de-fe-RA-si-rox

Therapeutic Classification: antidotes

Pharmacologic Classification: chelating agents

• Chronic iron overload due to blood transfusions.
• Chronic iron overload in non-transfusion-dependent thalassemia syndromes in patients with a liver iron concentration of 5 mg/g of liver dry weight and a serum ferritin >300 mcg/L.

• Selectively chelates iron and eliminates it in feces.

• Decreased iron with decreased sequelae of iron excess (hemosiderosis).

Absorption: Well absorbed (70%) following oral administration; absorption is less in children.

Distribution: Unknown.

Protein Binding: 99%.

Metabolism/Excretion: Mostly metabolized by the liver, followed by enterohepatic recycling. 84% excreted in feces (deferasirox and metabolites); minimal renal excretion.

Half-life: 8–16 hr.

(plasma concentrations)

Contraindicated in:

• Hypersensitivity
• CCr <40 mL/min or serum creatinine >2 times the upper limit of normal
• Poor performance status
• High-risk myelodysplastic syndromes or advanced malignancies
• Platelet count <50,000/mm³
• Severe hepatic impairment
• Lactation: Lactation.

Use Cautiously in:

• Renal impairment (↑ risk of worsening renal function)
• Mild or moderate hepatic impairment
• OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk
• Pedi: Children <2 yr (safety and effectiveness not established); ↑ risk of GI hemorrhage in children
• Geri: ↑risk of renal/hepatic impairment in older adults; ↑ risk of GI hemorrhage in older adults with malignancy and/or low platelet counts.

Derm: rash, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), ERYTHEMA MULTIFORME, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS.

EENT: ↑intraocular pressure, cataracts, hearing loss, lens opacities, retinal disorders.

GI: diarrhea, nausea , vomiting, ↑ liver enzymes, abdominal pain, drug-induced hepatitis, GI BLEEDING/ULCERATION, GI PERFORATION, HEPATOTOXICITY.

GU: ↑serum creatinine, renal failure.

Hemat: agranulocytosis, neutropenia, thrombocytopenia, worsening anemia.

MS: arthralgia.

Neuro: headache, dizziness.

Resp: cough.
Misc: fever, (INCLUDING ANAPHYLAXIS AND ANGIOEDEMA)HYPERSENSITIVITY REACTIONS .

Drug-Drug:

• Aluminum-containing antacids may ↓ levels and effectiveness.
• Cholestyramine, rifampin, phenytoin, phenobarbital, and ritonavir may ↓ levels and effectiveness; avoid concurrent use or ↑ deferasirox dose.
• Avoid concurrent use with other iron chelators.
• ↑risk of GI bleeding or ulceration with NSAIDs, corticosteroids, bisphosphonates, or anticoagulants.
• May ↓ levels and effectiveness of CYP3A4 substrates.
• May ↑ levels of and risk of hypoglycemia with repaglinide; ↓ dose of repaglinide.
• May ↑ levels and risk of toxicity of theophylline; avoid concurrent use or ↓ theophylline dose.
• May ↑ levels and risk of toxicity of CYP1A2 substrates, including cyclobenzaprine, imipramine, haloperidol, fluvoxamine, mexiletine, olanzapine, tizanidine, zileuton, and zolmitriptan.
• May ↑ levels and risk of toxicity of busulfan; monitor busulfan levels and adjust busulfan dose as needed.

Chronic Iron Overload Due to Blood Transfusions

• PO (Adults and Children 2 yr): Exjade: 20 mg/kg once daily; adjusted by 5–10 mg/kg every 3–6 mo on the basis of serum ferritin levels (not to exceed 40 mg/kg/day); Jadenu: 14 mg/kg once daily; adjusted by 3.5–7 mg/kg every 3–6 mo on the basis of serum ferritin levels (not to exceed 28 mg/kg/day).

Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

• PO (Adults and Children 10 yr): Exjade: 10 mg/kg once daily; if baseline liver iron concentration (LIC) >15 mg/g of liver dry weight, consider ↑ dose to 20 mg/kg/day after 4 wk. If liver iron concentration remains >7 mg/g of liver dry weight after 6 mo, ↑ dose to 20 mg/kg/day (maximum dose). If LIC is 3–7 mg/g of liver dry weight after 6 mo, continue therapy with no more than 10 mg/kg/day. When LIC <3 mg/g of liver dry weight, may discontinue therapy (restart when liver iron concentration >5 mg/g of liver dry weight); Jadenu: 7 mg/kg once daily; if baseline LIC >15 mg/g of liver dry weight, consider ↑ dose to 14 mg/kg/day after 4 wk. If LIC remains >7 mg/g of liver dry weight after 6 mo, ↑ dose to 14 mg/kg/day (maximum dose). If LIC is 3–7 mg/g of liver dry weight after 6 mo, continue therapy with no more than 7 mg/kg/day. When LIC <3 mg/g of liver dry weight, may discontinue therapy (restart when LIC >5 mg/g of liver dry weight).

