Leflunomide - Uses, Indications, Contraindications, and Adverse Effects

Overview:

Leflunomide comes under the category of disease-modifying anti-rheumatic drugs, which is approved by the Food and Drug Administration (FDA). Leflunomide is a non-biological novel isoxazole derivative that has anti-inflammatory and immunomodulatory characteristics. In patients with rheumatoid arthritis, Leflunomide delays articular cartilage and bone disintegration and thereby limits irreversible joint damage. It is used to treat rheumatoid arthritis, psoriatic arthritis, and synovitis. However, there is no Food and Drug Administration approval for Leflunomide for the treatment of psoriatic arthritis due to its minimal impact on skin improvement. It has the property of potent dihydro-orate dehydrogenase and is used clinically to treat cancer, but unfortunately, it failed to get Food and Drug Administration approval.

Uses:

Leflunomide is an anti-rheumatic drug used for the treatment of rheumatoid arthritis and psoriatic arthritis.

What Are the Indications of Leflunomide?

• To reduce signs and symptoms.

• To inhibit structural damage as seen in x-rays.

• To improve physical function.

Dosage and Administration:

The initially recommended dosages can be started with 100 mg once a day for three continuous days, followed by 20 mg or 10 mg per day.

For Patients:

What Is Meant by Rheumatoid Arthritis?

It is an autoimmune and inflammatory disease. Here, the immune system attacks the healthy cells in the body and causes painful swelling.

What Is Meant by Psoriatic Arthritis?

It is a progressive inflammatory condition of the joints characterized by joint pain, swelling, and morning stiffness.

What Is Leflunomide?

Leflunomide is an anti-rheumatic drug used for the treatment of rheumatoid arthritis and psoriatic arthritis.

How Is the Drug Available and How to Administer It?

• Leflunomide is available in oral tablets of 10 mg, 20 mg, and 100 mg.

• The initially recommended dosages can be started with 100 mg once a day for three continuous days, followed by 20 mg or 10 mg per day.

• Leflunomide effectiveness will be noticed after four to eight weeks of treatment.

What Are the Adverse Effects?

• Diarrhea.

• Elevation in liver enzymes.

• Hypertension.

• Rash.

• Nausea.

• Abdominal pain.

• Back pain.

• Alopecia (baldness).

What Are the Contraindications?

• Pregnancy.

• Liver impairment.

• Lung diseases.

• Hypersensitivity.

• Previous or current skin reactions.

• Immunosuppression.

• Impaired bone marrow function.

What Are the Important Tests That Are Done to Monitor?

• Liver function tests.

• Complete blood count.

• Blood pressure.

• Pregnancy.

For Doctors:

What Are the Indications of Leflunomide?

• To reduce signs and symptoms.

• To inhibit structural damage as seen in x-rays.

• To improve physical function.

What Are the Warnings?

• Pregnancy:

  • Pregnancy must be considered before treatment with Leflunomide, as it is contraindicated in pregnant women of childbearing age.

  • Pregnancy must be avoided during treatment with Leflunomide or prior to the drug getting completely eliminated.

• Hepatotoxicity:

  • Severe liver injury and fatal liver failure are reported in some patients treated with Leflunomide.

  • Patients with acute or chronic liver disease, and those with serum alanine aminotransferase greater than 2 ULN before treatment, should not be treated with Leflunomide.

  • The physician should use Leflunomide with caution when given other potentially hepatotoxic drugs.

  • Monitoring of alanine aminotransferase levels for six months during the start of Leflunomide and after that every six to eight weeks.

  • If alanine aminotransferase is greater than 3 ULN, then stop taking Leflunomide therapy.

  • If the tests suggest leflunomide-induced, then start washout using cholestyramine and should monitor liver tests weekly until it comes to normal.

  • If it is not leflunomide-induced liver injury, then a resumption of Leflunomide therapy may be considered.

• Immunosuppression Potential/Bone Marrow Suppression:

  • Leflunomide is not prescribed for patients with severe immunodeficiency, uncontrolled infections, and bone marrow dysplasia. In case of a serious infection, it is necessary to terminate therapy with Leflunomide and administer cholestyramine or charcoal to wash out the contents of the drug.

  • Leflunomide has immunosuppression potential that makes the patients susceptible to opportunistic infections, Pneumocystis jiroveci pneumonia, tuberculosis, and aspergillosis.

  • Severe infections like sepsis have also been reported in some cases.

  • Pancytopenia, thrombocytopenia, and agranulocytosis have been reported in a few cases which take treatment.

