Arava (Leflunomide)

Leflunomide (Arava) is a disease-modifying anti-rheumatic drug (DMARD) indicated (approved for use) for the treatment of adults with RA to reduce signs and symptoms, inhibit structural damage, and improve physical functioning.1

Leflunomide was introduced about two decades ago and is considered a second choice to methotrexate. It provides efficacy similar to methotrexate, including similar ACR20 disease control, slowing of disease progression (as shown by x-ray), and improvement of functioning. Additionally, it is associated with greater improvement in quality of life compared with methotrexate.2,3

 

How dose leflunomide work?

Leflunomide is an immunodulatory drug that inhibits the production of immune system cells. Specifically, leflunomide inhibits the production of chemical compounds that are necessary for synthesis of lymphocytes.2

 

How is leflunomide taken?

Leflunomide is taken orally as a tablet. Daily dosing of leflunomide in patients with RA typically ranges from 10 mg to 20 mg. Your doctor will determine which dose is appropriate for you based on how well you tolerate and respond to the medication. Treatment with leflunomide is usually started with a large initial dose (called a loading dose) of 100 mg per day (given in a single tablet) taken for three consecutive days.1

 

How long does it take for leflunomide to achieve full effect?

Because it takes time for leflunomide (as well as most other conventional DMARDs) to build-up in the body, it may take several weeks before the drug takes full effect. You may not experience the full benefits of leflunomide until 6 to 12 weeks after you start therapy.4

 

What should I do if I miss a dose of leflunomide?

If you miss a dose of leflunomide, take the missed dose as soon as you remember it. However, if it is close to the time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.5

 

How should I store leflunomide?

You should store leflunomide in the original container that it came in. Make sure that it is tightly sealed and kept out of reach of children. Keep the container at room temperature and away from moisture (not in your bathroom). Make sure that you discard any leflunomide that is outdated. Your pharmacist can tell you how to safely dispose of outdated or unused medication.5

 

Are there people who should not take leflunomide?

You should not take leflunomide if you are pregnant or planning to become pregnant. This is because leflunomide may cause harm to a fetus. Before you start leflunomide, your doctor will give you a pregnancy test to make sure that you are not pregnant. You should use effective birth control before beginning treatment with leflunomide, during treatment, and for two years after discontinuing treatment. Talk to your doctor if you become pregnant within two years after stopping treatment with leflunomide.5

Leflunomide can cause liver damage that can be fatal. The risk is highest in patients with liver disease or those taking other drugs known to cause liver damage. So, if you drink or have ever drunk large amounts of alcohol or if you have or have ever had liver disease, you may not be a candidate for treatment with leflunomide.5

You should not take leflunomide if you are allergic to the drug or any of its ingredients.5

 

What evidence do we have that leflunomide works in RA?

The effectiveness of leflunomide in RA was demonstrated in three randomized, controlled trials. Results from these studies showed that leflunomide reduced the symptoms of RA and slowed the process of damage to joints and related structures.

One two-year study (US301) compared leflunomide (20 mg/day) with methotrexate (7.5 mg/week) and placebo in a total of 508 patients.1

A 52-week, randomized, controlled study (MN302) conducted in 999 patients with RA compared leflunomide (20 mg/day) with methotrexate (7.5 to 15 mg/week whilea folic acid supplement was given to 10% of patients). This study was followed by a 1-year double-blind extension (MN304).1

A 24-week, randomized, controlled trial (MN301) conducted in 358 patients with RA compared leflunomide 20 mg/day with sulfasalazine 2.0 g/day and placebo. This study was followed by a 6-month blinded extension (MN303). Patients who completed both of these studies were given the opportunity to participate in a 1-year double-blind extension, in which all patients received an active treatment (those who had originally received leflunomide continued on that drug and placebo patients received sulfasalazine).1

Across these trials leflunomide was significantly more effective than placebo and similarly effective as methotrexate in providing disease control, with ACR20 response ranging from 51% to 55% for leflunomide compared with 46% to 65% for methotrexate. Leflunomide was also similar to sulfasalazine in RA disease control.1

 

ACR response rates in pivotal studies of leflunomide

Study Comparators
ACR20
ACR50
ACR70

US301 (12 months)

Leflunomide
52%
34%
20%
Placebo
26%
8%
4%
Methotrexate
46%
23%
9%

MN301 (6 months)

Leflunomide
55%
30%
8%
Placebo
29%
14%
2%
Sulfasalazine
57%
30%
8%

MN302 (12 months)

Leflunomide
51%
31%
10%
Methotrexate
65%
44%
16%

 

