Leflunomide

Leflunomide is marketed under the brand name Arava. It is used to treat adult rheumatoid arthritis and psoriatic arthritis. Rheumatoid arthritis is an autoimmune disease characterized by painful and swollen joints, which can cause impaired physical function and bone deterioration and deformities. Psoriatic arthritis is psoriasis (a skin disease) that also involves joint pain. Leflunomide is a disease-modifying antirheumatic drug (DMARD) that suppresses the immune system and alleviates many symptoms of the diseases.

Extremely rare cases of liver damage have been reported during treatment with the drug. These problems have manifested as jaundice, hepatitis, or liver failure. This liver damage and other serious adverse events, such as dangerous infections or a potential increase in the risk of cancer, have prompted some public watchdog groups to call for its removal from the market.

Leflunomide was approved for use by the Food and Drug Administration (FDA) in September 1998 and is now approved for use in many other countries, including Canada and the European Union.

Uses

Leflunomide is used to treat adults with active rheumatoid arthritis or psoriatic arthritis. In the United States, it is an orphan drug (one used to treat diseases or conditions that occur in fewer than 200,000 patients) used to suppress the immune system in patients receiving transplants of organs such as the kidney or liver. Sometimes leflunomide is used off-label to treat viral damage (polyomavirus nephropathy) in kidney transplant recipients being treated with immunosuppressant drugs.

Normal joint vs. joint affected by rheumatoid arthritis. Courtesy of National Institutes of Health

How It Works

Leflunomide is a type of drug called a DMARD (disease-modifying antirheumatic agent). These drugs are designed to suppress the immune system. Unlike non-steroidal anti-inflammatory drugs (NSAIDs), which treat short-term symptoms only, DMARDs are thought to actually modify the course of the disease by slowing down or preventing its progression. This immunosuppressant effect is helpful in patients who are undergoing organ transplants and need to have their immune systems suppressed so as not to reject the organs.

Leflunomide suppresses the immune system by preventing the activation and replication of B cells and T cells (white blood cells that are partly responsible for the immune response). The inflammatory response is suppressed by reducing the production of cytokines, which are proteins that activate the immune system. It works by inhibiting the synthesis of pyrimidines, which are part of the DNA molecule.

How Leflunomide is Taken

Leflunomide is available in tablets of 10 mg, 20 mg, and 100 mg. The highest dose is given to rapidly achieve peak plasma levels (high levels in the bloodstream), whereas the 10 mg and 20 mg are taken daily as the maintenance dosage. Leflunomide may be given together with other anti-inflammatory drugs to treat arthritis, and with other immunosuppressants in transplant patients.

How the Body Affects Leflunomide

Following ingestion, leflunomide is metabolized (broken down) to a compound called M1 (A771726), which is the active form of the drug. The CYP1A2 enzyme in the liver at least partly converts leflunomide into M1.^[1] M1 reaches peak levels in plasma 6 to 12 hours after ingestion. Leflunomide is eliminated slowly from the body. The concentration of leflunomide in the blood is reduced by half, called the half-life, after two weeks. M1 is recycled in the body by the bile, and this probably accounts for its long half-life. Leflunomide is eliminated from the body in both urine and feces.

Side Effects

• Liver damage: A major concern during treatment with leflunomide is the development of hepatotoxicity, or liver damage. This complication is extremely rare. The damage may manifest as cirrhosis or necrosis (death of liver cells). Patients can develop jaundice, hepatitis, or liver failure. In very rare cases the toxicity can result in death. Hepatotoxicity is detected by blood tests, which are done before and during treatment. The treatment is stopped if the test results are abnormal.

• Increased risk of infection: The immunosuppression caused by leflunomide alone or when used in combination with other drugs may increase a person's susceptibility to serious infections like sepsis, tuberculosis or pneumonia. Myelosuppression, or dangerously low levels of immune cells and other blood cells, has also been reported. These disorders include anemia, neutropenia, leukopenia, and thrombocytopenia. Profound immunosuppression may also increase the risk of developing cancer, but an actual cause-effect link has not been shown with leflunomide.

• Respiratory problems: Some patients develop inflammation in the lungs. Symptoms include coughing, difficulty in breathing, and sometimes fever.

• Gastrointestinal: Some gastrointestinal side effects may include diarrhea, abdominal pain, rash, and sores in the mouth.

• Hair loss

• Fatigue

Risks and Precautions

• Pregnancy and breastfeeding: Leflunomide is a pregnancy category X drug, meaning that animal studies have shown that leflunomide is harmful to the fetus. Women who are planning to become pregnant should not take the drug. Prior to beginning leflunomide, a physician will want to rule out pregnancy, and make sure the patient is using a reliable form of birth control. A physician must be notified if an unplanned pregnancy occurs. If a patient decides to become pregnant, leflunomide is discontinued, and an elimination procedure is undertaken to rapidly remove leflunomide and its breakdown products from the body. Men, too, are advised to undergo the leflunomide elimination regimen if a pregnancy is planned. Without this elimination procedure, it can take up to 2 years for the drug metabolites to reach a safe level in the body. Whether leflunomide is present in breast milk has yet to be determined, but to be safe, women are advised not to breastfeed infants when taking the drug.