  • These are reported most frequently in patients who take methotrexate or other immunosuppressive agents and those who discontinued treatment.

  • Patients taking Leflunomide should check their platelet, white blood cell count, and hemoglobin count monthly for six months following initiation of therapy and every six to eight weeks after that.

  • If the patient is taking Leflunomide with concomitant methotrexate and immunosuppressive agents, then chronic monitoring should be done.

  • In case bone marrow suppression occurs, then the use of Leflunomide should be stopped.

  • If the patient switches to taking other anti-rheumatic drugs, then hematologic monitoring should be done as sometimes it may lead to hematologic toxicity.

• Skin Reactions:

  • Skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported rarely in patients taking Leflunomide.

  • In case of patients experiencing any of the skin reactions, then the use of Leflunomide should be stopped, and washout should be considered.

• Malignancy:

  • Lymphoproliferative disorders can occur due to the overuse of immunosuppressant medications.

  • However, there is no evidence of malignancy associated with Leflunomide, as evident from the clinical trials.

• Use in Women of Childbearing Potential:

  • It is contraindicated in patients who are planning for pregnancy or are not under reliable contraception.

  • Before treatment, the patient must be counseled about the serious risk factors for fetal growth.

  • In case the individual has a delay in their onset of menstruation, or if they suspect pregnancy during the treatment, then they should inform the physician as soon as possible for pregnancy testing.

  • If the test is positive, then abrupt stopping of the drug is mandatory and should start the drug elimination process.

• Peripheral Neuropathy:

  • It is reported that the use of Leflunomide causes peripheral neuropathy.

  • Most of the patients recovered back to normal, but some have few persistent symptoms.

  • In case the individual develops neuropathy, then the use of Leflunomide should be stopped, and should start the washout procedure.

What Is the Description of the Drug Leflunomide?

• It is a pyrimidine synthesis inhibitor.

• Chemical name- N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide.

• Empirical formula - C12H9F3N2O2

• Molecular weight - 270.2.

• Leflunomide is available as a tablet for oral administration - 10, 20, or 100 mg of active drugs.

• Inactive ingredients are Colloidal silicon dioxide, hypromellose, crospovidone, magnesium stearate, lactose monohydrate, povidone, polyethylene glycol, starch, titanium dioxide, talc, and yellow ferric oxide.

What Is the Mechanism of Action?

• Leflunomide is an isoxazole immunomodulatory agent dehydrogenase that has antiproliferative activity and inhibits dihydroorotate.

• Some studies show that Leflunomide has an anti-inflammatory effect.

Pharmacokinetics of Leflunomide:

• Once after oral intake, Leflunomide is metabolized to an active metabolite A77 1726- referred to as M1, which is responsible for the essential activity of the drug in vivo.

• Sometimes, plasma levels of Leflunomide are very low.

Absorption:

• Following oral administration, the active metabolite M1 reaches peak levels between 6 - 12 hours.

• Due to the long half-life of M1- approximately two weeks, an initial dose of 100 mg for three days was used in clinical studies to achieve the steady-state levels of M1.

• Without an initial dose, it is estimated that attainment of steady-state will take nearly two months.

• From the results, the plasma concentrations following loading doses and continued clinical doses indicate that M1 plasma levels are dose-proportional.

• The bioavailability of Leflunomide is eighty percent.

Distribution:

• M1 has a low volume of distribution and is extensively bound to albumin in healthy individuals.

• Protein binding is linear at therapeutic concentrations.

• The free fraction of M1 is higher in patients with rheumatoid arthritis and doubled in patients with chronic renal failure.

Metabolism:

• Leflunomide is metabolized to one primary metabolite, M1, and many minor metabolites.

• The minor metabolite 4-trifluoromethylaniline is quantifiable, which lowers plasma levels in some patients.

• However, the parent compound is rarely detectable in the plasma. In contrast, the specific site of leflunomide metabolism is unknown.

• From the in vivo and in vitro studies, it is found that the gastrointestinal wall and the liver has a role in drug metabolism.

• It is found that hepatic cytosolic and microsomal cellular fractions are the sites of drug metabolism.

Elimination:

The active metabolite M1 of Leflunomide is eliminated by further metabolism, followed by renal excretion and direct biliary excretion.

What Are the Contraindications of Leflunomide?

• The use of Leflunomide is contraindicated in patients with known hypersensitivity.

• Leflunomide, when administered to a pregnant woman, can cause harm to the fetus.

• Leflunomide is contraindicated in women who may become pregnant.

• Leflunomide causes liver impairment due to hepatotoxicity.

