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DEFERASIROX

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Deferasirox is an iron chelating agent.

Specific Substances

    1) Exjade(R)
    2) ICL670
    3) 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-y1]-benzoic acid
    4) CAS 201530-41-8
    1.2.1) MOLECULAR FORMULA
    1) C21H15N3O4 (Prod Info EXJADE(R) tablets for oral suspension, 2005)

Available Forms Sources

    A) FORMS
    1) Deferasirox is available as 125 mg, 250 mg, and 500 mg oral tablets for suspension, and 90 mg, 180 mg, and 360 mg tablets(Prod Info EXJADE(R) oral tablets, oral suspension, 2015).
    B) USES
    1) Deferasirox is approved for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years and older. It is also indicated for the treatment of chronic iron overload in adults and children 10 years or older with non-transfusion-dependent thalassemia syndromes who have liver iron concentrations of at least 5 mg Fe/g dry weight and serum ferritin levels greater than 300 mcg/L (Prod Info EXJADE(R) oral tablets, oral suspension, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Deferasirox is used for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years or older. It is also used for the treatment of chronic iron overload in adults and children 10 years or older with non-transfusion-dependent thalassemia syndromes who have liver iron concentrations of at least 5 mg iron/g dry weight and serum ferritin levels greater than 300 mcg/L.
    B) PHARMACOLOGY: Deferasirox, a tridentate ligand, is an orally active chelating agent that is selective for iron (Fe(3+)) with a high affinity binding ratio of 2:1. It has very low affinity for zinc and copper, although variable decreases in serum concentrations of zinc and copper have been observed after administration of deferasirox. At 10, 20, and 40 mg/kg/day, deferasirox induces a mean net iron excretion of 0.119, 0.329, and 0.445 mg Fe/kg body weight/day, respectively.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects reported with the use of deferasirox included the following: increased serum creatinine, proteinuria, acute renal failure, elevated liver enzymes, drug-induced hepatitis, agranulocytosis, neutropenia, worsening anemia, thrombocytopenia, rash, urticaria, erythema multiforme, Stevens-Johnson syndrome, abdominal pain, nausea, vomiting, diarrhea, gastrointestinal hemorrhage, fever, back and joint pain, headache, and fatigue.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events. Hepatitis was reported in one patient who received 2 to 3 times the prescribed dose of deferasirox over a period of several weeks. In iron overloaded beta-thalassemic patients, single doses up to 80 mg/kg have been tolerated with nausea and diarrhea noted. Single doses up to 40 mg/kg were tolerated in healthy volunteers.
    0.2.20) REPRODUCTIVE
    A) Animal studies have demonstrated no evidence of impaired fertility or harm to the fetus due to deferasirox. No human studies of pregnancy outcomes after exposure to deferasirox have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy. It is not known whether deferasirox is excreted in human milk. Deferasirox is in pregnancy category B.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic activity of deferasirox in humans.

Laboratory Monitoring

    A) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe anaphylaxis should be treated with antihistamines, corticosteroids, and epinephrine. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) MYELOSUPPRESSION
    1) Severe neutropenia: filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia, bleeding.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding (approximately 99%) and large volume of distribution (14.37 +/- 2.69 L).
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected deferasirox overdose, the possibility of multidrug involvement should be considered.
    K) PHARMACOKINETICS
    1) Tmax: About 1.5 to 4 hours. Absolute bioavailability: 70%. Protein binding: Approximately 99% is protein bound, almost exclusively to serum albumin. Vd: 14.37 +/- 2.69 L.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: Hepatitis was reported in one patient who received 2 to 3 times the prescribed dose of deferasirox over a period of several weeks. In iron overloaded beta-thalassemic patients, single doses up to 80 mg/kg have been tolerated with nausea and diarrhea noted. Single doses up to 40 mg/kg were tolerated in healthy volunteers.
    B) THERAPEUTIC DOSE: Varies by indication; 10 mg/kg/day or 20 mg/kg/day; up to 40 mg/kg with lack of control.