• Patients with preexisting kidney or liver disease: The use of leflunomide in patients with kidney or liver disease has not been studied adequately. Because metabolites (breakdown products) of leflunomide are excreted by the kidney, however, the drug should be used with caution in patients with kidney disease. Similarly, treatment with leflunomide should be avoided in people with liver disease because the drug is metabolized and excreted by the liver and because it can cause liver damage.

• Immunosuppressed patients: Leflunomide is contraindicated (should be avoided) in patients with moderate to severe disorders of the immune system or bone marrow, and those with serious infections.

Drug Interactions

• Leflunomide may interact with other drugs that are metabolized by the cytochrome P450 enzyme system of the liver. Leflunomide inhibits—slows down the function of—an enzyme called CYP2C9, which normally breaks down drugs such as NSAIDs, phenytoin, warfarin, tolbutamide, and other drugs. No evidence exists for an interaction with NSAIDs. However, a couple of case reports have shown that giving warfarin with leflunomide increased the INR (international normalized ratio, a measure of how thinned the blood has become), which required the dose of warfarin to be reduced. ^{[2] [3]}

• Some drugs increase the activity of CYP1A2, the enzyme that metabolizes leflunomide. For example, smoking increases the clearance of leflunomide, but this interaction has not been shown to influence effectiveness. Rifampin increases the formation of M1, which may decrease levels of leflunomide in the body. Caution is usually advised if these drugs are to be given together.

• Caution is advised when leflunomide is given with other drugs that can damage the liver, such as methotrexate or alcohol. Indeed, alcohol consumption is discouraged during treatment with leflunomide.

Clinical Trials

In rheumatoid arthritis, leflunomide effectively relieves symptoms such as pain and inflammation, and it reduces joint damage and improves physical function. In an early clinical trial of the drug, successful treatment of rheumatoid arthritis was achieved in 41% and 35% of patients treated for one year with leflunomide or methotrexate, respectively.^[4] A greater than 20% response was seen in 52% and 46% of patients receiving leflunomide and methotrexate, respectively. X-rays showed that both drugs slowed progression of the disease, and patients in both treatment groups reported improvements in quality of life. Benefits of leflunomide are usually obtained after 4 to 6 weeks of treatment and have been sustained for over five years.^[5] Leflunomide can be combined with other DMARDs (disease-modifying antirheumatic drug) or NSAIDs in patients for whom a single drug alone does not work.

The effectiveness of leflunomide for the treatment of psoriatic arthritis was demonstrated in a randomized, double-blind clinical trial of 190 patients. ^[6] Patients received either leflunomide or placebo for 24 weeks. At the end of treatment, 58% and 30% of leflunomide- and placebo-treated patients responded, respectively. Improvements were seen in the severity of symptoms, the area affected, and quality of life.

Controversy

The incidence of liver damage and other adverse events associated with the use of leflunomide has spurred much concern about the safety of the drug. The FDA was presented with a citizens' petition by the group Public Citizen in March 2002 that called for leflunomide to be banned. The FDA launched a year-long investigation into the safety and effectiveness of leflunomide using data taken from clinical trials, post-marketing surveillance, health databases, and hospital records. The results were presented in March 2003. The FDA concluded that Arava can cause a three-fold increase in liver enzymes (a marker of liver damage) in 2%-4% of patients. Furthermore, leflunomide-related hospitalizations for hepatitis occurred in 0.02% of treated patients. They noted that the evidence for leflunomide toxicity is confounded (made less clear) by many factors, such as co-administration of other drugs that are toxic to the liver. Considering that leflunomide is effective, the FDA upheld the decision to keep Arava on the market. Despite the FDA’s conclusions, several public safety groups around the world continue to fight for the banning of leflunomide.

References

1. ↑ Kalgutkar AS, Nguyen HT, Vaz AD, et al. In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent leflunomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes. Drug Metab Dispos PDF 2003;31:1240-50. PMID 12975333
2. ↑ Chonlahan J, Halloran MA, Hammonds A. Leflunomide and warfarin interaction: case report and review of the literature. Pharmacotherapy 2006;26:868-71. PMID 16716139
3. ↑ Lim V, Pande I. Leflunomide can potentiate the anticoagulant effect of warfarin. BMJ PDF 2002;325(7376):1333. PMID 12468482
4. ↑ Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med PDF1999;159:2542-50. PMID 10573044
5. ↑ Kalden JR, Schattenkirchner M, Sörensen H, et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year followup study. Arthritis Rheum PDF 2003;48:1513-20. PMID 12794818
6. ↑ Kaltwasser JP, Nash P, Gladman D, et al. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial. PDF Arthritis Rheum 2004;50:1939-50. PMID 15188371

External Links

• Cochrane Database: Leflunomide for Treating Rheumatoid Arthritis
• American College of Rheumatology: FDA Meeting March 2003
• Medline Plus: Drug Information: Leflunomide
• The Arthritis Society: The Arthritis Society Main Page
• Aventis Pharmaceuticals: Arava Homepage