Arava

Arava (leflunomide) is a drug used to treat rheumatoid arthritis (RA) and other inflammatory joint diseases. It belongs to a class of drugs known as desmethylazothiomidines (DMARDs), which are used to suppress the immune system and reduce inflammation in the joints.

The active ingredient leflunomide is a pyrimidine synthesis inhibitor, meaning it targets immune cells that play a role in the development of joint inflammation in rheumatoid arthritis. Arava helps slow the progression of the disease, reduce inflammation, relieve pain, and improve joint function.

The drug is available as a tablet to take by mouth. It is usually taken daily, but the dosage and schedule may vary depending on your doctor's recommendations and the severity of your condition.

Indications Araves

1. Rheumatoid arthritis: The drug is used to reduce inflammation in the joints, relieve pain and improve joint function in patients with rheumatoid arthritis.

Arava may also sometimes be used to treat other inflammatory conditions, such as psoriatic arthritis and inflammatory bowel disease arthritis, but this decision is made by a physician on a case-by-case basis.

Release form

Arava is usually available as a tablet to take by mouth.

Pharmacodynamics

Leflunomide, the active ingredient in Arava, has anti-inflammatory and immunomodulatory properties, which allows it to effectively treat rheumatoid arthritis (RA) and other inflammatory diseases.

The principal action of leflunomide is related to its ability to inhibit the activity of the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme plays an important role in the synthesis of pyrimidine nucleotides necessary for cell division, including lymphocytes. Blocking DHODH leads to a decrease in the formation of pyrimidine nucleotides, which inhibits cell division and the activation of immune cells, such as lymphocytes.

As a result of the use of leflunomide, the immune response and inflammation are suppressed, which helps to reduce inflammatory processes in the joints and reduce the symptoms of rheumatoid arthritis.

However, it should be noted that the exact mechanism of action of leflunomide in the treatment of rheumatoid arthritis is not fully understood, and some of its effects may also be related to other mechanisms, including antioxidant and anti-inflammatory properties.

Pharmacokinetics

• Absorption: Leflunomide is well absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations are usually reached within 6-12 hours.
• Bioavailability: The bioavailability of leflunomide is approximately 80-90%.
• Distribution: Leflunomide has a large volume of distribution, meaning that it is widely distributed throughout the body. It is highly bound to plasma proteins.
• Metabolism: The main metabolic pathway of leflunomide is hydrolysis, which results in the formation of the active metabolite, terephthalamide. This metabolite also has anti-inflammatory activity.
• Excretion: The main mechanism of leflunomide elimination from the body is the biliary tract. It is excreted as metabolites with feces, and also in small quantities through the kidneys.
• Elimination half-life: The elimination half-life of leflunomide from the body is long, approximately 14-18 days.

Dosing and administration

• Dosage: The usual recommended starting dose of leflunomide is 100 mg per day. This can be taken as one leflunomide tablet (100 mg) daily.
• Taking with food: Leflunomide is usually taken with food as this may help reduce possible gastrointestinal side effects.
• Dosage regimen: An increased dose (usually 100 mg for three days) may be used at the beginning of treatment, followed by the standard maintenance dose.
• Maintenance dose: After the initial increased dose, leflunomide is taken at a dose of 20 mg daily. However, the dosage may be adjusted as recommended by your doctor.
• Monitoring: It is important to monitor the patient's condition regularly, including checking liver function and other parameters, to assess the effectiveness of treatment and to prevent possible side effects.
• Duration of treatment: The duration of treatment and dosage regimen will be determined by your doctor depending on the severity of the disease and your individual response to treatment.

Use Araves during pregnancy

• Fetotoxicity and teratogenicity:

  • Leflunomide has demonstrated teratogenic and fetotoxic effects in animal studies, causing developmental defects and death of fetuses (Brent, 2001). In one study in mice, leflunomide caused multiple external, skeletal, and visceral abnormalities in fetuses (Fukushima et al., 2007).

