Deferasirox (Monograph)

Brand name: Exjade
Drug class: Heavy Metal Antagonists
ATC class: V03AC03
VA class: AD300
Chemical name: 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]-benzoic acid
Molecular formula: C₂₁H₁₅N₃O₄
CAS number: 201530-41-8

Medically reviewed by Drugs.com on Jan 23, 2023. Written by ASHP.

Introduction

Heavy metal antagonist; chelating agent for iron.

Uses for Deferasirox

Chronic Iron Overload

Treatment of chronic iron overload resulting from multiple transfusions in patients with thalassemia or other chronic anemias (designated an orphan drug by FDA for this use).

Current indication based on effects on markers of iron overload (e.g., liver iron concentration); long-term safety and clinical benefit, including efficacy in prolonging survival or reducing cardiac complications associated with chronic iron overload, remain to be established.

Decision to initiate deferasirox therapy should be individualized; weigh anticipated clinical benefits and potential risks for the individual patient, taking life expectancy and presence of comorbidities into consideration (see Warnings under Cautions).

If patient requires iron chelation therapy, initiate therapy when there is evidence of chronic iron overload (e.g., following transfusion of approximately 100 mL/kg of packed RBCs [approximately 20 units in a 40-kg patient] and a serum ferritin concentration consistently >1000 mcg/L).

In patients with MDS and chronic iron overload, National Comprehensive Cancer Network (NCCN) guidelines state that deferasirox may be considered in low- to intermediate-1-risk patients receiving >20 RBC transfusions for whom such transfusions are expected to be ongoing. NCCN recommends that therapy be considered in patients with serum ferritin concentrations >2500 mcg/L with reduction of these concentrations to <1000 mcg/L as the goal of therapy.

Safety and efficacy of deferasirox when administered concomitantly with other iron chelation therapy not established.

Deferasirox Dosage and Administration

General

Determine baseline serum ferritin and iron concentrations prior to initiation of therapy. Risk of toxicity may be increased when deferasirox is administered to patients with low iron burden or only slightly elevated serum ferritin concentrations.

Restricted Distribution Program

• Patients must obtain deferasirox through the Exjade Patient Assistance and Support Services (EPASS) program. The clinician and patient must jointly complete a prescription and reimbursement application. Following verification of prescription information and review of healthcare benefits, an authorized specialty pharmacy ships deferasirox directly to the patient or the clinician’s office. To enroll in this program, call 888-903-7277 or visit [Web].

Administration

Oral Administration

Administer orally once daily on an empty stomach (≥30 minutes before eating), preferably at the same time each day.

Deferasirox tablets for oral suspension should not be chewed or swallowed whole.

Completely disperse tablets for oral suspension by stirring in water, orange juice, or apple juice.

Disperse doses of <1 g in 3.5 oz and doses of ≥1 g in 7 oz of liquid.

Use the suspension immediately following preparation.

Following administration, resuspend any residue in a small volume of liquid and swallow.

Dosage

Pediatric Patients

Chronic Iron Overload

Oral

Children ≥2 years of age: Initially, 20 mg/kg daily, rounded to the nearest whole-tablet dosage strength.

Adjust dosage every 3–6 months as needed based on trends in serum ferritin concentrations (monitor monthly).

Adjust dosage in increments of 5 or 10 mg/kg daily according to the patient’s clinical response and therapeutic goals.

In pediatric patients not adequately controlled with dosages of 30 mg/kg daily (e.g., serum ferritin concentrations consistently >2500 mcg/L and not showing a downward trend over time), consider dosages up to 40 mg/kg daily. Dosages >40 mg/kg daily not recommended.

Consider temporarily interrupting therapy if serum ferritin concentrations are consistently <500 mcg/L.

Dosage Modification for Adverse Renal Effects

Oral

Interrupt therapy if a progressive increase in S_cr beyond the age-appropriate ULN occurs. (See Renal Effects under Cautions.) Once S_cr returns to within normal limits, reinitiate therapy at a lower dosage followed by gradual dosage escalation if clinical benefit is expected to outweigh potential risks.

