norgestimate: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Ethinyl Estradiol; Norgestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Etodolac: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Etonogestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide if used concomitantly with deferasirox. Deferasirox is an inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Exemestane: (Moderate) Use caution if coadministration of exemestane with deferasirox is necessary, and monitor for a possible decrease in the efficacy of exemestane. Exemestane is a CYP3A4 substrate; deferasirox is a moderate CYP3A4 inducer. In a pharmacokinetic interaction study (n = 10) with a strong CYP3A4 inducer, rifampicin (600 mg daily for 14 days), the mean Cmax and AUC of exemestane (single dose) decreased by 41% and 54%, respectively. The manufacturer of exemestane recommends a dose increase when concomitant use with a strong CYP3A4 inducer is necessary; recommendations are not available for moderate CYP3A4 inducers.
    Ezetimibe; Simvastatin: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as simvastatin. If these drugs are used together, monitor patients for a decrease in the effects of simvastatin.
    Famotidine; Ibuprofen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Fenoprofen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Ferric Citrate: (Severe) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It would be illogical for a patient to receive both ferric citrate and deferasirox simultaneously.
    Flurbiprofen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Fluticasone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Fluticasone; Salmeterol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Fluticasone; Vilanterol: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Fluvastatin: (Moderate) Deferasirox inhibits CYP2C8. Fluvastatin is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and fluvastatin are not available, a similar interaction may occur. The dose of fluvastatin may need to be decreased if coadministered with deferasirox.
    Fondaparinux: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Food: (Moderate) The bioavailability (AUC) of deferasirox was variably increased when administered with food. Deferasirox should be taken on an empty stomach 30 minutes before eating. Deferasirox tablets for oral suspension can be dispersed in water, orange juice, or apple juice.
    Fosphenytoin: (Major) Deferasirox undergoes UGT metabolism, and phenytoin is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and phenytoin or fosphenytoin are not available, a similar interaction may occur. Avoid the concomitant use of phenytoin or fosphenytoin and deferasirox if possible. If coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Gefitinib: (Major) Monitor for clinical response of gefitinib if used concomitantly with deferasirox. Gefitinib is metabolized significantly by CYP3A4 and deferasirox is a CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Gentamicin: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Guanfacine: (Major) Deferasirox may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if deferasirox is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If deferasirox is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and deferasirox is a moderate CYP3A4 inducer.
    Heparin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Hydrocodone; Ibuprofen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Ibandronate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including ibandronate.
    Ibuprofen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Ibuprofen; Oxycodone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Ibuprofen; Pseudoephedrine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Indomethacin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Iron - Injectable Only: (Major) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It would be illogical for a patient to receive both iron supplementation and deferasirox simultaneously.
    Iron Salts: (Severe) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It is illogical for a patient to receive both iron supplementation and deferasirox simultaneously. Do not give iron supplementation during Deferasirox treatment.
    Iron: (Severe) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It is illogical for a patient to receive both iron supplementation and deferasirox simultaneously. Do not give iron supplementation during Deferasirox treatment.
    Isavuconazonium: (Major) Concomitant use of isavuconazonium with deferasirox may result in decreased serum concentrations of isavuconazonium and the potential for treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of CYP3A4; deferasirox is an inducer of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Deferasirox undergoes UGT metabolism, and rifampin is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Avoid the concomitant use of rifampin and deferasirox if possible. If rifampin and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Isoniazid, INH; Rifampin: (Major) Deferasirox undergoes UGT metabolism, and rifampin is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Avoid the concomitant use of rifampin and deferasirox if possible. If rifampin and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Ivabradine: (Major) Avoid coadministration of ivabradine and deferasirox. Ivabradine is primarily metabolized by CYP3A4; deferasirox is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Kanamycin: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Ketoprofen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Ketorolac: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Lansoprazole; Naproxen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Lepirudin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Leuprolide; Norethindrone: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Levonorgestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Lidocaine: (Major) Concomitant use of systemic lidocaine and deferasirox may alter lidocaine plasma concentrations; avoid concurrent use. If use together is necessary, monitor patients closely for lidocaine toxicity and therapeutic efficacy. Lidocaine is a CYP3A4 and CYP1A2 substrate; deferasirox inhibits CYP1A2 and induces CYP3A4.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2C8 substrate, may be altered when administered concurrently with deferasirox, an inducer of CYP3A4 and an inhibitor of CYP2C8. If these drugs are used together, monitor for altered response to loperamide and loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2C8 substrate, may be altered when administered concurrently with deferasirox, an inducer of CYP3A4 and an inhibitor of CYP2C8. If these drugs are used together, monitor for altered response to loperamide and loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Deferasirox undergoes UGT metabolism, and ritonavir is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and ritonavir are not available, a similar interaction may occur. Avoid the concomitant use of ritonavir and deferasirox if possible. If ritonavir and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Magnesium Salicylate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with deferasirox is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and deferasirox is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Meclofenamate Sodium: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Mefenamic Acid: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Meloxicam: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Mestranol; Norethindrone: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Metformin; Repaglinide: (Moderate) Repaglinide is metabolized by CYP2C8 and deferasirox is a CYP2C8 inhibitor. Co-administration of deferasirox (30 mg/kg/day for 4 days) and repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Methylprednisolone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Midazolam: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. If these drugs are used together, monitor patients for a decrease in the effects of midazolam.
