Side effects of leflunomide

Contents

Arava

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

  • Hepatotoxicity
  • Immunosuppression
  • Bone marrow suppression
  • Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Peripheral neuropathy
  • Interstitial lung disease

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with ARAVA administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years.

Elevation of Liver Enzymes

Treatment with ARAVA was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild ( ≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations ( > 3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.

Table 1: Liver Enzyme Elevations > 3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3**

In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, ARAVA was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo.

Most Common Adverse Reactions

The most common adverse reactions in ARAVA-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year ( ≥ 5% in any ARAVA treatment group).

Table 2: Percentage Of Patients With Adverse Events ≥ 5% In Any ARAVA Treated Group in all RA Studies in Patients with RA

Adverse events during a second year of treatment with ARAVA in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.

Less Common Adverse Reactions

In addition, in controlled clinical trials, the following adverse events in the ARAVA treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug.

Blood and Lymphatic System: leukocytosis, thrombocytopenia;

Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein;

Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage;

Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth;

General Disorders: malaise;

Immune System: anaphylactic reaction;

Infection: abscess, flu syndrome, vaginal moniliasis;

Nervous System: dizziness, headache, somnolence;

Respiratory System: dyspnea;

Post Marketing Experience

The following additional adverse reactions have been identified during postapproval use of ARAVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia;

Infection: opportunistic infections, severe infections including sepsis;

Gastrointestinal: acute hepatic necrosis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure

Immune System: angioedema;

Nervous system: peripheral neuropathy;

Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;

Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.

Read the entire FDA prescribing information for Arava (Leflunomide)

Leflunomide Side Effects

Medically reviewed by Drugs.com. Last updated on Nov 5, 2018.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

In Summary

Commonly reported side effects of leflunomide include: alopecia, diarrhea, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, and skin rash. Other side effects include: bronchitis, hypersensitivity condition, hypertension, pruritus, rhinitis, and tenosynovitis. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to leflunomide: oral tablet

Warning

Oral route (Tablet)

Leflunomide is contraindicated in pregnant women due to potential for fetal harm. Pregnancy must be excluded before the start of treatment and must be avoided during treatment or prior to the completion of the accelerated drug elimination procedure after treatment with leflunomide. Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide. Do not use in patients with acute or chronic liver disease or an ALT greater than 2 times the ULN, and ALT monitoring is recommended after starting leflunomide. Stop leflunomide and use an accelerated drug elimination procedure if pregnancy occurs or leflunomide-induced liver injury is suspected.

Along with its needed effects, leflunomide may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking leflunomide:

More common

  • Bloody or cloudy urine
  • cough
  • difficult or painful breathing
  • difficult, burning, or painful urination
  • dizziness
  • fever
  • frequent urge to urinate
  • headache
  • loss of appetite
  • nausea or vomiting
  • sneezing
  • sore throat
  • tightness in the chest
  • yellow eyes or skin

Less common

  • Burning feeling in the chest or stomach
  • burning, prickling, or tingling sensation in the fingers or toes
  • chest pain
  • diarrhea
  • fast or pounding heartbeat
  • indigestion
  • joint or muscle pain or stiffness
  • severe stomach pain
  • tenderness in the stomach area
  • unusual tiredness or weakness

Incidence not known

  • Area rash
  • black or tarry stools
  • bleeding gums
  • blistering, peeling, or loosening of the skin
  • bloating
  • blood in the stools
  • burning, numbness, tingling, or painful sensations
  • chills
  • clay-colored stools
  • confusion
  • constipation
  • continuing vomiting
  • cough or hoarseness
  • dark urine
  • fainting
  • fever with or without chills
  • general feeling of tiredness or weakness
  • high fever
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • light-colored stools
  • lightheadedness
  • lower back or side pain
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • pale skin
  • pinpoint red spots on the skin
  • rapid, shallow breathing
  • red skin lesions, often with a purple center
  • red, irritated eyes
  • sores, ulcers, or white spots in the mouth or on the lips
  • swollen glands
  • unexplained bleeding or bruising
  • unpleasant breath odor
  • unsteadiness or awkwardness
  • unusual bleeding or bruising
  • upper right abdominal or stomach pain
  • vomiting of blood
  • weakness in the arms, hands, legs, or feet