Clinical Effects

Summary Of Exposure

    A) USES: Deferasirox is used for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years or older. It is also used for the treatment of chronic iron overload in adults and children 10 years or older with non-transfusion-dependent thalassemia syndromes who have liver iron concentrations of at least 5 mg iron/g dry weight and serum ferritin levels greater than 300 mcg/L.
    B) PHARMACOLOGY: Deferasirox, a tridentate ligand, is an orally active chelating agent that is selective for iron (Fe(3+)) with a high affinity binding ratio of 2:1. It has very low affinity for zinc and copper, although variable decreases in serum concentrations of zinc and copper have been observed after administration of deferasirox. At 10, 20, and 40 mg/kg/day, deferasirox induces a mean net iron excretion of 0.119, 0.329, and 0.445 mg Fe/kg body weight/day, respectively.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects reported with the use of deferasirox included the following: increased serum creatinine, proteinuria, acute renal failure, elevated liver enzymes, drug-induced hepatitis, agranulocytosis, neutropenia, worsening anemia, thrombocytopenia, rash, urticaria, erythema multiforme, Stevens-Johnson syndrome, abdominal pain, nausea, vomiting, diarrhea, gastrointestinal hemorrhage, fever, back and joint pain, headache, and fatigue.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events. Hepatitis was reported in one patient who received 2 to 3 times the prescribed dose of deferasirox over a period of several weeks. In iron overloaded beta-thalassemic patients, single doses up to 80 mg/kg have been tolerated with nausea and diarrhea noted. Single doses up to 40 mg/kg were tolerated in healthy volunteers.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Pyrexia occurred in 18.9% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 23.8% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).
    2) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including 27 cases of pyrexia (U.S.Food and Drug Administration, 2007).