(Generic available)

• Sprinkle granules (Jadenu): 90 mg/sachet; 180 mg/sachet; 360 mg/sachet;
• Tablets (Jadenu): 90 mg; 180 mg; 360 mg;
• Tablets for oral suspension (Exjade): 125 mg; 250 mg; 500 mg;

• Assess hearing and vision (split lamp and dilated fundoscopy) prior to and periodically during therapy. May cause high frequency hearing loss and visual disturbances (lens opacities, cataracts, increased intraocular pressure, retinal disorders).
• Assess patient for rash during therapy. Mild to moderate rashes usually resolve without change in dose. If severe rash occurs, deferasirox may be interrupted and reintroduced at a lower dose with escalation.
• Assess for GI pain and bleeding during therapy; especially in patients receiving medications that increase risk of bleeding (NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants).
• Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, and/or facial swelling), associated with involvement of other organ systems (hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) during therapy. May resemble an acute viral infection. Eosinophilia is often present. Discontinue therapy if signs occur.

• Prior to starting therapy, measure serum ferritin level, baseline serum creatinine in duplicate, creatinine clearance, serum transaminases and bilirubin, and baseline auditory and ophthalmic examinations. Monitor serum ferritin monthly.Evidence of chronic iron overload is considered with a transfusion of 100 mL/kg of packed red blood cells and a serum ferritin consistently >1000 mcg/L. Monitor serum ferritin monthly to assess response and to evaluate for overchelation of iron. Make dose adjustments every 3–6 mo in steps of 3.5 or 7 mg/kg based on serum ferritin. If serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose ↓, especially if dose >17.5 mg/kg/day. If serum ferritin falls below 500 mcg/L, hold therapy and continue monitoring.In non-transfusion-dependent thalassemia syndromes, iron overload is considered when LIC 5 mg Fe/g dry weight and serum ferritin >300 mcg/L. Monitor serum ferritin monthly. If serum ferritin <300 mcg/L, obtain an LIC to determine whether LIC has fallen to <3 mg Fe/g dry weight. Monitor LIC every 6 mo. After 6 mo of therapy, if the LIC remains >7 mg Fe/g dry weight, ↑ dose of deferasirox. If after 6 mo of therapy, LIC is 3–7 mg Fe/g dry weight, continue treatment with deferasirox at a dose of not >7 mg/kg/day. When LIC <3 mg Fe/g dry weight, interrupt therapy and continue to monitor LIC.
  • Monitor blood counts monthly during therapy. Interrupt therapy if blood counts drop until cause is determined. Do not administer if platelet counts <50 × 10⁹/L.
  • Monitor serum creatinine prior to and weekly during first mo or modification of dose and at least monthly thereafter. Monitor serum creatinine and/or CCr more frequently if creatinine levels are increasing. Elevations require dose reduction, interruption, or discontinuation.
  • Monitor liver function tests (AST, ALT, bilirubin) every 2 wk during first mo and monthly during therapy. May cause ↑ AST and ALT.
  • Monitor urine protein periodically during therapy.

• PO: Exjade: Administer once daily on an empty stomach at least 30 min prior to food, preferably at the same time each day. DNC: Do not chew or swallow tablets whole. Tablets must be completely dispersed in water, orange juice, or apple juice and the resulting suspension drunk immediately. Resuspend remaining residue in small amount of liquid and drink. Jadenu: Swallow tablets whole with water or other liquids on an empty or stomach or with a light meal (contains less than 7% fat content and approximately 250 calories, such as 1 whole wheat English muffin, 1 packet jelly [0.5 ounces], and skim milk [8 fluid ounces] or a turkey sandwich [2 oz. turkey on whole wheat bread with lettuce, tomato, and 1 packet mustard]). For patients with difficulty swallowing, tablets may be crushed and mixed with soft foods (yogurt, applesauce) immediately before administration. Administer Jadenu sprinkle granules on an empty stomach or with a light meal by sprinkling full dose on soft food; administer immediately.
  • Do not administer aluminum-containing antacids simultaneously with deferasirox.
  • If converting from Exjade to Jadenu, reduce Jadenu dose by approximately 30%.

• Instruct patient to take deferasirox as directed at same time each day.
• Advise patient not to take aluminum-containing antacids with deferasirox.
• May cause dizziness. Advise patient to avoid driving and other activities requiring alertness until response to medication is known.
• Advise patient to maintain adequate hydration if vomiting or diarrhea occurs.
• Advise patient to notify health care professional if signs and symptoms of liver problems (drowsiness, upper right abdominal pain, yellowing or increased yellowing of skin or eyes, dark urine), allergic reaction (difficulty breathing or swallowing; chest pain; rapid heartbeat; feeling faint; swelling of face, lips, mouth, tongue, or throat; severe itching of the skin with a red rash or raised bumps; hives), DRESS (rash or red skin, blisters on lips or around mouth or eyes, mouth sores, skin peeling, high fever, flu-like symptoms, enlarged lymph nodes), stomach pain, bleeding, or changes in vision or hearing occur.
• Advise parents of children taking deferasirox to notify health care professional immediately if child develops fever, vomiting, or diarrhea and cannot drink fluids normally, or is passing less urine than normal; child may be dehydrated.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any other Rx, OTC, or herbal products, especially NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants.
• Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding. Caution patient to use nonhormonal contraceptive, as deferasirox ↓ effectiveness of hormonal contraceptives.

• Decreased iron with decreased sequelae of iron excess (hemosiderosis).

Exjade, Jadenu