Exjade

deferasirox

Exjade

FDA Box Warning

Deferasirox may cause renal and hepatic impairment (including failure) and GI hemorrhage. In some reported cases, these reactions were fatal and were more frequently observed in patients with advanced age, high-risk myelodysplastic syndromes, underlying renal or hepatic impairment, or low platelet count (less than 50 × 109/L).

Deferasirox therapy requires close patient monitoring, including measurement of serum creatinine and creatinine clearance before starting therapy and monthly thereafter.

In patients with underlying renal impairment or risk factors for renal impairment, monitor serum creatinine and creatinine clearance weekly for the first month, then monthly thereafter.

In patients with underlying hepatic impairment, monitor serum transaminase and bilirubin levels before starting therapy, every 2 weeks during first month, and monthly thereafter.

Action

Binds selectively to iron

Availability

Tablets for oral suspension: 125 mg, 250 mg, 500 mg

Indications and dosages

➣ Chronic iron overload caused by blood transfusions

Adults and children ages 2 and older: Initially, 20 mg/kg (calculated to nearest whole tablet) P.O. daily on empty stomach at least 30 minutes before a meal, preferably at same time each day. Don't exceed 30 mg/kg daily.

Dosage adjustment

• Serum creatinine elevation

• Severe, persistent liver enzyme elevations; moderate (Child-Pugh B) hepatic impairment

• Administration with potent UDP-glucuronosyltransferase (UGT) inducers or cholestyramine

Contraindications

• Hypersensitivity to drug or its components

• Creatinine clearance below 40 ml/minute or serum creatinine level above two times age-appropriate upper limit of normal

• Poor performance status and highrisk myelodysplastic syndromes or advanced malignancies

• Platelet count below 50 × 109/L

Precautions

Use cautiously in:

• serum creatinine elevation, liver enzyme elevation, severe rash

• severe hepatic impairment (Child-Pugh C) (avoid use)

• concurrent use of drugs with ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs, corticosteroids, oral bisphosphonates, anticoagulants; or drugs metabolized by CYP3A4

• potent UGT inducers or cholestyramine (avoid use if possible)

• pregnant or breastfeeding patients.

Administration

Make sure patient doesn't swallow tablets whole.

• Disperse tablets completely in water, orange juice, or apple juice; have patient consume suspension immediately. If residue remains, resuspend it in small amount of liquid and have patient swallow it. Disperse doses lower than 1 g in 3.5 oz liquid; disperse doses higher than 1 g in 7 oz liquid.

• Adjust dosage every 3 to 6 months in increments of 5 to 10 mg/kg based on ferritin levels, treatment goals, and response.

Adverse reactions

CNS: headache, fatigue, dizziness

EENT: cataract, retinal disorder, increased intraocular pressure, ear infection, hearing loss, rhinitis, nasopharyngitis, pharyngolaryngeal pain, pharyngitis, acute tonsillitis

GI: nausea, vomiting, diarrhea, abdominal pain, irritation, ulceration, hemorrhage

GU: renal dysfunction

Hematologic: cytopenias (agranulocytosis, neutropenia, thrombocytopenia) Hepatic: liver dysfunction

Musculoskeletal: arthralgia, back pain

Respiratory: cough, respiratory tract infection, bronchitis

Skin: rash, urticaria, erythema multiforme

Other: fever, influenza hypersensitivity reactions (including anaphylaxis, angioedema)

Interactions

Drug-drug. Aluminum-containing antacids: possible binding with antacid Cholestyramine, potent UGT inducers (such as phenobarbital, phenytoin, rifampin, ritonavir): decreased deferasirox systemic exposure (area under the curve)

Drugs metabolized by CYP3A4 (such as cyclosporine, hormonal contraceptives, simvastatin): possible decrease in CYP3A4 substrate concentration and potential loss of effectiveness of these drugs

Drug-diagnostic tests. Liver function tests, serum creatinine: increased

Drug-food. Any food: increased deferasirox bioavailability

Patient monitoring

Discontinue drug if hypersensitivity reactions are severe and institute appropriate medical intervention.

• Perform baseline auditory and ophthalmic testing; repeat every 12 months.

• Monitor serum ferritin levels monthly. If levels fall consistently below 500 mcg/L, consider temporarily interrupting therapy.

• Monitor serum creatinine level and creatinine clearance before starting drug and monthly thereafter. In patients with additional renal risk factors, monitor serum creatinine level and creatinine clearance weekly during first month after initiation or modification of therapy and monthly thereafter. Consider dosage reduction, therapy interruption, or drug discontinuation if levels increase.

• Monitor serum transaminase and bilirubin levels before starting drug, every 2 weeks during first month of therapy, and monthly thereafter. Consider dosage modifications or interruption of treatment for severe or persistent elevations.

• Monitor CBC regularly. Consider interrupting treatment in patients who develop unexplained cytopenia.

Stay alert for signs and symptoms of GI ulceration and hemorrhage during therapy; promptly initiate additional evaluation and treatment if serious GI adverse event is suspected.

Patient teaching

• Instruct patient to take drug on empty stomach at least 30 minutes before food, preferably at same time each day.

• Instruct patient to place tablets in water, orange juice, or apple juice and stir until completely dissolved. Tell him not to chew or swallow them.

• Advise patient not to take aluminum-containing antacids during therapy.

• Tell patient drug may cause vision and hearing disturbances, necessitating routine ophthalmic and auditory testing.

• Caution patient to avoid driving and other hazardous activities until drug effects are known.

