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Synonyms | |||
Arava, known generically as leflunomide, is a disease-modifying antirheumatic drug (DMARD) specifically approved for the management of active rheumatoid arthritis. It’s not a dietary supplement but a prescription medication with immunomodulatory properties, acting as a pyrimidine synthesis inhibitor to reduce autoimmune activity and structural joint damage.
I remember when we first started using Arava in our rheumatology department back in the early 2000s - we were transitioning patients from older DMARDs like gold injections and penicillamine, and the difference in efficacy and tolerability was immediately noticeable. Dr. Chen, our department head, was initially skeptical about the liver toxicity warnings, but the clinical results spoke for themselves.
1. Introduction: What is Arava? Its Role in Modern Rheumatology
Arava represents a significant advancement in autoimmune disease management, specifically engineered to target the underlying pathological mechanisms of rheumatoid arthritis rather than merely suppressing symptoms. This synthetic DMARD has established itself as a cornerstone in rheumatology practice due to its ability to modify disease progression and prevent joint destruction.
What sets Arava apart from earlier DMARDs is its specific mechanism targeting rapidly dividing immune cells, which provides a more targeted approach to autoimmune regulation. The medication’s primary metabolite, teriflunomide, achieves sustained therapeutic levels with once-daily dosing, offering practical advantages for long-term disease management.
2. Key Components and Pharmacokinetics of Arava
The active pharmaceutical ingredient in Arava is leflunomide, which undergoes rapid conversion to its active metabolite teriflunomide following oral administration. This conversion occurs primarily in the gut wall and liver, with teriflunomide demonstrating an exceptionally long half-life of approximately 15-18 days due to extensive enterophepatic recirculation.
Formulation specifics:
- Available as 10mg, 20mg, and 100mg tablets
- Standard loading dose: 100mg daily for 3 days
- Maintenance dosing: 20mg daily (may be reduced to 10mg for tolerability)
- Bioavailability: >80% for teriflunomide
- Protein binding: >99% (primarily albumin)
The pharmacokinetic profile means steady-state concentrations are achieved slowly, typically requiring several months of consistent dosing. This has practical implications for both efficacy onset and toxicity management, as well as the need for the elimination procedure when rapid clearance is required.
3. Mechanism of Action: Scientific Substantiation
Arava operates through inhibition of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme crucial for de novo pyrimidine synthesis. This mechanism selectively targets activated lymphocytes, which rely heavily on this pathway during rapid proliferation in autoimmune responses.
The biochemical cascade works as follows:
- DHODH inhibition blocks conversion of dihydroorotate to orotate
- Reduced uridine monophosphate (UMP) synthesis
- Depletion of pyrimidine pools in activated T-cells and B-cells
- Cell cycle arrest in G1 phase
- Reduced autoimmune antibody production and inflammatory cytokine release
What’s fascinating clinically is how this translates to reduced radiographic progression - we’ve seen patients on Arava maintain joint space width and show minimal erosive changes even after 5+ years of disease. The cellular targeting means it doesn’t cause generalized immunosuppression like older agents.
4. Indications for Use: What is Arava Effective For?
Arava for Rheumatoid Arthritis
The primary indication for Arava is active rheumatoid arthritis in adults, with demonstrated efficacy in reducing signs and symptoms, inhibiting structural damage, and improving physical function. Multiple randomized controlled trials have shown comparable efficacy to methotrexate with different safety profiles.
Arava for Psoriatic Arthritis
While off-label, Arava shows benefit in psoriatic arthritis, particularly for peripheral joint involvement. The mechanism addressing T-cell activation aligns well with psoriatic disease pathophysiology.
We had a patient, Maria Rodriguez (62, with 15-year RA history), who failed three previous DMARDs due to gastrointestinal intolerance. Within 4 months of Arava initiation, her DAS28 score dropped from 5.8 to 3.2, and she regained the ability to knit - something she hadn’t been able to do for years due to hand deformities and pain.
5. Instructions for Use: Dosage and Administration
| Indication | Loading Dose | Maintenance Dose | Administration | Duration |
|---|---|---|---|---|
| Active RA | 100mg daily × 3 days | 20mg daily | With or without food | Long-term |
| RA (elderly/hepatic impairment) | Consider skipping | 10mg daily | With food | Long-term |
| Transition from methotrexate | None | 20mg daily after washout | Monitor closely | Long-term |
Clinical pearls:
- No dosage adjustment needed for renal impairment
- Consider 10mg maintenance for patients >65 years or with low body weight
- Therapeutic response typically observed within 4-12 weeks
- Maximum effect may take 6 months or longer
The loading dose controversy was something we debated extensively - some clinicians argued it accelerated response, while others felt it increased early dropout due to side effects. Our current practice individualizes this decision based on disease activity and patient tolerance.
