What dose adjustments need to be made for antirheumatic medications in patients with severe hepatobiliary disease?
Severe liver disease can be defined as a combination of one or more of the following factors: elevated bilirubin > 3 mg/dL, albumin < 3 g/dL with ascites, elevated prothrombin time/international normalized ratio not fully corrected by vitamin K, and/or cirrhosis on liver biopsy. Elevated transaminases greater than three times upper limit of normal should also be a concern. Also note that since creatine is synthesized in the liver, serum creatinine may be an overestimate of renal function.
Hepatobiliary disease may substantially impair the elimination or activation of drugs that the liver metabolizes or excretes. Although glucuronidation is spared, oxidation and acetylation are slowed. In addition, decreased synthesis of albumin may lead to increased free fraction of the active drug. Decreased synthesis of vitamin K-dependent clotting factors may lead to increased risk of bleeding if a medication affects platelet function or number.
The following are guidelines for antirheumatic drug therapy in severe liver disease:
• Pro-drug metabolism —azathioprine, leflunomide, cyclophosphamide, prednisone, and sulindac need to be converted to the active moiety by the liver. This is impaired in patients with severe hepatic insufficiency. Consequently, these drugs should be avoided or replaced with active form (i.e., 6-mercaptopurine, prednisolone).
• Biliary excretion —methotrexate, cyclosporine, colchicine, leflunomide, indomethacin, and sulindac are excreted in the bile and undergo enterohepatic circulation. These should be avoided in patients with impaired biliary function.
• Change in drug dosage for severe liver disease
– Acetaminophen: Use up to maximum dose of 2 g/day or not at all.
– Antimalarials: Use with caution and at lower doses. The American College of Rheumatology (ACR) guidelines recommend avoidance in patients with Child–Pugh class C liver disease.
– Anti-TNFα inhibitors: Probably safe. Avoid in setting of untreated hepatitis B, but may be safe during treatment. Safe in hepatitis C. Frequent liver enzyme monitoring advised.
– Allopurinol: Little data. Use with caution. Can cause severe hepatitis.
– Apremilast: No adjustment necessary.
– Azathioprine: Use 6-mercaptopurine instead but use at low dose with caution since toxicity can occur quickly.
– Bisphosphonates: Probably safe.
– Biologics (other): Little data. Would avoid or use tocilizumab and tofacitinib with caution since they can have liver toxicity. Avoid all in setting of viral hepatitis.
– Colchicine: Avoid.
– Cyclophosphamide: May not be converted to active form.
– Cyclosporine and tacrolimus: Eliminated by liver, so avoid.
– Febuxostat: Metabolized by the liver. Can cause liver toxicity. Avoid or use with caution at lower doses.
– Janus Kinase inhibitors: Little data, but pharmacokinetic studies of tofacitinib indicate 70% hepatic metabolism and 30% renal excretion for clearance of the drug. Thus, a dose adjustment is likely needed for Child–Pugh class B and recommend avoidance in class C. No information for viral hepatitis.
– Leflunomide: Avoid.
– Methotrexate: Avoid.
– Mycophenolate mofetil: No dosage change, but do not exceed 2 g/day.
– Narcotics: Most metabolized by liver. Fentanyl and hydromorphone safest. Need to lower dose or extend interval. Avoid meperidine.
– NSAIDs: Lower dose 50%. Avoid diclofenac, sulindac, and indomethacin. Note that NSAIDs even at low doses increase risk of bleeding and renal failure.
– Prednisone: Use prednisolone or methylprednisolone instead.
– Sulfasalazine: Use with caution and at lower doses. Can cause hepatic failure rarely. ACR guidelines recommend avoidance in Child–Pugh class C liver disease.
– Tramadol: Double dosing interval from 6 to 12 hours. Start at dose of 25 mg.