    Nabumetone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Naproxen: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Naproxen; Pseudoephedrine: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Naproxen; Sumatriptan: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Neratinib: (Major) Avoid concomitant use of deferasirox with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and deferasirox is a moderate CYP3A4 inducer. The effect of moderate CYP3A4 induction on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inducer decreased neratinib exposure by 87% and decreased exposure to active metabolites M6 and M7 by 37% to 49%. Because of the significant impact on neratinib exposure from strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers should be considered as they may also significantly decrease neratinib exposure.
    Niacin; Simvastatin: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as simvastatin. If these drugs are used together, monitor patients for a decrease in the effects of simvastatin.
    Non-Ionic Contrast Media: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including radiopaque contrast agents, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly.
    Nonsteroidal antiinflammatory drugs: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Norethindrone: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Norgestrel: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as hormonal combination contraceptives (i.e., oral contraceptives and non-oral combination contraceptives).
    Olaparib: (Major) Avoid the coadministration of olaparib with deferasirox if possible; if concomitant use is necessary, be aware of a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and deferasirox is a moderate CYP3A4 inducer. In healthy volunteers, deferasirox decreased the AUC and Cmax of another CYP3A4 substrate, midazolam, by 17% and 23%, respectively; in the clinical setting, the effect may be more pronounced. Simulations have suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of olaparib by 50% to 60% and the Cmax by 20% to 30%; deferasirox may also decrease olaparib exposure.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concurrent administration of deferasirox with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in altered deferasirox plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Deferasirox is an inducer of CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, deferasirox is a substrate for uridine glucuronyltransferase (UGT); dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. In addition, ritonavir may induce UGT. (Major) Concurrent administration of deferasirox with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered deferasirox plasma concentrations. Deferasirox is a substrate for uridine glucuronyltransferase (UGT); dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. In addition, ritonavir may induce UGT. Caution and close monitoring are advised if these drugs are administered together. (Major) Deferasirox undergoes UGT metabolism, and ritonavir is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and ritonavir are not available, a similar interaction may occur. Avoid the concomitant use of ritonavir and deferasirox if possible. If ritonavir and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Oxaprozin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Paclitaxel: (Moderate) Deferasirox inhibits CYP2C8. Paclitaxel is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and paclitaxel are not available, a similar interaction may occur. The dose of paclitaxel may need to be decreased if coadministered with deferasirox.
    Palbociclib: (Major) Use caution and monitor patients for decreased palbociclib efficacy if deferasirox is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and deferasirox is a moderate CYP3A inducer. Coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    Paromomycin: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Pentosan: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Phenobarbital: (Major) Deferasirox undergoes UGT metabolism, and phenobarbital is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and phenobarbital are not available, a similar interaction may occur. Avoid the concomitant use of phenobarbital and deferasirox if possible. If phenobarbital and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Phenytoin: (Major) Deferasirox undergoes UGT metabolism, and phenytoin is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and phenytoin are not available, a similar interaction may occur. Avoid the concomitant use of phenytoin and deferasirox if possible. If phenytoin and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Piroxicam: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Polysaccharide-Iron Complex: (Severe) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It is illogical for a patient to receive both iron supplementation and deferasirox simultaneously. Do not give iron supplementation during Deferasirox treatment.
    Pomalidomide: (Major) Avoid the concomitant use of pomalidomide and deferasirox; significantly increased pomalidomide exposure may occur increasing the risk of pomalidomide adverse events. If concomitant use is unavoidable, decrease the pomalidomide dose by 50% and monitor for pomalidomide adverse events. Pomalidomide is a CYP1A2 substrate and deferasirox inhibits CYP1A2. In healthy volunteers, the Cmax and AUC values for pomalidomide were increased by 24% and 125%, respectively, when pomalidomide was co-administered with a strong CYP1A2 inhibitor. Additionally, the AUC value of a sensitive CYP1A2 substrate about doubled when deferasirox was co-administered with a sensitive CYP1A2 substrate in healthy volunteers.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with deferasirox, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Prednisolone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Prednisone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Repaglinide: (Moderate) Repaglinide is metabolized by CYP2C8 and deferasirox is a CYP2C8 inhibitor. Co-administration of deferasirox (30 mg/kg/day for 4 days) and repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with deferasirox is necessary, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and deferasirox is a CYP3A4 inducer.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with deferasirox is necessary, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and deferasirox is a CYP3A4 inducer.
