Drug Interactions between ifosfamide and inotersen

MONITOR CLOSELY: Coadministration of inotersen with other nephrotoxic agents may increase the risk of renal impairment due to additive adverse effects on the kidney. Inotersen can cause glomerulonephritis that may result in dialysis-dependent renal failure. In a premarketing clinical trial, glomerulonephritis occurred in three (3%) patients receiving inotersen versus no patient receiving placebo. Stopping inotersen alone did not resolve manifestations of glomerulonephritis, and treatment with an immunosuppressive medication was necessary. One patient did not receive immunosuppressive treatment and remained dialysis-dependent. Inotersen-induced glomerulonephritis may also be accompanied by nephrotic syndrome, complications of which can include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. Additionally, antisense oligonucleotides such as inotersen can accumulate in proximal tubule cells of the kidney and cause increased tubular proteinuria. Urine protein to creatinine ratio (UPCR) greater than 5 times the upper limit of normal and increase from baseline in serum creatinine greater than 0.5 mg/dL occurred in 15% and 11% of inotersen-treated patients, respectively, compared to 8% and 2% of patients on placebo, respectively.

MANAGEMENT: Caution is advised when inotersen is prescribed with nephrotoxic drugs and other drugs that may impair renal function (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; aminosalicylates; antiviral/antiretroviral agents such as acyclovir, adefovir, cidofovir, foscarnet, ganciclovir, and tenofovir; antineoplastics such as aldesleukin, cisplatin, clofarabine, ifosfamide, streptozocin, and high intravenous dosages of methotrexate; chelating agents such as deferasirox, deferoxamine, edetate disodium, and edetate calcium disodium; immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus; intravascular contrast media; intravenous bisphosphonates; intravenous pentamidine; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents; gallium nitrate; lithium; penicillamine) . Serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and a urinalysis should be obtained prior to initiation of inotersen and regularly during and for at least 8 weeks after treatment in accordance with the product labeling. Inotersen should generally not be initiated in patients with a UPCR of 1000 mg/g or higher, or in patients who are unable to adhere to the recommended laboratory monitoring and management guidelines. Patients or their caregivers should be apprised of the signs and symptoms of glomerulonephritis and to seek medical attention if they occur, including edema, shortness of breath, coughing, hematuria, and decreased urination. Inotersen should be withheld in patients who develop a UPCR of 1000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m2, pending further evaluation of the cause. Weekly dosing may be resumed once eGFR increases to at least 45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the renal function decline is corrected. In patients with UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis as clinically indicated. If acute glomerulonephritis is confirmed, inotersen should be permanently discontinued.

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