Slowing radiographic progression. A systematic review of results from studies of conventional DMARDs (the review encompassed 25 trials including almost 4,000 patients) has shown that leflunomide and other DMARDs are significantly more effective than placebo and similar in their effectiveness in slowing joint erosion. Results from the extensions of the pivotal studies of leflunomide have shown that benefits in terms of slowing of progression (as shown by x-ray evidence) continue beyond 2 years.2

Physical functioning. Similar to other DMARD treatments, leflunomide is effective in improving function as well as reducing disease activity. Functional improvements as measured by the Health Assessment Questionnaire (HAQ) are similar in scope to decreases in disease activity. A study looking at short-term changes in functioning in 807 RA patients who received leflunomide found that over a 6-month period HAQ scores fell (indicating improvement) by 0.38 compared with no change among patients who received placebo.2

 

What are the side effects of leflunomide?

Common side effects with leflunomide include5:

  • Vomiting
  • Diarrhea
  • Headache
  • Heartburn
  • Dizziness
  • Weight loss
  • Back pain
  • Muscle pain or weakness
  • Hair loss
  • Mouth sores
  • Nerve sensations including pain, burning, numbness, or tingling affecting the hands or feet

 

In some patients, leflunomide can cause serious side effects. These include rash, hives, difficulty breathing, chest pain, new or worsening cough, skin peeling or blistering, and pale skin. If you experience any of these, or nausea, extreme tiredness, unusual bleeding or bruising, lack of energy, loss, appetite loss, pain affecting the upper right part of the stomach, yellowing of the skin or eyes, dark-colored urine, or flu-like symptoms, contact your doctor immediately.5

 

Warnings and precautions with leflunomide

You should not take leflunomide if you are pregnant or planning to become pregnant. This is because leflunomide may cause harm to a fetus. Before you start leflunomide, your doctor will give you a pregnancy test to make sure that you are not pregnant. You should use effective birth control before beginning treatment with leflunomide, during treatment, and for two years after discontinuing treatment. Talk to your doctor if you become pregnant within two years after stopping treatment with leflunomide.5

If you are planning to take leflunomide, tell your doctor if you are breast-feeding.5

If you are planning on fathering a child, you should tell your doctor so that you can stop taking leflunomide and receive a treatment that will speed up clearance of the drug from your system.5

Leflunomide can cause your blood pressure to increase. You should have your blood pressure checked before starting leflunomide and regularly during treatment.5

Because leflunomide dampens or decreases your immune system activity (this is why it is effective in RA), your risk for developing serious infections is increased while you take leflunomide. Alert your doctor immediately if you develop any infection while taking leflunomide. Also, let your doctor know if you have ever had a serious infection, if you frequently get infections, or if you have ever had a condition that affects your immune system function (eg. cancer affecting your bone marrow, HIV or AIDS, or kidney disease).5

You should not receive any vaccination while you are taking leflunomide without first talking with your doctor.5

If you have been exposed to tuberculosis (TB) (a serious infection that affects your lungs) but do not have symptoms, leflunomide can make you develop symptoms. Make sure to tell your doctor if you have ever had TB. Your doctor will give you a test to determine whether you have TB.5

Leflunomide can cause liver damage that can be fatal. The risk is highest in patients with liver disease or those taking other drugs known to cause liver damage. So, if you drink or have ever drunk large amounts of alcohol or if you have or have ever had liver disease, you may not be a candidate for treatment with leflunomide.5

 

Drug interactions

Leflunomide can interact with a number of medications when taken at the same time. If you are taking leflunomide, talk to your doctor before taking Tylenol (acetaminophen) or non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, Advil or Motrin (ibuprofen), or Aleve or Naprosyn (naproxen) or cholesterol-lowering medications (statins), Enbrel (etanercept), the DMARD hydroxychloroquine, iron products, isoniazid (a TB treatment contained in Nydrazid and Rifamate), methotrexate, niacin (nicotinic acid), or rifampin (Rifadin, Rimactane, Rifamate, Rifater).5

Leflunomide can also interact with blood thinners (also called anticoagulants) such as Coumadin (warfarin) and other drugs including cholestyramine (Prevalite, Questran), colestipol (Colestid),  gold compounds including auranofin (Ridaura) and aurothioglucose (Aurolate, Solganol), anti-cancer drugs, and other immunosuppressive drugs including azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), sirolimus (Rapamune), and tacrolimus (Prograf).5

 

Is a generic available for leflunomide?

No.

Written by: Jonathan Simmons | Last reviewed: September 2013.
View References