Exjade Label Update
May 26, 2009 – Following is a recent update to the label for Exjade from April, 2009.
On June 10, 2009, MedScape published an article that presented more details on the Exjade label update. Below are excerpts from that piece.
According to the FDA, postmarketing cases of hepatic failure have been reported in patients receiving deferasirox. Some of these events resulted in fatality; most occurred in patients older than 55 years with significant comorbidities, including liver cirrhosis and multiorgan failure. The FDA advises measurement of serum transaminase and bilirubin levels at baseline, every 2 weeks during the first month of therapy, and monthly thereafter. Dose modifications or interruption of treatment should be considered for severe or persistent elevations.
The agency also warned of drug interactions with deferasirox that can affect blood levels for concomitantly administered medications via effects on hepatic cytochrome P450 isoenzymes 3A4 (CYP 3A4) and CYP 2C8.
Study data from a pharmacokinetic study of healthy volunteers have revealed that concomitant use of deferasirox yielded significant decreases in peak concentration (23%) and exposure (17%) of midazolam, a CYP 3A4 probe substrate. Because this effect may be more pronounced in a clinical setting and lead to loss of therapeutic efficacy, caution is advised with coadministration of drugs metabolized by CYP 3A4 (eg, cyclosporine, simvastatin, and hormonal contraceptive agents).
Deferasirox administration also has significant effects on drugs metabolized by CYP 2C8; in a pharmacokinetic study of healthy volunteers, the systemic exposure (area under the receiver-operating curve) of repaglinide (a CYP 2C8 probe) was increased 2.3-fold and steady-state maximal concentration (Cmax) was elevated by 62%. Patients requiring concomitant treatment with deferasirox may require decreased doses of repaglinide with careful monitoring of blood glucose levels. Concomitant use of other CYP 2C8 inhibitors such as paclitaxel should be approached with caution.
Also, some drug interactions are known to affect deferasirox levels. Because glucoronidation is the main metabolic pathway for deferasirox, concomitant use of potent UDP-glucuronosyltransferase (UGT) inducers (eg, rifampicin, phenytoin, phenobarbital, and ritonavir) may lead to a decrease in deferasirox blood levels and efficacy. In a study of healthy volunteers, coadministration of rifampicin (600 mg/day for 9 days) decreased exposure to a single 30-mg/kg dose of deferasirox by 44%.
Clinicians are advised to increase the dose of deferasirox and monitor serum ferritin levels and clinical response for further dose modification used concomitantly with potent UGT inducers; doses above 40 mg/kg are not recommended.
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Section 2.2 Dosage and Administration Dose Modification
In patients not adequately controlled with doses of 30 mg/kg (e.g. serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg/kg may be considered. Doses above 40 mg/kg are not recommended. Increase the dose of Exjade and monitor serum ferritin levels and clinical response for further dose modification when it is used concomitantly with potent UGT inducers (e.g. rifampicin, phenytoin,phenobarbital, ritonavir). Doses above 40 mg/kg are not recommended.
Section 5.3 Warnings and Precautions, Hepatic Dysfunction and Failure
Serum transaminases and bilirubin should be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.
If you have any questions, please consult your physician or contact CAF Patient Services (800-522-7222 or firstname.lastname@example.org).