Drug Interactions between aspirin / caffeine / salicylamide and vitamin e

MONITOR: Vitamin E may potentiate the effects of anticoagulants and platelet inhibitors. Vitamin E is thought to inhibit the oxidation of reduced vitamin K and interfere with the functions of vitamin K-dependent clotting factors. These effects appear to be dose-dependent and greater in individuals with preexisting vitamin K deficiency. In one study, administration of vitamin E 42 units/day for one month increased the hypoprothrombinemic effect of a single dose of dicumarol in 3 healthy volunteers, as demonstrated by a decrease in prothrombin activity from 52% to 33% thirty-six hours postdose. The interaction was also suspected in a patient who developed ecchymoses and hematuria following two months of vitamin E supplementation at a dosage of 800 to 1200 units/day while taking warfarin. In contrast, two studies found no significant effect of vitamin E on the hypoprothrombinemic effect of chronic warfarin therapy when administered at relatively high dosages (800 or 1200 units/day) to 21 subjects for one month or at low dosages (100 or 400 units/day) to 12 subjects for four weeks. With respect to antiplatelet activities, data from in vitro and ex vivo human studies suggest that vitamin E can inhibit collagen-induced platelet activation and protein kinase C-dependent platelet aggregation. Clinically significant antiplatelet effects have not been consistently observed in published studies, particularly at dosages below 400 units/day. However, there have been isolated reports of excessive bleeding in surgical patients who had taken vitamin E regularly prior to surgery, and one controlled clinical trial found that supplementation with only 50 mg/day of vitamin E resulted in an increase in subarachnoid hemorrhage in male smokers aged 55 to 74 years (n=409). In a random sampling of that same population of male smokers, gingival bleeding was also more common in subjects who received vitamin E with aspirin compared to those who received either agent alone or neither.

MANAGEMENT: Patients should consult a healthcare provider before taking any nutritional supplements like vitamin E. Close clinical and laboratory observation for hematologic complications may be appropriate when vitamin E supplementation at dosages greater than 400 units/day is initiated in patients stabilized on anticoagulant or antiplatelet therapy. The dose of the anticoagulant or antiplatelet drug may require adjustment during and after treatment with vitamin E. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

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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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