Drug Interactions between aspirin / caffeine / salicylamide and inotersen

MONITOR CLOSELY: Coadministration of inotersen and drugs that interfere with platelet function or coagulation 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 antiplatelet agents, anticoagulants, or other medications that commonly cause thrombocytopenia or bleeding. 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.

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MONITOR: The combined use of low-dose or high-dose aspirin with other nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. Aspirin at anti-inflammatory dosages or higher may also decrease the plasma concentrations of many NSAIDs. The decreases have ranged from none or small (piroxicam, meloxicam, naproxen, tolmetin) to substantial (flurbiprofen, ibuprofen). However, the therapeutic response does not appear to be affected. Investigators theorize that aspirin may displace NSAIDs from plasma protein binding sites, resulting in increased concentration of unbound, or free, drug available for clearance. The increase in NSAID free fraction, and possibly some contributory anti-inflammatory effect from aspirin, may account for the lack of overall effect on therapeutic response.

MANAGEMENT: Caution is advised if aspirin, particularly at anti-inflammatory dosages, is used with other NSAIDs. Concomitant administration of NSAIDs is considered contraindicated or not recommended with aspirin at analgesic/anti-inflammatory dosages by many NSAID manufacturers. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as abdominal pain, bloating, sudden dizziness or lightheadedness, nausea, vomiting, hematemesis, anorexia, and melena.

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One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

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