Usage
Leflunomide is prescribed for the treatment of active rheumatoid arthritis (RA) and psoriatic arthritis in adults. It belongs to the pharmacological classification of disease-modifying antirheumatic drugs (DMARDs), specifically a pyrimidine synthesis inhibitor. It works by inhibiting the enzyme dihydroorotate dehydrogenase (DHODH), which plays a crucial role in the de novo synthesis of pyrimidines, essential building blocks for DNA and RNA. By reducing pyrimidine availability, leflunomide suppresses the proliferation of lymphocytes, key components of the immune system driving inflammation in conditions like RA.
Alternate Names
Leflunomide is also known by its brand name Arava. It’s marketed under various other brand names internationally, such as Arabloc. The principal active metabolite of Leflunomide is teriflunomide.
How It Works
Pharmacodynamics: Leflunomide’s primary effect is the inhibition of DHODH, leading to a reduction in pyrimidine biosynthesis. This, in turn, suppresses the proliferation of activated lymphocytes, particularly T cells, which mediate immune responses and drive inflammation in rheumatoid arthritis.
Pharmacokinetics: Leflunomide is rapidly absorbed after oral administration and is almost completely metabolized to its active metabolite, teriflunomide (A77 1726), in the gut and liver. Teriflunomide is responsible for the majority of the drug’s therapeutic effect. It reaches peak plasma concentrations within 1 to 24 hours with a loading dose and 1 to 4 weeks without a loading dose. It is highly protein-bound and has a long half-life of approximately 2 weeks, resulting in prolonged drug effects. The mode of action at the cellular level is the inhibition of DHODH, thereby disrupting pyrimidine synthesis necessary for cell division and proliferation, primarily affecting rapidly dividing cells like activated lymphocytes. Teriflunomide is primarily eliminated through hepatic metabolism and biliary excretion, with a minor portion excreted unchanged in the urine. While leflunomide has minimal affinity to DHODH, its metabolite A77 1726 inhibits DHODH efficiently.
Dosage
Standard Dosage
Adults:
- With Loading Dose: 100 mg orally once daily for 3 days, followed by a maintenance dose of 20 mg orally once daily.
- Without Loading Dose: 20 mg orally once daily.
- Lower Maintenance Dose: For patients with difficulty tolerating the 20 mg dose, a reduction to 10 mg once daily can be considered.
- Psoriatic Arthritis: 20 mg orally once daily.
Children:
Leflunomide is not recommended for use in patients under 18 years of age as efficacy and safety have not been established.
Special Cases:
- Elderly Patients: No dosage adjustment is generally required.
- Patients with Renal Impairment: Caution should be exercised in patients with mild renal insufficiency. For moderate to severe renal impairment, leflunomide is contraindicated.
- Patients with Hepatic Dysfunction: Leflunomide is contraindicated in patients with pre-existing liver disease or significant hepatic impairment.
- Patients with Comorbid Conditions: Monitor patients closely with comorbid conditions such as diabetes or cardiovascular diseases. Close monitoring and dosage adjustment are necessary in high-risk patients, e.g., those with active infection, those taking other hepatotoxic or hematotoxic agents, and those with active viral or bacterial infections. Dose reduction to 10 mg daily is recommended for patients concurrently taking methotrexate, as this combination increases the risk of hepatotoxicity.
Clinical Use Cases
Leflunomide is specifically indicated for the management of rheumatoid arthritis and psoriatic arthritis and does not have clinical applications in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dosage adjustments may be required in patients with hepatic or renal impairment or those experiencing adverse effects. Therapeutic drug monitoring may be helpful, especially when adjusting dosage and before switching to another DMARD, and also when managing adverse effects or during pregnancy.
Side Effects
Common Side Effects
- Diarrhea
- Nausea
- Alopecia (hair loss)
- Elevated liver enzymes
- Headache
- Dizziness
- Weight loss
- Rash
- Hypertension
- Respiratory infections
Rare but Serious Side Effects
- Severe liver injury (including fatal liver failure)
- Bone marrow suppression (leading to anemia, leukopenia, thrombocytopenia)
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Interstitial lung disease
- Peripheral neuropathy
Long-Term Effects
- Potential for chronic liver disease with prolonged use
- Increased risk of infections
Adverse Drug Reactions (ADR)
Clinically significant ADRs include severe liver injury, bone marrow suppression, serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), interstitial lung disease and peripheral neuropathy.
