Teriflunomide and Liver Function: How to Monitor & Manage Risks

When prescribing Teriflunomide is a pyrimidine synthesis inhibitor approved for relapsing‑remitting multiple sclerosis (RRMS), doctors immediately think about the liver. The drug’s metabolism involves the hepatic cytochrome system, and real‑world data show a small but measurable risk of liver enzyme elevations. That’s why Teriflunomide liver monitoring is a non‑negotiable part of any treatment plan.

Why Teriflunomide Can Stress the Liver

Teriflunomide interferes with dihydroorotate dehydrogenase, a key enzyme in de novo pyrimidine synthesis. While this blocks the proliferation of activated lymphocytes (the therapeutic goal), the same pathway is present in hepatocytes. In clinical trials, about 6 % of patients experienced a rise in liver enzymes greater than three times the upper limit of normal (ULN), and a handful progressed to clinical hepatitis.

Understanding the mechanism helps clinicians anticipate who might be most vulnerable. Older adults, patients with pre‑existing fatty liver disease, or those on other hepatotoxic drugs (e.g., methotrexate, statins) are at a higher baseline risk.

Key Liver‑Related Entities You’ll Encounter

• ALT (alanine aminotransferase) is a liver enzyme that rises early in hepatocellular injury.
• AST (aspartate aminotransferase) reflects both liver and muscle damage; its pattern alongside ALT helps differentiate causes.
• Alkaline Phosphatase increases in cholestatic injury or biliary obstruction.
• Bilirubin is the breakdown product of hemoglobin; elevated levels indicate impaired excretion or severe hepatocellular injury.
• Hepatotoxicity describes any drug‑induced liver damage ranging from mild enzyme spikes to fulminant failure.
• Liver Function Test (LFT) is the collective term for the panel that includes ALT, AST, alkaline phosphatase, and bilirubin.
• Multiple Sclerosis (MS) is a chronic autoimmune disorder of the central nervous system; Teriflunomide is one of several disease‑modifying therapies.

Standard Monitoring Schedule

Guidelines from the European Medicines Agency (EMA) and the FDA converge on a similar timeline. Below is a practical checklist you can copy into your clinic workflow:

1. Baseline LFT panel (ALT, AST, alkaline phosphatase, bilirubin) before the first dose.
2. Repeat LFTs at week 2 and week 4 after initiation.
3. Monthly LFTs for the first six months.
4. Every 3 months thereafter as long as values stay within normal limits.
5. If any value exceeds 3 × ULN, repeat the test in 1 week.
   • If the repeat remains >3 × ULN, consider dose interruption.
   • If >5 × ULN, stop Teriflunomide and initiate accelerated elimination (cholestyramine 4 g tid or activated charcoal 50 g tid for 11 days).

Interpreting LFT Results: Action Thresholds

Managing Mild Elevations (≤ 3 × ULN)

Most clinicians keep patients on therapy if the rise is isolated, asymptomatic, and the trend is stable. Helpful steps:

• Review concomitant medications for other hepatotoxins.
• Advise alcohol moderation (≤ 1 drink day for women, ≤ 2 for men).
• Screen for fatty liver disease using ultrasound or FibroScan if risk factors exist.
• Re‑check enzymes in 1-2 weeks; if they decline, return to routine schedule.

When to Stop or Switch Therapy

Anything over 5 × ULN, or a bilirubin rise above 2 × ULN, warrants immediate discontinuation. In practice:

1. Inform the patient promptly; discuss the risk of disease rebound.
2. Arrange accelerated drug elimination (cholestyramine 4 g tid for 11 days) to bring serum levels down rapidly.
3. Transition to an alternative disease‑modifying therapy (e.g., dimethyl fumarate, ocrelizumab) after confirming safe liver values.

Document the event in the patient’s electronic health record, including the exact enzyme values and the steps taken, to satisfy both medicolegal and reimbursement requirements.

Special Populations

Pregnancy and Breastfeeding

Teriflunomide is teratogenic in animal studies, and human data suggest a birth‑defect risk of around 2 %. Women of child‑bearing potential must undergo a mandatory pregnancy‑prevention program, including effective contraception and monthly pregnancy testing.

If pregnancy occurs, initiate accelerated elimination immediately and switch to a pregnancy‑compatible MS therapy such as interferon‑β.

Elderly Patients (≥ 65 years)

Age‑related decline in hepatic blood flow can magnify drug exposure. Start at the standard 14 mg dose but monitor LFTs every 4 weeks for the first three months, then quarterly.

Patients on Polypharmacy

Strong CYP3A4 inhibitors (e.g., ketoconazole) can raise teriflunomide levels. Review the full medication list, adjust doses, or select non‑interacting alternatives.

Lifestyle Tips to Support Liver Health While on Teriflunomide

• Maintain a balanced Mediterranean‑style diet rich in antioxidants.
• Exercise at least 150 minutes of moderate activity per week; improves hepatic perfusion.
• Stay hydrated; water helps the liver process metabolites.
• Avoid over‑the‑counter pain relievers like acetaminophen > 2 g daily.

Quick Checklist for Clinicians

• Baseline LFTs before first dose.
• Follow the 2‑week, 4‑week, monthly, then quarterly schedule.
• Know the 3 × ULN and 5 × ULN thresholds.
• Have cholestyramine or activated charcoal on hand for rapid drug removal.
• Document contraception compliance in women of child‑bearing age.
• Reassess hepatic risk when adding new meds.

Frequently Asked Questions

By staying vigilant with the schedule above, interpreting results wisely, and having a clear action plan, clinicians can keep patients on Teriflunomide safely while protecting liver health.