Reduce dosage by 10 mg/kg daily if S_cr at 2 consecutive visits increases to a level exceeding the age-appropriate ULN.

Dosage Modification for Adverse Hepatic Effects

Oral

Consider dosage adjustment or interruption of therapy in patients with severe, persistent, progressive, or unexplained elevations of liver function test results. (See Hepatic Effects under Cautions.)

Dosage Modification for Concomitant Use of Cholestyramine or UGT Inducers

Oral

If concomitant use of cholestyramine or potent UGT inducers (e.g., phenobarbital, phenytoin, rifampin, ritonavir) cannot be avoided (see Interactions), consider increasing initial deferasirox dosage to 30 mg/kg daily. Make further dosage adjustments according to patient’s clinical response and serum ferritin concentrations.

Adults

Chronic Iron Overload

Oral

Initially, 20 mg/kg daily, rounded to the nearest whole-tablet dosage strength.

Adjust dosage every 3–6 months as needed based on trends in serum ferritin concentrations (monitor monthly).

Adjust dosage in increments of 5 or 10 mg/kg daily according to the patient’s clinical response and therapeutic goals.

In adults not adequately controlled with dosages of 30 mg/kg daily (e.g., serum ferritin concentrations consistently >2500 mcg/L and not showing a downward trend over time), consider dosages up to 40 mg/kg daily. Dosages >40 mg/kg daily not recommended.

Consider temporarily interrupting therapy if serum ferritin concentrations are consistently <500 mcg/L.

Dosage Modification for Adverse Renal Effects

Oral

Interrupt therapy if a progressive increase in S_cr beyond the ULN occurs. (See Renal Effects under Cautions.) Once S_cr returns to within normal limits, reinitiate therapy at a lower dosage followed by gradual dosage escalation if clinical benefit is expected to outweigh potential risks.

Reduce dosage by 10 mg/kg daily if S_cr at 2 consecutive visits increases to a level >33% above the average pretreatment value and the increase cannot be attributed to other causes.

Dosage Modification for Adverse Hepatic Effects

Oral

Consider dosage adjustment or interruption of therapy in patients with severe, persistent, progressive, or unexplained elevations of liver function test results. (See Hepatic Effects under Cautions.)

Dosage Modification for Concomitant Use of Cholestyramine or UGT Inducers

Oral

If concomitant use of cholestyramine or potent UGT inducers (e.g., phenobarbital, phenytoin, rifampin, ritonavir) cannot be avoided (see Interactions), consider increasing initial deferasirox dosage to 30 mg/kg daily. Make further dosage adjustments according to patient’s clinical response and serum ferritin concentrations.

Prescribing Limits

Pediatric Patients

Chronic Iron Overload

Oral

Children ≥2 years of age: Maximum 40 mg/kg daily.

Adults

Chronic Iron Overload

Oral

Maximum 40 mg/kg daily.

Special Populations

Hepatic Impairment

Not studied in patients with preexisting hepatic impairment. No specific dosage recommendations for these patients. Has been initiated at usual recommended dosages in patients with baseline transaminase concentrations up to 5 times the ULN. (See Hepatic Effects under Cautions.)

Renal Impairment

Not studied in patients with preexisting renal impairment. (See Contraindications and also Renal Effects under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

Cautions for Deferasirox

Contraindications

• Cl_cr <40 mL/minute or S_cr >2 times the age-appropriate ULN.

• Poor performance status and high-risk MDS or advanced malignancy.

• Platelet counts <50,000/mm³.

• Known hypersensitivity to deferasirox or any ingredient in the formulation.

Warnings/Precautions

Warnings

Renal Effects

Renal effects including acute renal failure (sometimes fatal or requiring dialysis), dose-related increases in S_cr, glomerulonephritis, interstitial nephritis, and renal tubulopathy reported. Most fatalities occurred in patients with multiple comorbid conditions and in advanced stages of hematologic disease. Most cases of renal tubulopathy occurred in children and adolescents with β-thalassemia and serum ferritin concentrations <1500 mcg/L.