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) EAR INFECTION
    a) Ear infection occurred in 5.4% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 2.4% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including 10 cases of dyspnea (U.S.Food and Drug Administration, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 15.9% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 20.3% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue occurred in 6.1% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 4.8% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including 7 cases of asthenia (U.S.Food and Drug Administration, 2007).
    D) DISORDER OF BRAIN
    1) WITH THERAPEUTIC USE
    a) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including cases of encephalopathy (U.S.Food and Drug Administration, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Dose-related abdominal pain occurred in 21% (63 of 296) of patients with transfusional hemosiderosis and beta-thalassemia who were treated with deferasirox, compared with 14% (41 of 290) of patients treated with deferoxamine in a clinical trial (Prod Info EXJADE(R) oral suspension tablets, 2013b).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Dose-related diarrhea occurred in 12% (35 of 296) of patients with transfusional hemosiderosis and beta-thalassemia who were treated with deferasirox, compared with 7% (21 of 290) of patients treated with deferoxamine in a clinical trial (Prod Info EXJADE(R) oral suspension tablets, 2013b).
    b) Diarrhea was dose-related in clinical trials (Prod Info EXJADE(R) oral suspension, 2007).
    2) WITH POISONING/EXPOSURE
    a) Nausea and diarrhea were reported in patients with beta-thalassemia who received single deferasirox doses up to 80 mg/kg/day (Prod Info EXJADE(R) oral suspension, 2007).
    C) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Dose-related nausea occurred in 11% (31 of 296) of patients with transfusional hemosiderosis and beta-thalassemia who were treated with deferasirox, compared with 5% (14 of 290) of patients treated with deferoxamine in a clinical trial (Prod Info EXJADE(R) oral suspension tablets, 2013b).
    b) Vomiting occurred in 10.1% (n=30/296) of patients with beta-thalassemia who were treated with deferasirox, compared to 9.7% (n=28/290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).
    c) Nausea and vomiting were dose-related in clinical trials (Prod Info EXJADE(R) oral suspension, 2007).
    2) WITH POISONING/EXPOSURE
    a) Nausea and diarrhea were reported in patients with beta-thalassemia who received single deferasirox doses up to 80 mg/kg/day (Prod Info EXJADE(R) oral suspension, 2007).
    D) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal hemorrhage has been reported during postmarketing surveillance of deferasirox. Upper gastrointestinal hemorrhage and ulceration have been reported in patients, including children and adolescents, receiving deferasirox (Prod Info EXJADE(R) oral suspension tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Increases in alanine aminotransferase (ALT) to more than 5 times the upper limit of normal (ULN) on at least 2 post-baseline visits occurred in 8.4% of patients (n=296) with beta-thalassemia who were treated with deferasirox, compared to 2.4% of patients (n=290) treated with deferoxamine in a randomized, controlled, clinical trial. Increases in ALT to over 5 times the ULN on at least 2 consecutive post-baseline visits occurred in 5.7% of patients in the deferasirox arm versus 1.7% of patients in the deferoxamine arm. Two patients (n=296) discontinued treatment due to increased ALT less than 5 times the ULN (Prod Info EXJADE(R) oral suspension tablets, 2013b).
    b) Increases in transaminases did not appear to be dose-related in clinical trials (Prod Info EXJADE(R) oral suspension, 2007).
    c) An 18-year-old man with beta-thalassemic major developed coma, Fanconi syndrome, elevated liver enzymes, and thrombocytopenia after receiving deferasirox (initial daily dose: 1000 mg [28.9 mg/kg/day] and titrated to 1375 mg [35.3 mg/kg/day]) for 27 months. He gradually recovered following the discontinuation of deferasirox and supportive therapy (Wei et al, 2011).
    d) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including 17 cases of increased ALT levels (U.S.Food and Drug Administration, 2007).
    B) CHOLECYSTITIS
    1) WITH THERAPEUTIC USE
    a) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including cases of cholecystitis (U.S.Food and Drug Administration, 2007).
    C) DRUG-INDUCED HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Two patients (n=296) with beta-thalassemia who were treated with deferasirox developed drug-induced hepatitis in a randomized, controlled, clinical trial. Both patients discontinued treatment (Prod Info EXJADE(R) oral suspension tablets, 2013b).
    b) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including cases of subclinical and clinical hepatitis (U.S.Food and Drug Administration, 2007).
    2) WITH POISONING/EXPOSURE
