Deferasirox

Pronunciation: dee-FER-a-sir-ox
Class: Chelating agent

Trade Names

Exjade
- Tablets for oral suspension 125 mg
- Tablets for oral suspension 250 mg
- Tablets for oral suspension 500 mg

Pharmacology

Orally active chelating agent that has a high affinity for binding with iron.

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Pharmacokinetics

Absorption

Bioavailability is 70%. Median time to T _max is approximately 1.5 to 4 h. C _max and AUC increase approximately linearly. The bioavailability (AUC) was variably increased when taken with a meal.

Distribution

Protein binding is approximately 99% and almost exclusively to serum albumin. Vd is approximately 14 L.

Metabolism

Major metabolic pathway is glucuronidation, with subsequent biliary excretion. Deferasirox is deconjugated in the intestine and undergoes enterohepatic recirculation.

Elimination

Primarily excreted in feces (84%) with minimal renal excretion (8%). Elimination half-life ranges from 8 to 16 h.

Special Populations

Minimal excretion (8%) via the kidney.

Pharmacokinetics were not influenced by liver transaminase levels up to 5 times the ULN.

Pharmacokinetics have not been studied in patients 65 yr of age and older.

In children younger than 6 yr of age, systemic exposure was approximately 50% lower than in adults.

Cl appears to be moderately lower (17.5%) in women than in men.

Indications and Usage

Treatment of chronic iron overload caused by blood transfusions (transfusional hemosiderosis) in patients 2 yr of age and older.

Contraindications

CrCl less than 40 mL/min or serum creatinine more than 2 times the age-appropriate ULN; poor performance status and high-risk myelodysplastic syndromes or advanced malignancies; platelet counts less than 50 × 10 ⁹ /L; known hypersensitivity to deferasirox.

Dosage and Administration

PO Start when patient has evidence of chronic iron overload and a serum ferritin consistently more than 1,000 mcg/L. Initial dosage is 20 mg/kg daily.

PO Adjust the dose as needed every 3 to 6 mo based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg/kg based on patient's response and therapeutic goals. For patients not adequately controlled with doses of 30 mg/kg, doses of up to 40 mg/kg (max dose) may be considered. Consider interrupting therapy if serum ferritin consistently falls below 500 mcg/L.

Dose reduction, interruption, or discontinuation should be considered for increases in serum creatinine. If there is a progressive increase in serum creatinine beyond the age-appropriate ULN, interrupt deferasirox therapy. Once creatinine has returned to within the normal range, therapy may be restarted at a lower dose followed by gradual dose escalation. For adult patients, reduce the daily dose by 10 mg/kg if serum creatinine increases to more than 33% above the average of the pretreatment measurements at 2 consecutive visits, and if the increase cannot be attributed to other causes. For children, reduce the dose by 10 mg/kg if serum creatinine levels rise above the age-appropriate ULN at 2 consecutive visits.

General Advice

• Administer once daily on an empty stomach at least 30 min before food, preferably at the same time each day.
• Tablets are for suspension only. Do not chew or swallow whole.
• Calculate dose to the nearest whole tablet.
• Completely disperse tablet by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses less than 1 g in 3.5 oz of liquid, and disperse doses of 1 g or more in 7 oz of liquid. Drink suspension immediately.
• Resuspend any residue in a small volume of liquid and swallow.

Storage/Stability

Store between 59° and 86°F. Protect from moisture.

Drug Interactions

Deferasirox absorption may be decreased. Avoid coadministration.

The risk of hemorrhage may be increased as a result of additive side effects. Use with caution. Monitor for signs and symptoms of hemorrhage. If serious bleeding occurs, initiate prompt evaluation and treatment.

The risk of GI irritation and ulcers may be increased as a result of additive side effects. Use with caution. Monitor for signs and symptoms of GI ulceration. If a serious GI adverse event occurs, initiate prompt evaluation and treatment.

Deferasirox efficacy may be decreased. If coadministration of deferasirox cannot be avoided, consider increasing the initial dose of deferasirox to 30 mg/kg. Monitor serum ferritin concentrations and the patient's clinical response for further dose modification.