    Rifampin: (Major) Deferasirox undergoes UGT metabolism, and rifampin is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Avoid the concomitant use of rifampin and deferasirox if possible. If rifampin and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Risedronate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including risedronate.
    Ritonavir: (Major) Deferasirox undergoes UGT metabolism, and ritonavir is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and ritonavir are not available, a similar interaction may occur. Avoid the concomitant use of ritonavir and deferasirox if possible. If ritonavir and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Rivaroxaban: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Rofecoxib: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Salicylates: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Salsalate: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
    Selexipag: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving deferasirox. Reduce the selexipag dose when deferasirox is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; deferasirox is a moderate CYP2C8 inhibitor.
    Simvastatin: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as simvastatin. If these drugs are used together, monitor patients for a decrease in the effects of simvastatin.
    Simvastatin; Sitagliptin: (Moderate) The concomitant administratin of midazolam, a CYP3A4 substrate, and deferasirox resulted in a decrease in the peak serum concentration of midazolam by 23% and midazolam exposure by 17% in healthy volunteers. This effect may be even more pronounced in patients. Although not specifically studied, reduced serum concentrations may also occur in patients taking other CYP3A4 substrates such as simvastatin. If these drugs are used together, monitor patients for a decrease in the effects of simvastatin.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Severe) Deferasirox chelates iron and is indicated as a treatment of iron toxicity or overdose. It is illogical for a patient to receive both iron supplementation and deferasirox simultaneously. Do not give iron supplementation during Deferasirox treatment.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with deferasirox. Taking these drugs together may significantly alter velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy or adverse effects. Velpatasvir is a substrate of CYP3A4 and CYP2C8; deferasirox is an inducer of CYP3A4 and an inhibitor of CYP2C8.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with deferasirox. Taking these drugs together may significantly alter velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy or adverse effects. Velpatasvir is a substrate of CYP3A4 and CYP2C8; deferasirox is an inducer of CYP3A4 and an inhibitor of CYP2C8. (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as deferasirox. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and deferasirox; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate deferasirox is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    Streptomycin: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Sulindac: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Tacrolimus: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including tacrolimus, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with deferasirox is necessary, due to the risk of decreased efficacy of temsirolimus. Temsirolimus is a CYP3A4 substrate and deferasirox is a moderate inducer of CYP3A4. The manufacturer of temsirolimus recommends a dose increase if coadministered with a strong CYP3A4 inducer, but recommendations are not available for concomitant use of moderate CYP3A4 inducers. Coadministration of temsirolimus with rifampin, a strong CYP3A4/5 inducer, had no significant effect on the AUC or Cmax of temsirolimus, but decreased the sirolimus AUC and Cmax by 56% and 65%, respectively.
    Tinzaparin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Tobramycin: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including aminoglycosides, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and aminoglycosides concomitantly.
    Tolmetin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and deferasirox is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and deferasirox is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Trandolapril; Verapamil: (Moderate) Deferasirox inhibits CYP2C8. Verapamil is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and verapamil are not available, a similar interaction may occur. The dose of verapamil may need to be decreased if coadministered with deferasirox.
    Triamcinolone: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including corticosteroids.
    Valdecoxib: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Vancomycin: (Moderate) Acute renal failure has been reported during treatment with deferasirox. Coadministration of deferasirox with other potentially nephrotoxic drugs, including vancomycin, may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with deferasirox is necessary, due to a possibly unpredictable effect on vandetanib efficacy and toxicity. Deferasirox is a moderate inducer of CYP3A4. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively. In healthy volunteers, the concomitant administration of deferasirox and midazolam (a CYP3A4 substrate) decreased midazolam Cmax by 23% and AUC by 17%. In the clinical setting, this effect may be more pronounced.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and deferasirox; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and deferasirox is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Verapamil: (Moderate) Deferasirox inhibits CYP2C8. Verapamil is a substrate for CYP2C8. The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide Cmax by 62% and an increase in AUC 2.3-fold. Although specific drug interaction studies of deferasirox and verapamil are not available, a similar interaction may occur. The dose of verapamil may need to be decreased if coadministered with deferasirox.
    Vinorelbine: (Moderate) Caution is warranted when deferasirox is administered with vinorelbine, as there is a potential for the metabolism of vinorelbine to be affected, decreasing drug efficacy. Monitor patients receiving these drugs concurrently for clinical effects. Vinorelbine is a substrate for cytochrome P450 (CYP) 3A4, and deferasirox is a CYP3A4 inducer.
    Warfarin: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as deferasirox. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies with the use of deferasirox in pregnant women to inform about drug-associated risks. In animal studies, the administration of deferasirox resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses less than the recommended human doses. Deferasirox should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