    a) Hepatitis occurred in one patient who received deferasirox at 2 to 3 times the prescribed dose for several weeks. Following dose withdrawal, the patient recovered without sequelae (Prod Info EXJADE(R) oral suspension, 2007).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: In one study, tubular and glomerular function of 10 children (mean age: 12.4 +/- 3.9 years) enrolled in a regular blood transfusion program for iron overload were examined before and 17.2 +/- 8.9 months after the initiation of deferasirox therapy (dose: 24.8 +/- 9.6 mg/kg/day; range 10 to 36 mg/kg). All children had normal glomerular function rate (GFR) (125 +/- 15 mL/min/1.73 m(2); range: 103 to 155) and normal tubular function before deferasirox treatment. A decrease in GFR (less than 100 mL/min/1.73 m(2)) was observed in 7 patients after deferasirox treatment. One patient had a GFR of less than 80 mL/min/1.73 m(2). At least one sign of proximal tubular dysfunction was observed in 9 patients. Hypophosphatemia (PO4 less than 0.75 mmol/L; normal for age 1.1 to 1.9) with a decrease in tubular maximal phosphate reabsorption corrected by GFR (TmP/GFR) (0.45 and 0.62 mmol/L, respectively) was observed in 2 patients. Glycosuria, increased urinary beta2-microglobulin concentration (beta2 M), and hypercalciuria were observed in 3, 5, and 3 patients, respectively. Global proximal tubular dysfunction (hypophosphatemia with reduced TmP/GFR, hypouricemia, increased beta2 M, and combined hypercalciuria plus glycosuria in one) was noted in 2 patients (Dubourg et al, 2012).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure has been reported following post-marketing use of deferasirox. In some cases, fatalities occurred, primarily in patients with multiple co-morbid conditions and who had advanced hematological disorders (Prod Info EXJADE(R) oral suspension, 2007).
    b) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including 7 cases of acute renal failure. The time to onset of acute renal failure was 15 days (range, 5 to 58 days) after starting deferasirox. Two patients died and 2 patients required hemodialysis and 4 patients improved or recovered (U.S.Food and Drug Administration, 2007).
    C) FANCONI SYNDROME
    1) WITH THERAPEUTIC USE
    a) Renal tubular damage, including Fanconi syndrome, has been reported with deferasirox therapy. Incidents were most common in children and adolescents with beta-thalassemia and serum ferritin levels greater than 1500 mcg/L (Prod Info EXJADE(R) oral suspension tablets, 2013).
    b) CASE SERIES: Eleven patients (age range, 6 to 78 years; median 18 years) developed de Toni-Debre-Fanconi syndrome, a proximal tubular dysfunction, after receiving oral iron chelator deferasirox (dose range, 20 to 38 mg/kg). Metabolic acidosis was reported in 8 patients. Most of the patients had features of de Toni-Debre-Fanconi syndrome, such as hypophosphatemia (n=10), hypokalemia (n=9), hypouricemia (n=7), glucosuria (with normal blood glucose concentration) (n=9), generalized hyperaminoaciduria (n=4), and mild proteinuria. Following supportive care, renal dysfunction and metabolic acidosis resolved in all patients within 3 months. Metabolic acidosis developed again in 2 patients after receiving deferasirox rechallenge (Dell'orto et al, 2013).
    c) CASE REPORT: An 18-year-old man with beta-thalassemic major who was receiving subcutaneous deferoxamine injections and oral deferiprone, developed Fanconi syndrome, presenting as hypophosphatemia, hypocalcemia, hyponatremia, hypokalemia, metabolic acidosis, prerenal azotemia, and low serum uric acid concentrations, 27 months after his iron chelation therapy was changed to deferasirox (initial daily dose: 1000 mg [28.9 mg/kg/day] and titrated to 1375 mg [35.3 mg/kg/day]) because of poor compliance (routine serum ferritin concentration range: 1059 to 6030 ng/mL; normal range: 10 to 291 ng/mL). He was admitted to the hospital 5 times for a variety of conditions, including twice for coma, elevated liver enzymes, and thrombocytopenia. He gradually recovered following the discontinuation of deferasirox and supportive therapy (Wei et al, 2011).
    D) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) Increases in serum creatinine were reported in 11% of patients (33 of 296) with transfusional hemosiderosis and beta-thalassemia who were treated with deferasirox, compared with 0% of patients (0 of 290) treated with deferoxamine in a clinical trial. Increases in serum creatinine, of more than 33% over baseline (but still within the ULN on at least 2 consecutive post-baseline visits) were reported in 38% of patients (113 of 296) with transfusional hemosiderosis and beta-thalassemia who were treated with deferasirox, compared with 14% of patients (41 of 290) treated with deferoxamine. Increases in serum creatinine more than 33% over baseline and above the ULN on at least 2 consecutive post-baseline visits occurred in 2% (7 of 296) of patients in the deferasirox arm vs 0% (1 of 290) of patients in the deferoxamine arm. Patients treated with deferasirox had a dose-dependent increase in serum creatinine; however, most serum creatinine levels remained within the normal range (Prod Info EXJADE(R) oral suspension tablets, 2013b).
    b) Increases in serum creatinine appeared to be dose-related in clinical trials (Prod Info EXJADE(R) oral suspension, 2007).
    E) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 milligrams/kilogram) occurred in 18.6% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 7.2% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial. Clinical significance of proteinuria is unknown (Prod Info EXJADE(R) oral suspension tablets, 2013).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Eleven patients (age range, 6 to 78 years; median 18 years) developed de Toni-Debre-Fanconi syndrome, a proximal tubular dysfunction, after receiving oral iron chelator deferasirox (dose range, 20 to 38 mg/kg). Metabolic acidosis was reported in 8 patients. Most of the patients had features of de Toni-Debre-Fanconi syndrome, such as hypophosphatemia (n=10), hypokalemia (n=9), hypouricemia (n=7), glucosuria (with normal blood glucose concentration) (n=9), generalized hyperaminoaciduria (n=4), and mild proteinuria. Following supportive care, renal dysfunction and metabolic acidosis resolved in all patients within 3 months. Metabolic acidosis developed again in 2 patients after receiving deferasirox rechallenge (Dell'orto et al, 2013).