• Directions for use:

  • The American College of Rheumatology (ACR) recommends stopping leflunomide at least 24 months before conception. If pregnancy occurs while taking leflunomide, a cholestyramine washout procedure is recommended to speed up elimination of the drug (Alothman et al., 2023).

• Human studies:

  • A study of 289,688 pregnant women in Montreal found no significant increase in the risk of major congenital anomalies, prematurity, low birth weight, or spontaneous abortion in women who took leflunomide during pregnancy (Bérard et al., 2017).
  • Other studies have also shown that leflunomide use was not associated with a significant increase in the risk of congenital anomalies when the washout procedure was followed (Chambers et al., 2010).

• Practical guide:

  • Women taking leflunomide and planning to become pregnant are advised to discontinue the drug and perform a washout procedure with cholestyramine to minimize the risk of teratogenic effects. In case of unintended conception while taking leflunomide, it is important to consult a physician and consider a washout procedure (Casanova Sorní et al., 2005).

Contraindications

• Pregnancy and lactation: Leflunomide can harm the fetus, so it is absolutely contraindicated during pregnancy. The drug is also not recommended for breastfeeding.
• Severe liver disease: In patients with severe liver disease, leflunomide should be used with caution or avoided altogether.
• Severe renal impairment: In patients with severe renal impairment, the drug should also be used with caution.
• Serious infections: Use of leflunomide may increase the risk of developing infections, especially in patients with underlying conditions that involve a weakened immune system.
• Hypersensitivity to leflunomide or other components of the drug: Any known hypersensitivity is a contraindication to the use of the drug.
• Acute or chronic alcohol pathology: Leflunomide can cause liver damage, so its use in alcohol pathology requires special caution.
• Acute infectious diseases: During acute infections, leflunomide is usually temporarily suspended due to possible suppression of the immune system.

Side effects Araves

• Increased risk of infections: Taking leflunomide may increase the risk of developing infections because it affects the immune system.
• Increased tiredness: Tiredness and weakness can be some of the most common side effects of taking leflunomide.
• Diarrhea: Some patients may experience diarrhea while taking leflunomide.
• Increased liver enzymes: Leflunomide may cause increased levels of liver enzymes in the blood, which may indicate liver damage.
• Decreased appetite and changes in taste preferences: Some patients may experience decreased appetite or changes in taste preferences while taking leflunomide.
• Increased blood creatinine levels: Leflunomide may cause increased blood creatinine levels, which may be a sign of impaired kidney function.
• Increased blood pressure: Some patients may experience increased blood pressure while taking leflunomide.
• Sleep disturbances: Some patients may experience sleep disturbances, such as insomnia or excessive sleepiness.

Overdose

• Increased side effects of the drug, such as nausea, vomiting, diarrhea, fatigue, and others.
• Increased activity of liver enzymes, which may indicate liver damage.
• Changes in blood pressure, heart rate and other cardiovascular responses may occur.

Interactions with other drugs

• Teratogenic drugs: Leflunomide may enhance the teratogenic effects of other drugs. Therefore, the use of leflunomide simultaneously with drugs such as methotrexate is contraindicated, especially in pregnant women.
• Drugs metabolized via cytochrome P450: Leflunomide may affect the activity of cytochrome P450 enzymes, which may lead to changes in the concentration of other drugs in the blood. This may be important when used in combination with drugs such as warfarin, phenytoin, theophylline, etc.
• Immunosuppressants: Concomitant use of leflunomide with other immunosuppressants such as cyclosporine or tacrolimus may enhance their therapeutic effect and increase the risk of infections.
• Drugs that cause hepatotoxicity: Coadministration of leflunomide with other drugs that can cause hepatotoxicity, such as methotrexate or dapsone, may increase the risk of liver damage.
• Medicines that cause hematological disorders: Concomitant use of leflunomide with other medicines that can cause hematological disorders, such as methotrexate or anticoagulants, may increase the risk of bleeding or other disorders.