Some side effects of leflunomide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  • Back pain
  • hair loss
  • heartburn
  • skin rash
  • stomach pain
  • weight loss (unexplained)

Less common

  • Acne
  • anxiety
  • decreased appetite
  • dry mouth
  • gas
  • irritation or soreness of the mouth
  • itching of the skin
  • pain or burning in the throat
  • runny nose

For Healthcare Professionals

Applies to leflunomide: oral tablet

Gastrointestinal

Very common (10% or more): Diarrhea (up to 22%), dyspepsia (up to 13%)

Frequency not reported: Pancreatitis

A 58-year-old female with longstanding rheumatoid arthritis experienced parastomal collection and stomach perforation coincident with leflunomide therapy. The patient had been taking leflunomide 20 mg per day and prednisone 5 mg per day. She presented with complaints of a one day history of abdominal pain. A CT scan showed a parastomal collection and stomach perforation. She proceeded to surgery for drainage of the collection and repair of the perforation. The leflunomide therapy was subsequently stopped and cholestyramine washout administered. She required prolonged hospital stay, with total parenteral nutrition and intravenous antibiotics.

Respiratory

A 54-year-old female with rheumatoid arthritis experienced acute respiratory failure coincident with leflunomide therapy. She developed the adverse event 2 weeks after cessation of 6-weeks treatment with leflunomide. She was diagnosed with interstitial pneumonia, probably induced by leflunomide because acute respiratory failure was preceded by hypertension and elevated serum liver enzyme concentration. She showed dramatic improvement with cholestyramine and prednisolone.

Very common (10% or more): Respiratory infection (up to 32%)

Common (1% to 10%): Bronchitis, cough, pharyngitis, pneumonia, rhinitis, sinusitis, asthma, dyspnea, epistaxis, lung disorder

Postmarketing reports: Interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal

Cardiovascular

Common (1% to 10%): Hypertension, chest pain

Postmarketing reports: Angina pectoris, migraine, palpitation, tachycardia, vasculitis, vasodilation, varicose vein

Dermatologic

A 46-year-old woman with erosive and refractory rheumatoid arthritis (RA) developed sudden focal hair loss (alopecia areata) after 3 weeks of treatment with leflunomide. Three months after leflunomide had been stopped due to poor control of RA, the patient’s hair was slowly recovering.

A 61-year-old female with severe rheumatoid arthritis experienced cellulitis coincident with leflunomide therapy. The patient had been taking leflunomide 20 mg alternate days and prednisone 10 mg per day. She presented with cellulitis of the left foot that had not responded to oral amoxicillin/clavulanic acid. Isolates from a plantar ulcer showed Staphylococcus aureus. Despite appropriate antibiotic treatment, the infection progressed rapidly and she developed necrosis of the left foot. She proceeded to surgical debridement with forefoot amputation and skin graft. On day 4 of admission, leflunomide therapy was discontinued and cholestyramine washout administered. She had a prolonged hospital stay that required 5 further debridement procedures.

Very common (10% or more): Alopecia (up to 17%), rash (up to 12%)

Common (1% to 10%): Eczema, pruritus, dry skin, acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin

Uncommon (0.1% to 1%): Diabetes mellitus, hyperthyroidism

Rare (less than 0.1%): Urticaria

Postmarketing reports: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis (including cutaneous necrotizing vasculitis), cutaneous lupus erythematosus, pustular psoriasis (or worsening psoriasis), angioedema

Nervous system

Very common (10% or more): Headache (up to 21%)

Common (1% to 10%): Asthenia, pain, dizziness, paresthesia, neuralgia, neuritis, sweating increased, vertigo

Postmarketing reports: Peripheral neuropathy

Genitourinary

Musculoskeletal

Metabolic

Hypersensitivity

A 69-year-old male with a 19-year history of rheumatoid arthritis experienced hypersensitivity pneumonitis coincident with leflunomide therapy. Three months after being administered leflunomide 20 mg once a day, he presented with a 1-month history of progressive dyspnea, decreased appetite, and weight loss. The temporal association and resolution following discontinuation suggest leflunomide was the causative agent.