    There are no data available on the presence of deferasirox or its metabolites in human milk, the effects on the breast-fed infant, or the effects on milk production. In animal studies, deferasirox and its metabolites were excreted in rat milk. Due to the potential for serious adverse reactions in the nursing infant from deferasirox, a decision should be made whether to discontinue breast-feeding or discontinue deferasirox, taking into account the mother's clinical need for deferasirox.

    MECHANISM OF ACTION

    Deferasirox is an orally active iron chelator that binds selectively to Fe3+. It is a tridentate ligand that requires two molecules of itself to form a stable complex with each iron atom. The efficiency of chelation of this compound is defined as the ratio of the amount of iron actually excreted to the amount of iron that could have been theoretically bound. In one clinical study, this capacity was calculated to be 20.5% in patients receiving a 20 mg/kg oral dose; one oral dose of deferasirox appears to be four to five times more effective than parenterally administered deferoxamine in promoting the excretion of chelatable iron from hepatocellular iron stores. This suggests that deferasirox chelates excess iron that enters the reticuloendothelial system as insoluble ferritin rather than iron required for enzyme activity. This may explain the lack of enzyme-related adverse effects seen with deferasirox treatment. At recommended doses, deferasirox is able to prevent net iron accumulation in most patients transfused with 12—15 ml packed red blood cells/kg/day.
     
    Deferasirox is highly selective for iron, while it does not appear to promote dietary absorption of iron. Although deferasirox has very low affinity for zinc and copper, there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. These transient decreases may, however, be clinically irrelevant. The iron complex of deferasirox appears to be inert and is excreted to a large extent in the feces, rather than being redistributed.

    PHARMACOKINETICS

    Deferasirox is administered orally. It is highly (about 99%) protein bound, binding almost exclusively to serum albumin. Only 5% is confined to the blood cells in humans. The volume of distribution at steady state (Vss) is 14.37 +/- 2.69 L in adults. The main metabolic pathway is glucuronidation, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Glucuronidation is carried out by UGT1A1 and to a lesser extent by UGT1A3. CYP450-catalyzed (oxidative) metabolism appears to be minor in humans (about 8%). No evidence for induction or inhibition of enzymes at therapeutic doses has been observed. Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the dose). The mean elimination half-life ranged from 8 to 16 hours following oral administration. In clinical evaluation, the total body iron elimination rate (range 7.7 to 28.5 mg iron/day) in patients treated with deferasirox was similar to values in patients receiving deferoxamine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, CYP2C19, UGT1A1, UGT1A3
    UGT1A1 is the primary enzyme involved in glucuronidation of deferasirox, and UGT1A3 is involved to a lesser extent. If a concomitantly administered drug undergoes selective metabolism by UGT1A1, competition for drug metabolism will exist, possibly resulting in the reduced clearance of deferasirox. During in vivo studies, deferasirox inhibited the actions of CYP1A2 and CYP2C8, and was an inducer of CYP3A4. In vitro studies showed inhibition of CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19.

    Oral Route

    Deferasirox is well absorbed and circulates in the plasma for several hours after once daily dosing. Maximum plasma concentration (Cmax) is reached in about 1.5 to 4 hours. After administration of a single dose, the Cmax and AUC of deferasirox increase in an approximate linear fashion under steady-state conditions. Deferasirox tablets for oral suspension have an absolute bioavailability of 70%, while the bioavailability of the tablet and sprinkle granules is 36% and 52% more, respectively. The bioavailability of deferasirox oral suspension is variably increased when taken with a meal; therefore, this formulation must be taken on an empty stomach 30 minutes before eating. Exposure (AUC) and Cmax of the oral tablets are decreased by 11% and 16%, respectively, when administered with a low-fat meal and are increased by 18% and 29%, respectively, when administered with a high-fat meal. The AUC and Cmax of the granule formulation after a low-fat meal or soft foods were similar to that under fasting conditions. When administered with a high-fat meal, the AUC of the granules increased by 18% with no changes in Cmax compared to fasting condition. The oral tablets and granules may be administered either on an empty stomach or with a light meal (less than 250 calories and less than 7% fat). After multiple dosing, exposure to deferasirox increases by an accumulation factor of 1.3 to 2.3.