Monitor S_cr and/or Cl_cr, particularly in geriatric patients, individuals at increased risk of complications, those with preexisting renal conditions or comorbid conditions, and/or those receiving drugs that may impair renal function. Closely monitor renal function of patients with Cl_cr between 40 and <60 mL/minute, particularly in those with additional risk factors that may further impair renal function (e.g., concomitant drugs, dehydration, severe infection). Assess S_cr and/or Cl_cr at 2 consecutive visits before initiation of therapy to establish a reliable pretreatment baseline; monitor S_cr and/or Cl_cr monthly thereafter. Monitor S_cr and/or Cl_cr of patients with underlying renal impairment or risk factors for renal impairment weekly during the first month following initiation or modification of therapy; monitor monthly thereafter.

Consider dosage reduction or interruption or discontinuance of therapy if increased S_cr reported. (See Dosage Modification for Adverse Renal Effects under Dosage and Administration.)

Intermittent proteinuria (i.e., urinary protein to creatinine ratio >0.6 mg/mg) reported. Monitoring for proteinuria recommended monthly.

Hepatic Effects

Hepatic abnormalities, including hepatic failure (sometimes fatal), drug-induced hepatitis, hepatic dysfunction, and increased serum transaminases, reported. Most cases of hepatic failure occurred in individuals >55 years of age and in those with serious comorbid conditions (e.g., hepatic cirrhosis, multiorgan failure).

Closely monitor liver function tests (serum transaminase and bilirubin concentrations) during treatment; consider dosage reduction or interruption of therapy if severe, persistent, progressive, or unexplained elevations occur. Assess serum transaminase and bilirubin concentrations before initiation of therapy, every 2 weeks during the first month of treatment, and monthly thereafter.

GI Effects

GI hemorrhage (sometimes fatal) reported. Most fatalities occurred in geriatric patients with advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration, and hemorrhage also reported in patients, including children and adolescents.

Be alert for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy. Promptly initiate additional evaluation and treatment if a serious adverse GI effect is suspected.

Use deferasirox and drugs with ulcerogenic or hemorrhagic potential (e.g., anticoagulants, oral bisphosphonates, corticosteroids, NSAIAs) concomitantly with caution. (See Interactions.)

Cytopenias

Cytopenias (sometimes fatal), including agranulocytosis, neutropenia, and thrombocytopenia, reported; causal relationship to deferasirox is unknown.

Most patients with cytopenias had preexisting hematologic disorders frequently associated with bone marrow failure.

Monitor blood counts at regular (weekly) intervals according to the standard of care for patients with hematologic disorders.

Consider interruption of therapy in patients with unexplained cytopenia. Resumption of therapy may be considered once cause of cytopenia determined.

Comorbid Conditions

Serious adverse reactions (sometimes fatal) reported, particularly in patients with advanced age, complications from underlying conditions, or very advanced disease. Fatalities generally occurred within 6 months of therapy initiation and involved worsening of the underlying condition. Possibility that deferasirox contributed to these deaths cannot be ruled out.

Ocular and Otic Effects

Ocular toxicity, including lens opacities, cataracts, increased IOP, and retinal disorders, reported rarely.

Ototoxicity, including high frequency hearing loss and decreased hearing, reported rarely.

Ophthalmologic examination (e.g., slit-lamp examinations, funduscopy) and auditory testing recommended prior to initiation of therapy and every 12 months thereafter.

Consider dosage reduction or interruption of therapy if ocular and/or otic effects occur.

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis and angioedema, reported.

Serious sensitivity reactions usually occur within the first month of therapy.

If reactions are severe, discontinue the drug and institute appropriate medical therapy.

General Precautions

Dermatologic Effects

Rashes, including erythema multiforme, reported.

Rash appears to be dose related.

For mild to moderate rashes, continue therapy without dosage adjustment; rashes of this type frequently resolve spontaneously.

In severe cases, temporarily interrupt therapy. Reinitiate deferasirox at a lower dosage and gradually increase the dosage following resolution of the rash. Concomitant therapy with a short course of oral corticosteroid treatment is recommended.

