Drug Interactions between famotidine / ibuprofen and inotersen

MONITOR CLOSELY: Coadministration of inotersen and drugs that interfere with platelet function such as nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of serious, potentially life-threatening bleeding complications, including spontaneous intracranial and intrapulmonary hemorrhage. Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia. In a premarketing clinical trial, platelet counts below 100 x 10^9/L and 75 x 10^9/L occurred in 25% and 14% of patients receiving inotersen, respectively, versus 2% and none of the patients receiving placebo, respectively. Thirty-nine percent of inotersen-treated patients with a baseline platelet count below 200 x10^9/L had a nadir platelet count below 75 x 10^9/L, compared to 6% of patients with baseline platelet counts 200 x10^9/L or higher. Three inotersen-treated patients (3%) developed sudden severe thrombocytopenia (i.e., platelet count below 25 x 10^9/L), all of whom had treatment-emergent antiplatelet IgG antibodies detected shortly before or at the time of the severe thrombocytopenia. In 2 patients, platelet clumping caused uninterpretable platelet measurements that delayed the diagnosis and treatment of severe thrombocytopenia. Platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA). In the clinical trial, 23% of inotersen-treated patients had at least one uninterpretable platelet count caused by platelet clumping, compared to 13% of placebo-treated patients.

MANAGEMENT: Caution is advised when inotersen is prescribed with NSAIDs. A platelet count 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 not be administered in patients with a platelet count below 100 x 10^9/L 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 thrombocytopenia and to seek medical attention if they occur, including any unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. If thrombocytopenia is suspected, obtain a platelet count as soon as possible and withhold further inotersen dosing until platelet count is confirmed to be acceptable. A prompt recheck of the platelet count is necessary if a platelet measurement is not interpretable (e.g., clumped sample). The manufacturer recommends glucocorticoid therapy in patients with a platelet count below 50 x 10^9/L and in patients with suspected immune-mediated thrombocytopenia. Additionally, consideration should be given to discontinuing any concomitant medications that may be contributing to the thrombocytopenia and/or bleeding complication, if clinically feasible.

MONITOR CLOSELY: Coadministration of inotersen with other potentially nephrotoxic agents such as NSAIDs 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 high dosages and/or chronic use of NSAIDs. 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.

H2 antagonists may alter the pharmacokinetic disposition of some nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data have been varied, even for the same NSAID. The mechanism may involve inhibition of metabolism, changes in gastric pH resulting in altered absorption, and/or reduced urinary elimination of the affected NSAIDs. Statistically significant changes have been small and of limited clinical significance when interactions have been observed.