• Lung diseases.

• Previous or current skin reactions.

• Immunosuppression.

• Impaired bone marrow function.

How to Eliminate the Drug?

1. Should administer Cholestyramine eight grams three times daily for about 11 days, either alternatively or consecutively.

2. After fourteen days, plasma levels should be verified, which should be less than 0.02 mg/L.

3. If the plasma levels are high, then additional treatment with Cholestyramine should be considered.

What Are the Precautions?

• Respiratory:

  • Treatment with Leflunomide causes interstitial lung diseases and results in fatal outcomes.

  • It may occur at any time during treatment with Leflunomide.

  • On discontinuation, new onset and worsening pulmonary symptoms- cough and dyspnea, with or without fever may occur.

• Tuberculosis Reactivation:

  • Before starting treatment with Leflunomide, patients are advised to take a tuberculin test to screen for latent tuberculosis infection.

  • In case of positive test results, then they should be treated before starting therapy with Leflunomide.

• Renal Insufficiency:

  • Leflunomide should be used with caution in patients with renal insufficiency.

• Vaccinations:

  • Vaccination with live vaccines is not recommended during treatment with Leflunomide.

• Blood Pressure Monitoring:

  • It is important to check blood pressure before starting the treatment with Leflunomide and also periodically.

How Is It Supplied?

• Leflunomide is available in 10 mg, 20 mg, and 100 mg.

• 10 mg and 20 mg are packed in bottles, whereas 100 mg are packed in blister packs.

• 10 mg comes in a bottle containing thirty tablets which are white and round film-coated.

• 20 mg comes in a bottle containing thirty tablets which are light yellow and triangular film-coated.

• 100 mg available in three-count blister packs, which are white and round film-coated.

• Should store at 25°C and protect from light.

Dosage and Administration:

The initially recommended dosages can be started with 100 mg once a day for three continuous days, followed by 20 mg or 10 mg per day.

What Are the Drug Interactions?

• Cholestyramine and charcoal.

• Hepatotoxic drugs.

• Nonsteroidal anti-inflammatory drugs.

• Tolbutamide.

• Rifampicin.

• Warfarin.

What Are the Adverse Reactions?

• The most common adverse reactions include abdominal pain, diarrhea, vomiting, nausea, oral ulcers, upper respiratory tract infections, headache, alopecia, dizziness, and rash.

• Less common adverse reactions include anemia, hypertension, and weight loss.

What to Do in Case of Overdosage?

It is recommended to administer cholestyramine and charcoal to eliminate the drug in case of overdosage.

What Are the Instructions for Patients?

• Patients should be informed about birth defects for those who are of childbearing age.

• Patients should be explained about the possible serious skin reactions.

• Patients should be informed about the hepatotoxicity of Leflunomide.

• Patients should be informed about lowering blood counts, and hence frequent monitoring of complete blood count is mandatory.

• Patients should be informed about the signs of interstitial lung disease.

What Are the Clinical Inferences?

• Adults:

The efficacy of Leflunomide was demonstrated in three controlled trials.

• Reduction of Signs and Symptoms:

  • The American College of Rheumatology assesses signs and symptoms of rheumatoid arthritis through a collection of clinical, laboratory, and functional measures.

  • An “ACR20 Responder” is a person who had ≥ 20 % improvement in both tender and swollen joints and in three of the following five criteria: global patient assessment, global physician assessment, visual analog pain scale, functional ability measure, and erythrocyte sedimentation rate.

  • An “ACR20 Responder at Endpoint” is a person who completed the study.

• Inhibition of Structural Damage:

  • Inhibition of structural damage compared to control was assessed using the sharp score, which includes a composite score of joint space narrowing in hands, wrists, and forefeet and x-ray erosions.

• Improvement in Physical Function:

  • The Health Assessment Questionnaire and the Medical Outcomes Survey Short Form assess the improvement in physical function.

  • In the monotherapy studies, an initial loading dose of 100 mg per day for three days was used, followed by 20 mg per day.

• Pediatric Patients:

  • A study of Leflunomide is conducted in a single multicenter, double-blind, and active-controlled trial with 94 patients.

  • Approximately 68 % of pediatric patients receive Leflunomide, whereas 89 % of pediatric patients receive the active comparator.

  • In this trial, the loading dose and maintenance dose of Leflunomide was based on three weight categories: less than 20 kg, 20 to 40 kg, and greater than 40 kg.

  • The response rate to Leflunomide in pediatric patients less than 40 kg was less robust than in patients greater than 40 kg.