Common (1% to 10%): Allergic reaction

Hematologic

Common (1% to 10%): Anemia (including iron deficiency anemia), ecchymosis

Rare (less than 0.1%): Eosinophilia, transient thrombocytopenia, leukopenia

Postmarketing reports: Agranulocytosis, neutropenia, pancytopenia

The risk of pancytopenia appears to be increased when leflunomide is combined with methotrexate and in older patients.

Endocrine

Frequency not reported: Hyperthyroidism

Ocular

Common (1% to 10%): Blurred vision, cataract, conjunctivitis, eye disorder

Renal

Frequency not reported: Renal failure

Hepatic

A 69-year-old male with stable rheumatoid arthritis experienced liver tuberculosis coincident with leflunomide therapy. The patient had been taking leflunomide 20 mg daily as monotherapy for 31 months. He presented with a 2 month history of anorexia, 10 kg weight loss, fever, and night sweats. A CT scan showed multiple low attenuation lesions in the liver. Initial liver biopsy was nondiagnostic, revealing only minor changes with no evidence of infection. Although Mycobacterium tuberculosis culture was negative, due to strong clinical suspicion, he was given empiric antituberculosis therapy. The patient’s condition improved dramatically over subsequent weeks. At 18 months review, he remained well taking prednisone monotherapy. Although culture negative, a diagnosis of probable mycobacterium infection was made on the basis of typical histological findings on liver biopsy, exclusion of other pathology and prompt response to antituberculosis treatment.

Common (1% to 10%): Abnormal liver enzymes

Postmarketing reports: Hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal

Other

Common (1% to 10%): Taste perversion, abscess, cyst, fever, hernia, malaise, pelvic pain

Immunologic

Common (1% to 10%): Flu Syndrome

Postmarketing reports: Opportunistic infections, severe infections including sepsis that may be fatal

Psychiatric

Common (1% to 10%): Anxiety, depression insomnia, sleep disorder

1. 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.” Arthritis Rheum 50 (2004): 1939-50

3. Cerner Multum, Inc. “Australian Product Information.” O 0

4. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

5. “Product Information. Arava (leflunomide).” Hoechst Marion-Roussel Inc, Kansas City, MO.

7. Hyeon Ju J, Kim SI, Lee JH, et al. “Risk of interstitial lung disease associated with leflunomide treatment in Korean patients with rheumatoid arthritis.” Arthritis Rheum 56 (2007): 2094-2096

8. Siva C, Eisen SA, Shepherd R, et al. “Leflunomide use during the first 33 months after food and drug administration approval: Experience with a national cohort of 3,325 patients.” Arthritis Rheum 49 (2003): 745-51

9. Gottenberg JE, Venancie PY, Mariette X “Alopecia areata in a patient with rheumatoid arthritis treated with leflunomide.” J Rheumatol 29 (2002): 1806-7

10. McCoy CM “Leflunomide-associated skin ulceration.” Ann Pharmacother 36 (2002): 1009-11

11. Bonnel RA, Graham DJ “Peripheral neuropathy in patients treated with leflunomide.” Clin Pharmacol Ther 75 (2004): 580-5

13. Hill RL, Topliss DJ, Purcell PM “Pancytopenia associated with leflunomide and methotrexate.” Ann Pharmacother 37 (2003): 149

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Related questions

  • What are the new drugs for the treatment of rheumatoid arthritis (RA)?

Medical Disclaimer

More about leflunomide

  • During Pregnancy
  • Dosage Information
  • Drug Images
  • Drug Interactions
  • Support Group
  • Pricing & Coupons
  • En Español
  • 71 Reviews
  • Drug class: antirheumatics

Consumer resources

  • Leflunomide
  • Leflunomide (Advanced Reading)

Other brands: Arava

Professional resources

  • Leflunomide (AHFS Monograph)
  • … +2 more

Related treatment guides

  • Psoriatic Arthritis
  • Rheumatoid Arthritis

Leflunomide Print Page

What is Leflunomide?

  • Leflunomide, its tradename Arava, is in a class of medications called Disease Modifying Anti-Rheumatic Drugs, or DMARDs. DMARDs are a slow acting but effective treatment for rheumatoid arthritis and other forms of inflammatory arthritis.
  • Leflunomide is a newer DMARD considered by some to be equivalent in effect to methotrexate for rheumatoid arthritis.
  • It can also used in the treatment of other types of inflammatory arthritis, vasculitis, myositis and others.

