Drug Interactions between aspirin / caffeine / salicylamide and riociguat

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.

MONITOR: Coadministration of riociguat with anticoagulant, antiplatelet, or other antithrombotic therapy may increase the risk of bleeding. Patients with pulmonary hypertension have an underlying risk for respiratory tract bleeding, which can be further exacerbated by riociguat and use of antithrombotic agents, particularly in the presence of additional risk factors such as recent episodes of serious hemoptysis (including those managed by bronchial arterial embolization) or concomitant prostacyclin use (e.g., epoprostenol, iloprost, and treprostinil) due to their inhibitory effect on platelet aggregation. In clinical trials, serious bleeding occurred in 2.4% and hemoptysis in 1% of patients taking riociguat compared to 0% of placebo patients. The proposed mechanism for the bleeding risk associated with riociguat is unknown. However, an in vitro study indicates that riociguat may inhibit von Willebrand factor elongation and platelet adhesion on the surface of pulmonary artery endothelial cells.

MANAGEMENT: Bleeding risk should be carefully evaluated before initiating riociguat in patients on antithrombotic therapy. Close clinical and laboratory monitoring for bleeding complications is recommended if concomitant use is required. Some authorities recommend avoiding riociguat in patients with a history of serious hemoptysis or who have previously undergone bronchial arterial embolization.

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.