• As appropriate, review all other significant adverse reactions and interactions, especially those related to the drugs, tests, and foods mentioned above.

deferasirox

(de-fe-ra-si-rox) deferasirox,

Exjade

(trade name)

Classification

Therapeutic: antidotes
Pharmacologic: chelating agents
Pregnancy Category: B

Indications

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.

Action

Selectively chelates iron and eliminates it in feces.

Therapeutic effects

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

Pharmacokinetics

Absorption: Well absorbed (70%) following oral administration, absorption is less in children.Distribution: .Protein Binding: 99%.Metabolism and 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.

Time/action profile (blood level)

ROUTEONSETPEAKDURATION
POunknown1.5–4 hr24 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity; CCr <40 ml/min or serum creatinine >2x the upper limit of normal; Poor performance status and high-risk myelodysplastic syndromes or advanced malignancies; Platelet count <50,000/mm3; Severe hepatic impairment.Use Cautiously in: Renal impairment (↑ risk of worsening renal function); Mild or moderate hepatic impairment; Geriatric: ↑ risk of renal/hepatic impairment and GI hemorrhage; Pediatric: Children <2 yr (safety not established); ↑ risk of GI hemorrhage in children; Obstetric: Use cautiously during lactation, use in pregnancy only if clearly needed.

Adverse Reactions/Side Effects

Central nervous system

  • headache (most frequent)
  • dizziness

Ear, Eye, Nose, Throat

  • hearing loss
  • ocular disturbances

Respiratory

  • cough (most frequent)

Gastrointestinal

  • gi bleeding/ulceration (life-threatening)
  • hepatic failure (life-threatening)
  • diarrhea (most frequent)
  • nausea (most frequent)
  • vomiting (most frequent)
  • abdominal pain
  • drug-induced hepatitis
  • ↑ liver enzymes

Genitourinary

  • renal failure (life-threatening)
  • ↑ serum creatinine (most frequent)
  • renal failure

Dermatologic

  • erythema multiforme (life-threatening)
  • stevens-johnson syndrome (life-threatening)
  • rash (most frequent)

Hematologic

  • agranulocytosis
  • neutropenia
  • thrombocytopenia
  • worsening anemia

Musculoskeletal

  • arthralgia

Miscellaneous

  • fever (most frequent)

Interactions

Drug-Drug interaction

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

Route/Dosage

Chronic Iron Overload Due to Blood Transfusions

Oral (Adults and Children ≥2 yr) 20 mg/kg/day; adjusted by 5–10 mg/kg every 3–6 mo on the basis of serum ferritin levels (not to exceed 30 mg/kg/day).

Hepatic Impairment

(Adults and Children ≥2 yr) Moderate hepatic impairment (Child-Pugh B)—↓ initial dose by 50%.

Renal Impairment

(Adults and Children ≥2 yr) CCr 40–60 mL/min—↓ initial dose by 50%

Chronic Iron Overload in Non-Transfusion Dependent Thalassemia Syndromes

Oral (Adults and Children ≥10 yr) 10 mg/kg/day; if baseline liver iron concentration >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 liver iron concentration is 3–7 mg/g of liver dry weight after 6 mo, continue therapy with no more than 10 mg/kg/day. When liver iron concentration <3 mg/g of liver dry weight, may discontinue therapy (restart when liver iron concentration >5 mg/g of liver dry weight).

Hepatic Impairment

(Adults and Children ≥10 yr) Moderate hepatic impairment (Child-Pugh B)—↓ initial dose by 50%.

Renal Impairment

(Adults and Children ≥2 yr) CCr 40–60 mL/min—↓ initial dose by 50%

Availability

Tablets for oral suspension: 125 mg, 250 mg, 500 mg

Nursing implications

Nursing assessment

  • 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 and a short period of oral steroid administration.
  • Assess for GI pain and bleeding during therapy; especially in patients receiving medications that increase risk of bleeding (NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants).
  • Lab Test Considerations: 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.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 5 or 10 mg/kg based on serum ferritin. If serum ferritin consistently falls below 500 mcg/L, temporary interruption of therapy should be considered. In Non-Transfusion-Dependent Thalassemia Syndromes, iron overload is considered when liver iron concentration (LIC) is at least 5 mg Fe/g dry weight and serum ferritin greater than 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 months. After 6 months of therapy, if the LIC remains > 7 mg Fe/g dw, increase dose of deferasirox. If after 6 months of therapy, LIC is 3–7 mg Fe/g dw, continue treatment deferasirox at no >10 mg/kg/day. When LIC <3 mg Fe/g dw, interrupt therapy and continue to monitor LIC.
    • Monitor blood counts periodically during therapy. Interrupt therapy if blood counts drop until cause is determined. Do not administer if platelet counts <50 x 109/L.
    • Monitor serum creatinine prior to and weekly during first month or modification of dose and at least monthly thereafter. Monitor serum creatinine and/or creatinine clearance more frequently if creatinine levels are increasing. Elevations require dose reduction, interruption, or discontinuation.
    • Monitor liver function tests every 2 wk during first month and monthly during therapy. May cause ↑ AST and ALT.
    • Monitor urine protein periodically during therapy.

Potential Nursing Diagnoses

Deficient knowledge, related to medication regimen (Patient/Family Teaching)

Implementation

  • Oral: Administer once daily on an empty stomach at least 30 min prior to food, preferably at the same time each day. 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.
    • Do not administer aluminum-containing antacids simultaneously with deferasirox.

Patient/Family Teaching

  • 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 rash, stomach pain, bleeding, or changes in vision or hearing occur.
  • 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.

Evaluation/Desired Outcomes

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