Warfarin With Fluoroquinolones, Sulfonamides, or Azole Antifungals: Interactions and the Risk of Hospitalization for Gastrointestinal Bleeding

Abstract

Objective-To determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users.Methods-We conducted a nested case-control and case-crossover study in US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, cotrimoxazole, or fluconazole, all versus no exposure and versus cephalexin, which would not be expected to interact with warfarin.Results-All anti-infectives examined exhibited an elevated odds ratio (OR) vs. no exposure. Using cephalexin as the reference category, ORs for cotrimoxazole (OR:1.68 [95% CI:1.21-2.33] in the prior 6-10 days) and fluconazole (OR:2.09 [95% CI:1.34-3.26] in the prior 11-15 days) were significantly elevated.Conclusions-Warfarin users who had received an anti-infective agent showed a substantially increased risk of GI bleeding. Nonetheless, a drug-drug interaction with warfarin was evident only for cotrimoxazole and fluconazole.

Evidence-Based Management of Anticoagulant Therapy

“…101,104 There was less consistency in the relationship between COX-2-selective NSAIDs plus VKAs vs VKA alone and bleeding outcomes, varying from a nonsignifi cant RR of 1.4 (95% CI, 0.44-4.30) to a signifi cant OR of 3.1 (95% CI, 1.4-6.7). 100 105,112,113,115 There is a suggestion that cephalosporins (ignoring the anomalously high RR provided for cefradine), metronidazole, amoxicillin, amoxicillin/clavulanic acid, doxycycline, and fl uconazole may have some impact on bleeding risk, but these drugs in general are insuffi ciently studied. [112][113][114] Similarly, some studies suggest that selective serotonin reuptake inhibitors, tramadol, acetaminophen, coenzyme Q, and ginger may increase the risk of bleeding, but these also require confi rmation.…”

“…100 105,112,113,115 There is a suggestion that cephalosporins (ignoring the anomalously high RR provided for cefradine), metronidazole, amoxicillin, amoxicillin/clavulanic acid, doxycycline, and fl uconazole may have some impact on bleeding risk, but these drugs in general are insuffi ciently studied. [112][113][114] Similarly, some studies suggest that selective serotonin reuptake inhibitors, tramadol, acetaminophen, coenzyme Q, and ginger may increase the risk of bleeding, but these also require confi rmation. 103,105,106,116,117 Recommendations 3.8.…”

Considerations when prescribing trimethoprim-sulfamethoxazole

“…60 Two recent population-based studies have shown that among patients receiving warfarin, the use of trimethoprim-sulfamethoxazole is associated with a two-to threefold increased risk of gastrointestinal hemorrhage relative to other antibiotics. 61,62 Interactions involving drug transporters Trimethoprim also inhibits the renal organic cation transporter and sulfamethoxazole inhibits the organic anion transporter, 68,69 transport systems that normally facilitate the renal elimination of several drugs. In children receiving methotrexate, treatment with trimethoprim-sulfamethoxazole decreases organic anion transporter-mediated renal clearance of methotrexate by 40%, 23,24 increasing the risk of methotrexate toxicity (including cytopenia, mucositis, hepatotoxicity and gastrointestinal symptoms).…”

Amoxicillin/clavulanic acid‐warfarin drug interaction: a randomized controlled trial

“…Amoxicillin/clavulanic acid (amoxiclav), a member of the penicillin class, also has been suggested to potentiate the effects of warfarin [3]. Several case reports and retrospective studies stated that amoxiclav increased INR and/or the risk of bleeding with an odds ratio (OR) of 7 in patients treated with warfarin [4][5][6][7][8].…”