Contraindications
- Pregnancy
- Breastfeeding
- Severe hepatic impairment
- Moderate to severe renal impairment
- Immunodeficiency states (e.g., AIDS)
- Bone marrow suppression
- Hypersensitivity to leflunomide or its components
Drug Interactions
Leflunomide can interact with several medications, including:
- Other DMARDs (e.g., methotrexate): Increased risk of liver toxicity.
- Hepatotoxic drugs: Increased risk of liver damage.
- Warfarin: Altered anticoagulant effect.
- Cholestyramine: Decreases leflunomide levels (used for drug elimination procedure).
- Rifampin: Increases leflunomide levels.
- Live vaccines: Should be avoided.
- CYP450 substrates: Potential for altered metabolism.
Additionally, interactions with other commonly prescribed medications (e.g. nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose corticosteroids), OTC drugs and supplements, food, and lifestyle factors should be considered.
Pregnancy and Breastfeeding
Leflunomide is contraindicated in pregnancy due to the risk of teratogenicity. Women of childbearing potential must use reliable contraception during and after treatment. A drug elimination procedure with cholestyramine is recommended for women planning pregnancy. Leflunomide is contraindicated during breastfeeding.
Drug Profile Summary
- Mechanism of Action: DHODH inhibitor, suppresses lymphocyte proliferation.
- Side Effects: Diarrhea, nausea, alopecia, elevated liver enzymes, headache, hepatotoxicity, bone marrow suppression, serious skin reactions, interstitial lung disease.
- Contraindications: Pregnancy, breastfeeding, hepatic impairment, renal impairment, immunodeficiency.
- Drug Interactions: Methotrexate, other hepatotoxic medications, warfarin, rifampin, live vaccines.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Adults: 20 mg once daily (with or without loading dose).
- Monitoring Parameters: Liver function tests (LFTs), complete blood count (CBC) including platelets, renal function. Lipid levels and blood pressure monitoring may also be required.
Popular Combinations
Methotrexate is sometimes used in combination with leflunomide, but this increases the risk of hepatotoxicity, requiring strict monitoring. Low-dose corticosteroids and NSAIDs can be used concomitantly.
Precautions
- General Precautions: Monitor liver function, blood counts, and renal function. Assess for infections, TB, and pregnancy before initiating treatment.
- Specific Populations: Contraindicated in pregnancy and breastfeeding. Caution in elderly and those with renal impairment.
- Lifestyle Considerations: Alcohol consumption should be minimized due to the potential for hepatotoxicity.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Leflunomide?
A: The recommended adult dosage is 20 mg orally once daily. A loading dose of 100 mg once daily for 3 days may be used but can increase the risk of side effects. For certain patient populations, a maintenance dose of 10 mg once daily can be considered.
Q2: How long does it take for Leflunomide to work?
A: The therapeutic effect is usually observed within 4-6 weeks, with potential further improvement up to 4-6 months.
Q3: What are the most common side effects of Leflunomide?
A: The most common side effects include diarrhea, nausea, alopecia, elevated liver enzymes, headache, and respiratory infections.
Q4: What are the serious side effects of Leflunomide?
A: Serious side effects can include liver damage, bone marrow suppression, severe skin reactions, interstitial lung disease, and peripheral neuropathy.
Q5: Can Leflunomide be used during pregnancy or breastfeeding?
A: No, Leflunomide is contraindicated during pregnancy and breastfeeding due to the potential for serious fetal harm.
Q6: What medications interact with Leflunomide?
A: Leflunomide can interact with methotrexate, other hepatotoxic medications, warfarin, rifampin, and live vaccines.
Q7: What monitoring is required while on Leflunomide?
A: Regular monitoring of liver function tests (LFTs), complete blood count (CBC) with platelets, renal function, and blood pressure are essential.
Q8: How is Leflunomide eliminated from the body if pregnancy occurs?
A: A drug elimination procedure using cholestyramine is implemented to expedite the removal of Leflunomide.
Q9: What is the mechanism of action of Leflunomide?
A: Leflunomide inhibits dihydroorotate dehydrogenase (DHODH), an enzyme crucial for pyrimidine synthesis, which ultimately reduces lymphocyte proliferation and inflammation.
Q10: Can Leflunomide be used in children?
A: Leflunomide is not recommended for children under 18, as safety and efficacy haven’t been established.