6. Contraindications and Drug Interactions
Absolute contraindications:
- Pregnancy (Category X) and women planning pregnancy
- Severe hepatic impairment
- Hypersensitivity to leflunomide
- Concurrent use with teriflunomide for multiple sclerosis
Significant drug interactions:
- Rifampin: Increases teriflunomide levels
- Warfarin: Requires frequent INR monitoring
- Live vaccines: Contraindicated due to immunosuppression
- Other hepatotoxic medications: Additive risk
The pregnancy warning is particularly crucial - we’ve implemented a strict protocol requiring two negative pregnancy tests before initiation and using the elimination procedure (cholestyramine 8g TID × 11 days) for women planning conception. This wasn’t always emphasized enough in early prescribing, leading to several unfortunate situations that changed our practice.
7. Clinical Studies and Evidence Base
The Arava evidence foundation includes multiple pivotal trials:
- US301 (New England Journal of Medicine, 1999): Demonstrated superior ACR20 response vs placebo (52% vs 26%) and comparable efficacy to methotrexate
- MN302 trial: Showed significant inhibition of radiographic progression at 12 and 24 months
- Combination therapy studies: Arava with biologic DMARDs showed additive benefit with acceptable safety
Long-term extension studies have confirmed sustained efficacy over 5+ years, with radiographic data showing near-complete arrest of joint damage progression in responsive patients.
What the trials don’t always capture is the real-world variability - we’ve found about 20% of patients achieve near-complete remission, 50% good control, and 30% either don’t respond or can’t tolerate the medication. The trick is identifying who will benefit early.
8. Comparing Arava with Similar DMARDs
| Parameter | Arava | Methotrexate | Sulfasalazine | Biologics |
|---|---|---|---|---|
| Onset of action | 4-12 weeks | 4-16 weeks | 8-12 weeks | 2-8 weeks |
| Monitoring | Monthly LFTs initially | Monthly LFTs/CBC | Periodic LFTs/CBC | Varies |
| Cost | Moderate | Low | Low | High |
| Pregnancy | Absolute contraindication | Contraindicated | Compatible | Varies |
| Convenience | Once daily oral | Once weekly oral/SC | Twice daily oral | Injection/IV |
The choice often comes down to patient factors rather than pure efficacy - we consider reproductive plans, comorbidity profile, monitoring feasibility, and cost. Arava frequently serves as either first-line after methotrexate failure or as combination therapy in persistent disease.
9. Frequently Asked Questions about Arava
How long does Arava stay in your system after discontinuation?
Teriflunomide’s prolonged half-life means detectable levels may persist for months to years after stopping. The elimination procedure reduces this to approximately 11 days.
Can Arava cause hair thinning?
Yes, approximately 10% of patients experience reversible hair thinning, typically within the first 6 months. This often improves with continued use or dose reduction.
Is routine liver function monitoring necessary?
Absolutely - monthly monitoring for the first 6 months, then every 6-8 weeks indefinitely. We’ve caught several cases of asymptomatic transaminase elevation requiring dose adjustment or discontinuation.
Can Arava be used in elderly patients?
Yes, but typically at reduced dose (10mg daily) with enhanced monitoring for hepatic and hematologic parameters.
10. Conclusion: Validity of Arava Use in Clinical Practice
The risk-benefit profile of Arava supports its position as a valuable DMARD option, particularly for rheumatoid arthritis patients who have failed or cannot tolerate methotrexate. The unique mechanism, oral administration, and demonstrated efficacy in preventing structural damage make it a mainstay in our therapeutic arsenal.
Looking back over two decades of use, the learning curve was significant - we initially underestimated the monitoring requirements and overestimated the tolerability. But the patients who have done well have done remarkably well.
James Wilson, a 48-year-old contractor, comes to mind - he presented with aggressive, erosive RA that was destroying his career. After 18 months on Arava, not only was his disease controlled, but follow-up radiographs showed no new erosions. At his last visit, he brought photos of a deck he’d built, saying “This medication gave me my life back.” Those are the outcomes that justify the vigilance required. The key is appropriate patient selection, diligent monitoring, and managing expectations - not a miracle drug, but a powerful tool when used correctly.