Drug General Information (ID: DDI4018G3Y)
Drug Name			Methotrexate		Drug Info		Leflunomide		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antimetabolites				Antiinflammatory Agents
Structure

Mechanism of Methotrexate-Leflunomide Interaction (Severity Level: Major)
Increased risk of hepatotoxicity Click to Show/Hide Mechanism Graph
Drug Name		Methotrexate				Leflunomide
Mechanism		Hepatotoxicity				Hepatotoxicity
Key Mechanism Factor 1
		Factor Name		Hepatotoxicity
		Factor Description		Combination of drugs that can induce hepatotoxicity may increase the risk of liver injury. Symptoms vary depending on the level of exposure and the total extent of liver damage, and may cause few symptoms if the damage is mild, and eventually lead to liver failure in patients with severe damage.
Mechanism Description		Increased risk of hepatotoxicity by the combination of Methotrexate and Leflunomide

Recommended Action
Management		The use of leflunomide or teriflunomide in combination with methotrexate is not recommended. Since the active metabolite of leflunomide may remain in the body for up to 2 years, the cholestyramine washout procedure is recommended when changing from leflunomide to methotrexate. Liver enzyme levels should be obtained before beginning leflunomide/teriflunomide and monthly during therapy. If ALT increases to 2 to 3 times normal, the dose should be reduced and liver enzymes monitored weekly. If ALT increases to more than 3 times normal, therapy should be discontinued and the washout procedure should be instituted.

References
1	EMEA "EMEA public statement on leflunomide (ARAVA) - severe and serious hepatic reactions.".
2	Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
3	Product Information. Aubagio (teriflunomide). Genzyme Corporation, Cambridge, MA.