Adequate Patient Monitoring

Close patient monitoring required.

Measure S_cr and/or Cl_cr prior to initiation of therapy and monthly thereafter. In patients with underlying renal impairment or risk factors for renal impairment, monitor S_cr and/or Cl_cr weekly for the first month following initiation or modification of therapy, then monthly thereafter. (See Renal Effects under Cautions.)

Measure serum transaminase and bilirubin concentrations prior to initiation of therapy, every 2 weeks during the first month, and monthly thereafter. (See Hepatic Effects under Cautions.)

Determine serum ferritin and iron concentrations prior to initiation of therapy. Monitor serum ferritin concentrations monthly to assess response to therapy.

Monitor for proteinuria monthly. (See Renal Effects under Cautions.)

Monitor blood counts at regular (weekly) intervals according to the standard of care for patients with hematologic disorders. (See Cytopenias under Cautions.)

Perform ophthalmologic examination (e.g., slit-lamp examinations, funduscopy) and auditory testing prior to initiation of therapy and every 12 months thereafter. (See Ocular and Otic Effects under Cautions.)

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk in rats; not known whether the drug is distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <2 years of age.

Systemic exposure of deferasirox in children 2 to <6 years of age is lower than that in adults. (See Absorption: Special Populations, under Pharmacokinetics.) However, safety and efficacy profile in pediatric patients is similar to that in adults; effect of the drug is comparable between younger (2 to <6 years of age) and older (6–16 years of age) pediatric patients.

Geriatric Use

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy. Monitor geriatric patients closely for early signs and/or symptoms of adverse reactions that may require dosage adjustment.

Higher incidence of adverse reactions occurred with deferasirox therapy in geriatric patients ≥65 years of age than in younger adults. Majority of these patients had MDS.

Hepatic Impairment

Safety and efficacy in patients with hepatic impairment not studied specifically to date. (See Hepatic Effects under Cautions and also see Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Safety and efficacy in patients with renal impairment not studied specifically to date. (See Contraindications and also Renal Effects under Cautions and see Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Diarrhea, vomiting, nausea, abdominal pain, rash, increases in S_cr.

Interactions for Deferasirox

Metabolized principally by UGT1A1 and to a lesser extent by UGT1A3; CYP isoenzymes appear to play minor role.

Inhibits CYP isoenzymes 3A4, 2C8, 1A2, 2A6, 2D6, and 2C19 in vitro. Clinical importance of inhibition of CYP isoenzymes 1A2, 2A6, 2D6, and 2C19 unknown.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Potential pharmacokinetic interaction. Deferasirox inhibits CYP3A4 activity in vitro; however, one study in healthy individuals receiving midazolam and deferasirox concomitantly suggests that deferasirox also weakly induces CYP3A4 activity and thereby may decrease plasma concentrations of drugs metabolized by CYP3A4. Use with caution.

CYP2C8 substrates: Potential pharmacokinetic interaction. Deferasirox inhibits CYP2C8 activity; may increase plasma concentrations of drugs metabolized by CYP2C8. Use with caution.

Drugs Affecting Uridine 5’-Diphosphate Glucuronosyltransferase (UGT) Enzymes

Potent UGT inducers: Potential pharmacokinetic interaction (decreased AUC of deferasirox, possibility of reduced efficacy). Avoid concomitant use of deferasirox and potent UGT inducers. If concomitant use cannot be avoided, consider increasing the initial dosage of deferasirox to 30 mg/kg daily. Monitor serum ferritin concentrations and clinical response carefully to determine need for further dosage adjustment.

Drugs with Ulcerogenic or Hemorrhagic Effects

Potential pharmacologic interaction (risk of GI ulceration or bleeding). Use concomitantly with caution.

Specific Drugs

Deferasirox Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak plasma concentrations usually attained within 1.5–4 hours.

Absolute oral bioavailability is 70%.

Food

Food variably increases bioavailability of deferasirox.