    b) CASE REPORT: A 17-year-old girl with beta-thalassemia major and on chronic transfusion therapy, who was receiving oral deferiprone and IV deferoxamine, presented with a 2-day history of nausea, vomiting, and mild abdominal pain 8 months after the parenteral deferoxamine was changed to oral deferasirox (initially 20 mg/kg and then 30 mg/kg) because of poor adherence. Laboratory results revealed isolated hyperchloremic metabolic acidosis (bicarbonate 12.9 mM, sodium 137 mM, chloride 111 mM, potassium 3.6 mM). Her condition gradually improved after the discontinuation of deferasirox and sodium bicarbonate therapy. Based on the Naranjo adverse drug reaction scale, the likelihood that deferasirox was responsible for hyperchloremic metabolic acidosis was probable (Dell'orto et al, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis, neutropenia, worsening anemia, and thrombocytopenia, including fatalities, have been reported with deferasirox therapy. Patients with preexisting hematological disorders are at increased risk (Prod Info EXJADE(R) oral suspension tablets, 2013).
    b) CASE REPORT: An 18-year-old man with beta-thalassemic major developed coma, Fanconi syndrome, elevated liver enzymes, and thrombocytopenia after receiving deferasirox (initial daily dose: 1000 mg [28.9 mg/kg/day] and titrated to 1375 mg [35.3 mg/kg/day]) for 27 months. He gradually recovered following the discontinuation of deferasirox and supportive therapy (Wei et al, 2011).
    c) From November 2005 to June 2006, the US Food and Drug Administration received 115 reports of suspected adverse reactions (resulting in 108 serious outcomes, including 17 deaths and 74 hospitalizations) in patients (age range, 6 to 91 years) receiving deferasirox, including 7 cases of sickle-cell anemia with crisis, 9 cases of decreased hematocrit levels, 18 cases of decreased hemoglobin levels, and 11 cases of decreased platelet counts (U.S.Food and Drug Administration, 2007).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash occurred in 8% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 3.1% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension tablets, 2013b).
    b) Skin rash was dose-related in clinical trials (Prod Info EXJADE(R) oral suspension, 2007).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria occurred in 3.7% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 5.9% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome was been reported during postmarketing surveillance of deferasirox (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    D) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Erythema multiforme has been reported with deferasirox therapy (Prod Info EXJADE(R) oral suspension tablets, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain occurred in 5.7% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 11% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia occurred in 7.4% (n=296) of patients with beta-thalassemia who were treated with deferasirox, compared to 4.8% (n=290) of patients treated with deferoxamine in a randomized, controlled, clinical trial (Prod Info EXJADE(R) oral suspension, 2007).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions, consisting of anaphylaxis and angioedema, have been reported in patients receiving deferasirox therapy, with the onset generally occurring within the first month of therapy (Prod Info EXJADE(R) oral suspension, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Animal studies have demonstrated no evidence of impaired fertility or harm to the fetus due to deferasirox. No human studies of pregnancy outcomes after exposure to deferasirox have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy. It is not known whether deferasirox is excreted in human milk. Deferasirox is in pregnancy category B.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pregnancy category B (Prod Info EXJADE(R) tablets for oral suspension, 2005).
    B) HUMANS
    1) No human studies of pregnancy outcomes after exposure to deferasirox have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy. (Prod Info EXJADE(R) tablets for oral suspension, 2005).
    C) ANIMAL STUDIES
    1) Animal studies have demonstrated no evidence of impaired fertility or harm to the fetus due to deferasirox. Studies included oral doses up to 100 mg/kg/day (about 0.8 times the recommended human oral dose based on body surface area) in pregnant rats and oral doses up to 50 mg/kg/day (about 0.8 times the recommended human oral dose based on body surface area) in pregnant rabbits (Prod Info EXJADE(R) tablets for oral suspension, 2005).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether deferasirox is excreted in human milk. No human studies of lactation outcomes after exposure to deferasirox have been published, and there have been no reports of outcomes after inadvertent exposure to the nursing infant. Following a 10-milligram/kilogram dose (0.08 times the recommended human oral dose based on body surface area) in rats, deferasirox and its metabolites were excreted in breast milk (Prod Info EXJADE(R) tablets for oral suspension, 2005).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT - At oral doses up to 75 mg/kg/day (approximately 0.6 times the recommended oral dose in humans based on body surface area) deferasirox had no adverse effect on fertility or reproductive performance in male and female rats (Prod Info EXJADE(R) tablets for oral suspension, 2005).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS201530-41-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic activity of deferasirox in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) In Wistar rats, a 104-week oral carcinogenicity study showed no evidence of carcinogenicity at doses up to 60 mg/kg/day (approximately 0.48 times the recommended oral dose for humans based on body surface area (BSA)). In p53 (+/-) transgenic mice, a 26-week oral carcinogenicity study showed no evidence of carcinogenicity at doses up to 200 mg/kg/day in males (approximately 0.81 times the recommended oral dose for humans based on BSA) and 300 mg/kg/day in females (approximately 1.21 times the recommended oral dose for humans based on BSA) (Prod Info EXJADE(R) oral suspension, 2009).