Concentrations may be reduced by deferasirox, decreasing the effectiveness. Use with caution. Monitor CYP3A4 substrate concentrations and observe the patient for signs of reduced response. Adjust the substrate dose as needed.

Hormonal contraceptive concentrations may be reduced, decreasing the efficacy. Because hormonal contraceptive failure is possible, consider use of an additional nonhormonal contraceptive.

Do not coadminister because safety has not been established.

Paclitaxel plasma concentrations may be elevated, increasing the pharmacologic effect and risk of toxicity. Use with caution. Monitor the patient and adjust treatment as needed.

Repaglinide systemic exposure (AUC) and plasma concentrations may be elevated, increasing the pharmacologic effect and risk of adverse reactions. If deferasirox and repaglinide are coadministered, consider decreasing the dose of repaglinide. Carefully monitor blood glucose concentrations for further repaglinide dose modifications.

Adverse Reactions

CNS

Anxiety, dizziness, fatigue, sleep disorder (0.1% to 1%).

Dermatologic

Rash (11%); pigmentation disorder (0.1% to 1%); leukocytoclastic vasculitis (postmarketing).

EENT

Early cataract, hearing loss, maculopathy (0.1% to 1%).

GI

Abdominal pain (28%); nausea (23%); vomiting (21%); diarrhea (20%); cholelithiasis, duodenal ulcers, gastric ulcer (including multiple ulcers), gastritis, GI hemorrhage (0.1% to 1%).

Genitourinary

Renal tubulopathy (Fanconi syndrome) (0.1% to 1%); acute renal failure (postmarketing).

Hematologic-Lymphatic

Cytopenias, including agranulocytosis, neutropenia, and thrombocytopenia (postmarketing).

Hepatic

Hepatic failure, some with fatal outcome (postmarketing).

Hypersensitivity

Anaphylaxis, angioedema (postmarketing).

Lab Tests

Increased creatinine (38%); increased ALT (8%).

Renal

Proteinuria (19%).

Miscellaneous

Edema, pharyngolaryngeal pain, pyrexia (0.1% to 1%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 2 yr of age.

Elderly

Use with caution, usually starting at the low end of the dosage range because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Hypersensitivity

Serious hypersensitivity reactions (eg, anaphylaxis, angioedema) have been reported, with the onset of the reaction occurring in the majority of cases within the first month of treatment.

Cytopenias

Agranulocytosis, neutropenia, and thrombocytopenia, including cases with fatal outcomes, have been reported.

GI effects

Fatal GI hemorrhages, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts, have been reported.

Rash

May occur. For rashes of mild to moderate severity, deferasirox may be continued without dose adjustment because the rash often resolves spontaneously. In severe rash, interrupt therapy and consider reintroduction at a lower dose in combination with a short course of oral steroids.

Special senses

Auditory disturbances (eg, decreased hearing, high-frequency hearing loss) and ocular disturbances (eg, cataract, elevations in IOP, lens opacities, retinal disorders) have been reported.

Overdosage

Symptoms

Diarrhea, hepatitis, nausea.

Patient Information

• Advise patient to take deferasirox once daily on an empty stomach at least 30 min prior to food, preferably at the same time each day.
• Advise patient not to chew or swallow the tablet whole.
• Instruct patient to completely disperse the tablet in water, orange juice, or apple juice, and to drink the resulting suspension immediately.
• Instruct patient to resuspend any remaining residue in a small volume of liquid and swallow.
• Caution patient to not take deferasirox with aluminum-containing antacids.
• Advise patients to exercise caution when driving or operating machinery if they experience dizziness.
• Advise patients to interrupt treatment if severe skin rashes occur.
• Inform patients about the potential risk of GI ulcers or bleeding when taking deferasirox with drugs such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants.
• Advise patients of the importance of auditory and ophthalmic testing at regular intervals during treatment.
• Advise patients to carefully monitor glucose levels when repaglinide is used concomitantly with deferasirox.
• Advise patients that there have been reports of severe kidney and liver problems and of blood disorders, and that blood tests will be performed at regular intervals to monitor for these severe reactions.

Copyright © 2009 Wolters Kluwer Health.