SAN FRANCISCO – The main reason older U.S. adults are hospitalized for drug interaction is an interaction with warfarin, so watch out for some of the main culprits: trimethoprim/sulfamethoxazole, acetaminophen, and oral steroids, advised Dr. Douglas S. Paauw.
"The biggest, most serious interaction we’re going to stumble into with warfarin" is with trimethoprim/sulfamethoxazole, he said at the annual meeting of the American College of Physicians.
Nearly 100,000 U.S. adults older than 65 years were hospitalized per year in 2007-2009 because of drug interactions, according to a study of data from the National Electronic Injury Surveillance System’s Cooperative Adverse Drug Event Surveillance Project. Warfarin led the four drug classes that caused 67% of "the mayhem," Dr. Paauw said, and was responsible for nearly three times the number of hospitalizations for drug interactions as any of the runner-ups – insulin, oral antiplatelet drugs, or oral hypoglycemics (N. Engl. J. Med. 2011;365:2002-12).
Dr. Douglas S. Paauw
Trimethoprim/sulfamethoxazole can decrease metabolism and increase prothrombin times in patients on warfarin. So can erythromycin, which "we don’t use much any more," said Dr. Paauw, professor of medicine at the University of Washington, Seattle. "Trimethoprim/sulfamethoxazole has had a resurgence because of MRSA [methicillin-resistant Staphylococcus aureus]" infection.
Other drugs that can cause similar and clinically important interactions with warfarin are amiodarone, propafenone, and three antifungals that can be a problem at high doses but not with single doses – ketoconazole/fluconazole, itraconazole, or metronidazole.
Drugs that possibly can interact with warfarin, especially in elderly patients and those on multiple medications, include quinolones, omeprazole, clarithromycin, and azithromycin.
One retrospective study of 104 patients on stable warfarin therapy found mean increases in the international normalized ratio (INR) of 1.76 in patients who also took trimethoprim/sulfamethoxazole, 0.85 with levofloxacin, and 0.51 with azithromycin, compared with a decrease of 0.15 in patients on terazosin, who served as a control group.
Another way to look at it, Dr. Paauw said, is that the INR increased beyond therapeutic levels in 69% of patients on warfarin plus trimethoprim/sulfamethoxazole, 33% of patients on warfarin plus levofloxacin, 31% on warfarin and azithromycin, or 5% on warfarin and terazosin (J. Gen. Intern. Med. 2005;20:653-6).
To treat a urinary tract infection in an anticoagulated patient, try not to use trimethoprim/sulfamethoxazole, and be worried about using quinolones, Dr. Paauw advised. Penicillins/cephalosporins are acceptable, or use nitrofurantoin, he said.
As for acetaminophen, "we always think of acetaminophen as a safe drug, but if you take enough of it – like three extrastrength Tylenol a day it can affect the INR," he said. Be aware of this, and if a patient on warfarin is taking acetaminophen regularly, check the INR more often than you normally would, he added.
Findings from three studies suggest there are INR effects from interactions of warfarin and acetaminophen.
One study of patients on warfarin who received 2 g or 4 g of acetaminophen or placebo found that 54% of patients on acetaminophen overshot their INR goal, compared with 17% on placebo (Pharmacotherapy 2007;27:675-83). In another study, taking more than 9,100 mg/wk of acetaminophen increased the risk 10-fold for developing an INR above 6.0 (JAMA 1998;279:657-62).
In a separate double-blind crossover trial, patients on warfarin and 4 g/day of acetaminophen had prothrombin times 75% greater than a control group (Clin. Res. 1984;32:698a).
Oral corticosteroids significantly increased the INR by a mean of 1.24 in patients on warfarin, giving 62% of patients an INR above their targeted range, one retrospective study found. The INR became elevated a mean of 7 days after starting steroids (Ann. Pharmacother. 2006;40:2101-6).
When you recognize that this interaction is developing, reduce the steroids but don’t decrease the warfarin dose, Dr. Paauw advised, because the INR will normalize as the steroids disappear. If you simultaneously reduce the warfarin dose, the INR will not be where you want it post corticosteroids.
Dr. Paauw reported having no relevant financial disclosures.
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