Genotoxicity

    A) Deferasirox was negative in the chromosome aberration test and Ames test with human peripheral blood lymphocytes and positive in 1 of 3 in vivo oral rat micronucleus tests (Prod Info EXJADE(R) oral suspension, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.

Methods

    A) A high-performance liquid chromatography and ultraviolet detection method for determination of deferasirox in plasma has been described. The mean accuracy ranged from 91% to 109% with a coefficient of variation from 4% to 8% (Rouan et al, 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs.

Monitoring

    A) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Severe anaphylaxis should be treated with antihistamines, corticosteroids, and epinephrine. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    2) Monitor CBC with differential and platelet count, renal function, and liver enzymes in symptomatic patients.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding (approximately 99%) and large volume of distribution (14.37 +/- 2.69 L).

Range Of Toxicity

Summary

    A) TOXICITY: Hepatitis was reported in one patient who received 2 to 3 times the prescribed dose of deferasirox over a period of several weeks. In iron overloaded beta-thalassemic patients, single doses up to 80 mg/kg have been tolerated with nausea and diarrhea noted. Single doses up to 40 mg/kg were tolerated in healthy volunteers.
    B) THERAPEUTIC DOSE: Varies by indication; 10 mg/kg/day or 20 mg/kg/day; up to 40 mg/kg with lack of control.

