Thomas Szymanski, PharmD Candidate 2017

Warfarin, a vitamin K antagonist, is used to prevent thrombotic events in conditions such as 

More than 30 million warfarin prescriptions are dispensed annually, but despite the widespread use, it has many limitations. Notable drug-drug interactions include antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs). 

NSAIDs, which are used for their analgesic effect and available without a prescription, inhibit platelets and may have adverse 

 effects.  Acetaminophen, an analgesic that is commonly used worldwide, is often preferred to NSAIDs due to its more appealing adverse effect profile. Up to 18% of patients taking warfarin also take acetaminophen, but clinicians may not recognize the potential interaction between the two medications.

            Numerous case reports have been published that describe patients taking warfarin who experienced supratherapeutic INRs and bleeding events after taking moderate-to-high doses of acetaminophen for multiple days.  The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding.  International normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with one study reporting a patient who had a prothrombin time (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while fresh frozen plasma and/or vitamin K was administered to reverse the effects of warfarin of the others.  Patients consumed a range from approximately 1 to 4 grams of acetaminophen per day over a range of 4 to 10 days in the case reports. In 2 case reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.

            A 2005 double-blind, crossover study that enrolled 11 patients on a stable dose of warfarin assigned patients to receive 1 g of acetaminophen or placebo 4 times daily for 15 days, with a washout period between the two phases.  The mean maximum increase in INR was 1.04 in the acetaminophen phase versus 0.20 in the placebo phase (

  A continuation of this study that enrolled 9 additional patients showed a mean maximum increase in INR of 1.20 in the acetaminophen phase versus 0.37 in the placebo phase 

 <0.001), as well as decreased activities of factors II, VII, IX, and X.  No bleeding events were reported during the study.

            A more recent randomized, placebo-controlled trial enrolled 45 patients on a stable dose of warfarin to receive acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio.  The mean maximum increase in INR was 0.70 and 0.67 in patients receiving 2 and 3 g/day, respectively (

 <.02 vs placebo).  Notably, treatment was discontinued when the INR rose to 3.5 or higher.

            A 2015 meta-analysis included 7 randomized controlled trials with patients taking vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The mean INR increase for patients taking acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding event occurred.  The trials excluded patients with labile INRs and the INR was carefully monitored throughout the trials, possibly contributing to the small number of bleeding events.

Several mechanisms have been proposed to explain the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a result of the metabolism of acetaminophen by CYP2E1, can be rapidly cleared by conjugation with glutathione in the liver.  NAPQI accumulation may be present in overdose and in the setting of induction of CYP2E1 by acetaminophen itself, ethanol, or 

.  NAPQI may disrupt vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), thus inhibiting the vitamin K cycle at multiple points.  Other mechanisms may include the production of peroxynitrite and subsequent inactivation of VKOR, as well as competitive inhibition of warfarin metabolism by acetaminophen through the CYP enzymes.

Despite the availability of evidence of the interaction between acetaminophen and warfarin since the 1960s, data concerning the clinical significance of the interaction remains scarce.  Recommendations regarding the management of patients taking both drugs are not strong because no studies examining outcomes, such as major bleeding, exist.  It may be prudent to monitor the INR more frequently if a patient who was previously stable on a dose of warfarin begins taking scheduled acetaminophen.  Finally, in otherwise unexplained INR variability, this interaction could be considered a contributing factor.

1.         Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. 

2.         Mahé I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic risk factor in patients on warfarin. 

3.         Mahé I, Bertrand N, Drouet L, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. 

4.         Zhang Q, Bal-dit-Sollier C, Drouet L, et al. Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial. 

5.         Caldeira D, Costa J, Barra M, Pinto FJ, Ferreira JJ. How safe is acetaminophen use in patients treated with vitamin K antagonists? A systematic review and meta-analysis. 

6.         Lopes RD, Horowitz JD, Garcia DA, Crowther MA, Hylek EM. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. 

Articles

Up to 18% of patients taking warfarin also take acetaminophen, but clinicians may not recognize the potential interaction between the two medications.

Acetaminophen and Warfarin: The Forgotten Interaction

	A patient dropped off a prescription for sucralfate at my community pharmacy and commented that she would not have needed this medication if she had been counseled on how to properly take her doxycycline. She took her doses without water and her second dose just before she went to bed; several days into her therapy, her throat began to burn and she experienced pain when swallowing.

Pharmacists, as medication experts and the most accessible healthcare professionals, are in the perfect position to prevent such situations. It is, therefore, imperative that pharmacists recognize the medications that are most likely to cause drug-induced esophagitis and know how to counsel patients.

The incidence of drug-induced esophagitis is estimated to be 3.9 per 100,000 population per year. The mean age is 41.5 years, with women being affected more often than men; this may be due to the fact that women consume more offending medications.

 Other risk factors include increasing age, decreased saliva production, and altered esophageal motility. Patients often present with retrosternal pain, odynophagia, and dysphagia, with abdominal pain and hematemesis being uncommon symptoms. Esophageal irregularities can be a result of systemic abnormalities, such as gastroesophageal reflux or compromise of the immune system, or direct esophageal irritation. Medications that cause direct esophageal mucosal injury will be reviewed here.

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications have a low pH when dissolved in solution, such as saliva, and cause transient esophageal injury that heals after withdrawal. Doxycycline has also been shown to accumulate within the basal layer of esophageal squamous epithelium, suggesting another possible mechanism for local irritation.

Potassium is known for causing small bowel ulceration, and as a hyperosmotic solution, it may cause esophageal damage. In a series of case reports of patients with drug-induced esophagitis, most patients had enlarged left atria, which delayed the passage of potassium, suggesting another risk factor.

Bisphosphonates, especially alendronate, are well-known causes of esophagitis. While bleeding is rare, inflammation and ulceration with thickening of the esophageal wall are often seen on endoscopy.

In studies, most patients with esophagitis failed to take the bisphosphonate with an adequate quantity of water (180 ml), failed to remain upright for 30 minutes, or both. Patients taking risedronate 5 mg daily, on the other hand, did not experience any more toxicity than did patients taking placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs disrupt the normal cytoprotective action of prostaglandins on gastric mucosa and may have similar effects on the esophageal mucosa. Drugs implicated in case reports include ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most common cause of esophagitis, as many as 40-50% of patients may develop strictures and some may experience non-fatal hemorrhages. In addition, most of the affected patients had prior symptoms of gastroesophageal reflux disease.

Most cases of drug-induced esophagitis resolve with no complications. Reinjury with the offending drug should be avoided with proper measures to prevent recurrence. Topical pain relievers, such as viscous lidocaine, are sometimes used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are used to protect the injured mucosa from gastric acid, but little evidence is available to support their use.

  Patients should be counseled to take medications known to be irritating to the esophagus with a full glass of water (180 ml) and to avoid lying down for at least 30 minutes after taking their dose.

1.         Zografos GN, Deorgiadou D, Thomas D, Kaltsas G. Drug-induced esophagitis. 

2.         Kikendall JW. Pill-induced esophagitis. 

3.         de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. 

4.         Taggart H, Bolognese MA, Lindsay R, et al. Upper gastrointestinal tract safety of risedronate: A pooled analysis of 9 clinical trials. 

A patient dropped off a prescription for sucralfate at my community pharmacy and commented that she would not have needed this medication if she had been counseled on properly taking certain medications.