Drug Interactions between aspirin / caffeine / salicylamide and leflunomide

MONITOR CLOSELY: The recent, concomitant, or subsequent use (without the recommended leflunomide washout period or procedure) of other agents known to induce hepatotoxicity including NSAIDs and salicylates may potentiate the risk of liver injury associated with leflunomide. The risk is thought to extend to teriflunomide, its principal active metabolite, because recommended dosages of both result in a similar range of plasma concentrations of teriflunomide. Elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis have been reported with the use of leflunomide. Liver enzyme elevations were generally mild (2 times the upper limit of normal or less) and resolved while continuing treatment. Marked elevations (greater than 3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment in most cases. However, fatalities associated with severe liver injury have also been reported rarely. A 2009 review of leflunomide adverse event reports by the FDA identified 49 cases of severe liver injury, including 14 cases of fatal liver failure, between August 2002 and May 2009. An additional five patients required a liver transplant and nine patients experienced a life-threatening event. In this review, concomitant use of other hepatotoxic drugs and preexisting liver disease were associated with the greatest risk for liver injury during leflunomide treatment. Specifically, 46 of the 49 patients were also taking other medications that have been associated with liver injury including methotrexate, TNF-alfa blockers, hydroxychloroquine, acetaminophen, nonsteroidal anti-inflammatory drugs and statins, and 14 patients had preexisting liver disease such as active or chronic hepatitis and/or a history of alcohol abuse. The estimated duration of leflunomide exposure before onset of severe liver injury ranged from 9 days to 6 years, with the majority occurring within the first 6 to 12 months of treatment.

Pharmacokinetically, the active metabolite of leflunomide has been shown to cause increases of 13% to 50% in the free fraction of diclofenac and ibuprofen. Additionally, in vitro studies indicate that the metabolite inhibits hepatic microsomal enzyme CYP450 2C9, which participates in the metabolism of many NSAIDs. The clinical significance is unknown.

MANAGEMENT: Patients receiving leflunomide or teriflunomide in combination with NSAIDs should be closely monitored for hepatotoxicity. Liver enzymes and bilirubin should be measured prior to initiation of leflunomide/teriflunomide therapy and at least monthly for the first six months of treatment and every 6 to 8 weeks thereafter. Patients with preexisting liver disease or elevated baseline liver enzymes (i.e., ALT greater than two times the upper limit of normal) should not receive leflunomide or teriflunomide. Patients who develop elevated serum ALT greater than three times ULN while receiving these medications should discontinue treatment and be given washout procedures with cholestyramine or activated charcoal to accelerate elimination of leflunomide's active metabolite from plasma, which otherwise may take up to two years. Follow-up monitoring should be conducted at least weekly until the ALT value is within normal range, and washout procedures repeated as necessary. All patients treated with leflunomide or teriflunomide should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, light colored stools, and jaundice.

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MONITOR CLOSELY: The recent, concomitant, or subsequent use (without the recommended leflunomide washout period or procedure) of other agents known to induce hepatotoxicity including NSAIDs and salicylates may potentiate the risk of liver injury associated with leflunomide. The risk is thought to extend to teriflunomide, its principal active metabolite, because recommended dosages of both result in a similar range of plasma concentrations of teriflunomide. Elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis have been reported with the use of leflunomide. Liver enzyme elevations were generally mild (2 times the upper limit of normal or less) and resolved while continuing treatment. Marked elevations (greater than 3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment in most cases. However, fatalities associated with severe liver injury have also been reported rarely. A 2009 review of leflunomide adverse event reports by the FDA identified 49 cases of severe liver injury, including 14 cases of fatal liver failure, between August 2002 and May 2009. An additional five patients required a liver transplant and nine patients experienced a life-threatening event. In this review, concomitant use of other hepatotoxic drugs and preexisting liver disease were associated with the greatest risk for liver injury during leflunomide treatment. Specifically, 46 of the 49 patients were also taking other medications that have been associated with liver injury including methotrexate, TNF-alfa blockers, hydroxychloroquine, acetaminophen, nonsteroidal anti-inflammatory drugs and statins, and 14 patients had preexisting liver disease such as active or chronic hepatitis and/or a history of alcohol abuse. The estimated duration of leflunomide exposure before onset of severe liver injury ranged from 9 days to 6 years, with the majority occurring within the first 6 to 12 months of treatment.

Pharmacokinetically, the active metabolite of leflunomide has been shown to cause increases of 13% to 50% in the free fraction of diclofenac and ibuprofen. Additionally, in vitro studies indicate that the metabolite inhibits hepatic microsomal enzyme CYP450 2C9, which participates in the metabolism of many NSAIDs. The clinical significance is unknown.

MANAGEMENT: Patients receiving leflunomide or teriflunomide in combination with NSAIDs should be closely monitored for hepatotoxicity. Liver enzymes and bilirubin should be measured prior to initiation of leflunomide/teriflunomide therapy and at least monthly for the first six months of treatment and every 6 to 8 weeks thereafter. Patients with preexisting liver disease or elevated baseline liver enzymes (i.e., ALT greater than two times the upper limit of normal) should not receive leflunomide or teriflunomide. Patients who develop elevated serum ALT greater than three times ULN while receiving these medications should discontinue treatment and be given washout procedures with cholestyramine or activated charcoal to accelerate elimination of leflunomide's active metabolite from plasma, which otherwise may take up to two years. Follow-up monitoring should be conducted at least weekly until the ALT value is within normal range, and washout procedures repeated as necessary. All patients treated with leflunomide or teriflunomide should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, light colored stools, and jaundice.

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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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