Special Populations

Systemic exposure to deferasirox is lower in children and adolescents than in adults. In children 2 to <6 years of age, systemic exposure about 50% lower than in adults.

Pharmacokinetics not specifically studied in geriatric patients ≥65 years of age.

Distribution

Extent

5% distributed into RBCs.

Distributed into milk in rats; not known whether the drug is distributed into human milk.

Plasma Protein Binding

Approximately 99% (mainly albumin).

Elimination

Metabolism

Metabolized principally in the liver via glucuronidation by UGT1A1 and to a lesser extent by UGT1A3.

Deconjugation of glucuronide metabolites and subsequent enterohepatic recirculation are likely to occur.

Minimally metabolized (8%) by oxidative CYP enzymes.

Elimination Route

Deferasirox and its metabolites eliminated principally in feces via bile (84%) and to a lesser extent in urine (8%).

Half-life

7–16 hours.

Special Populations

Principally eliminated via glucuronidation in the liver. No data currently available in patients with hepatic impairment. However, no alteration of pharmacokinetics reported in patients with baseline liver transaminase concentrations up to 5 times the ULN.

Minimally excreted via the kidneys. No data currently available in patients with renal impairment.

No data currently available in geriatric patients ≥65 years of age.

Clearance in females is moderately lower (i.e., 17.5%) than that in males.

Stability

Storage

Oral

Tablets for Oral Suspension

25°C (may be exposed to 15–30°C).

Protect from moisture.

Actions

• Chelates iron by binding ferric ions and forming a stable, soluble complex.

• A tridentate ligand with high binding affinity for iron in a 2:1 ratio (2 ligand molecules binding 1 iron atom).

• At dosages of 10, 20, and 40 mg/kg daily, deferasirox is capable of sequestering 0.1, 0.3, and 0.4 mg of iron, respectively, per kg of body weight daily.

• Demonstrates 2–5 times higher potency than deferoxamine in mobilizing and excreting tissue iron.

• Reduces liver iron burden; preliminary data suggest that deferasirox also mobilizes cardiac iron stores.

• Chelates zinc and copper, but with very low binding affinity. Decreased concentrations of zinc and copper reported in humans during therapy; however, clinical importance of this effect unknown.

• Deferasirox has potential to chelate with aluminum, but has lower binding affinity for aluminum than for iron.

Advice to Patients

• Advise the patient to take the drug once daily on an empty stomach ≥30 minutes before eating, preferably at the same time every day.

• Advise the patient to avoid chewing or swallowing deferasirox tablets whole; completely disperse the tablets in water, orange juice, or apple juice, and drink the mixture immediately after mixing. Advise the patient to disperse any residue in a small amount of liquid and swallow.

• Potential for drug to cause dizziness; use caution when driving or operating machinery until effects on individual are known.

• Importance of discontinuing the drug and informing clinician if a severe hypersensitivity reaction occurs.

• Risk of renal effects (e.g., renal failure). Importance of regular monitoring of renal function.

• Risk of hepatic effects (e.g., hepatitis, hepatic failure). Importance of regular monitoring of liver function.

• Risk of GI effects (e.g., diarrhea, vomiting, nausea, abdominal pain). Importance of maintaining adequate hydration if diarrhea and/or vomiting occurs.

• Risk of GI ulcers or bleeding when deferasirox is used concomitantly with drugs that have ulcerogenic or hemorrhagic potential (e.g., anticoagulants, oral bisphosphonates, corticosteroids, NSAIAs).

• Risk of blood disorders. Importance of regular monitoring of blood cell counts.

• Risk of auditory and ocular disturbances. Importance of regular auditory testing and ophthalmologic examinations.

• Risk of rash. Advise patient that rashes may resolve spontaneously, but if symptoms are severe, dosage reduction or temporary interruption of therapy may be necessary.

• Advise patient not to take aluminum-containing antacids simultaneously with deferasirox.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., aluminum-containing antacids) and herbal supplements, as well as any concomitant illnesses (e.g., history of kidney or liver disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of deferasirox is restricted. (See General under Dosage and Administration.)

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