Deferasirox (Exjade) Linked to Risks for Hepatic Dysfunction and Drug Interactions
On April 22, the FDA approved safety labeling changes for deferasirox tablets for oral suspension (Exjade; Novartis Pharmaceuticals, Inc) to warn of the risks for hepatic dysfunction and advise of drug interactions.
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 chromosome P450 isoenzymes 3A4 (CYP 3A4) and CYP2C8.
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 CYP3A4 (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 and deferasirox should be approached with caution because interactions cannot be excluded.
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.
Deferasirox is indicated for the treatment of chronic iron overload from blood transfusions (transfusional hemosiderosis) in patients 2 years and older.
Icodextrin Solution (Extraneal) May Interfere With Some Blood Glucose–Monitoring Methods
On April 7, the FDA approved safety labeling revisions for icodextrin peritoneal dialysis solution (Extraneal; Baxter Healthcare Corp) to emphasize the need for glucose-specific methods when monitoring blood glucose levels to avoid test result interference by maltose released from the formulation.
Instead, the agency advises use of glucose dehydrogenase nicotine–adenine dinucleotide or glucose-oxidase–based or glucose-hexokinase–based tests in patients receiving icodextrin therapy.
Use of glucose-nonspecific methods such as glucose dehydrogenase pyrroloquinolinequinone (GDH-PDQ) or glucose-dye-oxidoreductase (GDO)–based monitoring systems can lead to falsely elevated readings in patients receiving products containing maltose or sugars that are metabolized to maltose, such as icodextrin.
Inappropriate insulin administration in patients with erroneously high glucose readings has lead patients or healthcare providers to withhold treatment of hypoglycemia or to administer insulin inappropriately; both of these situations have resulted in unrecognized hypoglycemia that has led to loss of consciousness, coma, permanent neurologic damage, and death.
Because plasma levels of icodextrin and its metabolites do not return to baseline for 14 days after cessation of therapy, falsely elevated glucose levels may be measured for up to 2 weeks when GDH-PDQ or GDO–based glucose monitors and test strips are used.
The FDA advises that healthcare providers of patients receiving peritoneal dialysis carefully review the product information for hospital blood glucose testing systems to ensure that they are suitable for use in patients receiving icodextrin.
Information regarding glucose monitor and test strip methodology can be obtained from their makers. A list of toll-free numbers for glucose monitor and test strip makers may be obtained from the Baxter Renal Clinical Help Line 1-888-RENAL-HELP.
Icodextrin peritoneal dialysis solution is indicated for a single daily exchange for the long (8- to 16-hour) dwell during continuous ambulatory peritoneal dialysis or automated peritoneal dialysis in the management of end-stage renal disease. It also may be used to improve (vs 4.25% dextrose) long-dwell ultrafiltration and clearance of creatinine and urea nitrogen levels in patients with high-average or greater transport characteristics, as defined with use of the peritoneal equilibration test.
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