Therapeutic Dose

    7.2.1) ADULT
    A) TRANSFUSIONAL IRON OVERLOAD
    1) EXJADE(R)
    a) INITIAL DOSE: 20 mg per kg body weight, calculated to the nearest whole tablet, once daily on an empty stomach (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    b) MAINTENANCE THERAPY: Adjust dose, if necessary, every 3 to 6 months based on serum ferritin trends, in increments of 5 or 10 mg/kg (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    c) MAXIMUM DOSE: 40 mg/kg (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    2) JADENU(TM)
    a) INITIAL DOSE: 14 mg per kg body weight, calculated to the nearest whole tablet, once daily on an empty stomach or with a light meal (less than 7% fat content and approximately 250 calories) (Prod Info JADENU(TM) oral tablets, 2015).
    b) MAINTENANCE THERAPY: Adjust dose, if necessary, every 3 to 6 months based on serum ferritin trends, in increments of 3.5 or 7 mg/kg (Prod Info JADENU(TM) oral tablets, 2015).
    c) MAXIMUM DOSE: 28 mg/kg (Prod Info JADENU(TM) oral tablets, 2015).
    B) IRON OVERLOAD IN NON-TRANSFUSION-DEPENDENT THALASSEMIA SYNDROMES
    1) EXJADE(R)
    a) INITIAL DOSE: 10 mg/kg, calculated to the nearest whole tablet, orally once daily (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    b) MAINTENANCE THERAPY: After 4 weeks, the dose may be increased to up to a MAX dose of 20 mg/kg/day, if the liver iron concentration is greater than 15 mg/g of liver dry weight (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    2) JADENU(TM)
    a) INITIAL DOSE: 7 mg/kg, calculated to the nearest whole tablet, once daily on an empty stomach or with a light meal (less than 7% fat content and approximately 250 calories) (Prod Info JADENU(TM) oral tablets, 2015).
    b) MAINTENANCE THERAPY: After 4 weeks, the dose may be increased to up to a MAX dose of 14 mg/kg/day, if the liver iron concentration is greater than 15 mg Fe/g of liver dry weight (Prod Info JADENU(TM) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) TRANSFUSIONAL IRON OVERLOAD
    1) CHILDREN YOUNGER THAN 2 YEARS: Safety and efficacy in the pediatric population less than 2 years of age have not been established (Prod Info JADENU(TM) oral tablets, 2015; Prod Info EXJADE(R) oral suspension tablets, 2013a).
    2) CHILDREN 2 TO 18 YEARS
    a) EXJADE(R)
    1) INITIAL DOSE: 20 mg per kg body weight, calculated to the nearest whole tablet, once daily on an empty stomach (Prod Info EXJADE(R) oral suspension tablets, 2013a)
    2) MAINTENANCE THERAPY: Adjust dose, if necessary, every 3 to 6 months based on serum ferritin trends, in increments of 5 or 10 mg/kg (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    3) MAXIMUM DOSE: 40 mg/kg (Prod Info EXJADE(R) oral suspension tablets, 2013a)
    b) JADENU(TM)
    1) INITIAL DOSE: 14 mg per kg body weight, calculated to the nearest whole tablet, once daily on an empty stomach or with a light meal (less than 7% fat content and approximately 250 calories) (Prod Info JADENU(TM) oral tablets, 2015).
    2) MAINTENANCE THERAPY: Adjust dose, if necessary, every 3 to 6 months based on serum ferritin trends, in increments of 3.5 or 7 mg/kg (Prod Info JADENU(TM) oral tablets, 2015).
    3) MAXIMUM DOSE: 28 mg/kg (Prod Info JADENU(TM) oral tablets, 2015).
    B) IRON OVERLOAD IN NON-TRANSFUSION-DEPENDENT THALASSEMIA SYNDROMES
    1) CHILDREN YOUNGER THAN 10 YEARS: Safety and efficacy in the pediatric population less than 10 years of age have not been established (Prod Info JADENU(TM) oral tablets, 2015; Prod Info EXJADE(R) oral suspension tablets, 2013a).
    2) CHILDREN 10 TO 18 YEARS
    a) EXJADE(R)
    1) INITIAL DOSE: 10 mg/kg, calculated to the nearest whole tablet, orally once daily (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    2) MAINTENANCE THERAPY: After 4 weeks, the dose may be increased to up to a MAX dose of 20 mg/kg/day, if the liver iron concentration is greater than 15 mg/g of liver dry weight (Prod Info EXJADE(R) oral suspension tablets, 2013a).
    b) JADENU(TM)
    1) INITIAL DOSE: 7 mg/kg, calculated to the nearest whole tablet, once daily on an empty stomach or with a light meal (less than 7% fat content and approximately 250 calories) (Prod Info JADENU(TM) oral tablets, 2015).
    2) MAINTENANCE THERAPY: After 4 weeks, the dose may be increased to up to a MAX dose of 14 mg/kg/day, if the liver iron concentration is greater than 15 mg Fe/g of liver dry weight (Prod Info JADENU(TM) oral tablets, 2015).

Maximum Tolerated Exposure

    A) Hepatitis was reported in one patient who received 2 to 3 times the prescribed dose of deferasirox over a period of several weeks. Following dose withdrawal, the patient recovered without sequelae (Prod Info EXJADE(R) oral suspension tablets, 2013).
    B) In iron overloaded beta-thalassemic patients, single doses up to 80 mg/kg have been tolerated with nausea and diarrhea noted. Single doses up to 40 mg/kg were tolerated in healthy volunteers (Prod Info EXJADE(R) oral suspension tablets, 2013).

Workplace Standards

    A) ACGIH TLV Values for CAS201530-41-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS201530-41-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS201530-41-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS201530-41-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Deferasirox is an orally active chelating agent that is selective for iron. Deferasirox is a tridentate ligand with a high affinity for iron (2:1 binding affinity) and low affinity for zinc and copper, although variable decreases in serum concentrations of zinc and copper have been observed after administration of deferasirox. At 10, 20, and 40 mg/kg/day, deferasirox induces a mean net iron excretion of 0.119, 0.329, and 0.445 mg Fe/kg body weight/day, respectively (Prod Info JADENU(TM) oral tablets, 2015a).

Physicochemical

Physical Characteristics

    A) Deferasirox is a slightly yellow or white powder (Prod Info EXJADE(R) tablets for oral suspension, 2005).

Molecular Weight

    A) 373.4 (Prod Info EXJADE(R) tablets for oral suspension, 2005)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
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