What is the typical dose for Leflunomide?

  • Leflunomide comes in tablet form. Most rheumatologists will start Leflunomide at 20mg daily. However, 10mg daily and 20mg every second day are also reasonable & common, and depends on the individual patient.

How does Leflunomide work?

  • While there has been extensive research into this area, it remains unclear as to the exact mechanism of action. Its primary mechanism is through an effect it has on lymphocyte function, a specific type of white blood cell.

How soon will I feel the effects of leflunomide?

  • Like all DMARDs, leflunomide takes time to work. Most patients start to feel the positive effects of leflunomide at 4-8 weeks, with maximum benefit at 3-6 months. Side effects can occur earlier.

What are the possible side effects of leflunomide?

  • Some of the side effects of leflunomide are similar to methotrexate. Side effects may include:

Side Effect Ways to Reduce Side Effects
  • Leflunomide can cause gastrointestinal upset. In particular, diarrhea can be a significant problem for some patients on leflunomide.
  • If you are having problems, discuss it with your rheumatologist immediately. They will either adjust the dose or stop it completely.
  • Hair Thinning
  • While not that common, it can be very distressing to some people. Speak to your rheumatologist if you notice this.
  • Leflunomide can decrease your blood counts.
  • Your rheumatologist will provide you with a requisition for monthly bloodwork to check your blood counts. While rare, if there is a problem, your rheumatologist will usually see it in your bloodwork well before you notice any problems. Make sure you always get your bloodwork.
  • Make sure your doctor knows if you have a pre-existing problem with your blood cells
  • Leflunomide can cause liver irritation.
  • Like your blood counts, your rheumatologist will also monitor liver tests on a monthly basis.
  • Limit your alcohol intake to 2-3 drinks per week.
  • Leflunomide can cause an increase in your blood pressure.
  • Have your blood pressure monitored by your rheumatologist or family physician.
  • Pregnancy miscarriages or malformations
  • You or your partner should not become pregnant if you are on leflunomide.
  • Leflunomide stays in your system for at least 1-2 years even once you stop it. Your doctor will need to give you special medication to remove leflunomide from your system prior to trying to become pregnant. Therefore, it is very important to discuss pregnancy plans with your rheumatologist.
  • Mothers should not nurse if on leflunomide as it can enter the breast milk.
  • More infections
  • There is a small increased risk of developing infections, particularly if used in combination with steroids. You should be more careful when you are sick, and let your doctor know if you have a fever.

My doctor started me on leflunomide and methotrexate at the same time. Because they both can affect my blood counts and liver, is this safe?

Both you and your rheumatologist should be more cautious if you are taking both methotrexate and leflunomide at the same time as there is an increased risk of some side effects. However, this is a common combination which can be effective in treating your condition. Often, your rheumatologist will lower the dose of one of these medications to improve the safety. Of course, it is also important to ensure you continue to do your regular bloodwork as scheduled.

What should I do if I miss a dose?

You can safely take your dose later in the day. If you do not remember until the next day, just take your regular dose; do not take a double dose. As long as this does not happen regularly, you should not experience any ill effects.

How can I safely stop leflunomide?

It is safe to just stop leflunomide; you do not need to slowly reduce the dose. However, keep in mind, if you were gaining any benefit from leflunomide, it will usually take at least 6 weeks to lose it. If you are stopping because of more severe side effects, your doctor may recommend a medication regimen to clear the leflunomide out of your system, as it can otherwise remain in you for 1-2 years.

For more information about leflunomide, or for questions that are specific to your situation, always consult your physician.

Generic Name: leflunomide (le FLOO noe mide)
Brand Names: Arava

Medically reviewed by Drugs.com. Last updated on Jan 24, 2019.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

What is Arava?

Arava (leflunomide) affects the immune system and reduces swelling and inflammation in the body.

Arava is used to treat the symptoms of rheumatoid arthritis.

Arava may also be used for purposes not listed in this medication guide.

Important information

Do not use Arava if you are pregnant, and stop taking this medicine if you think you might be pregnant. Use birth control to prevent pregnancy while you are taking Arava, and until you complete a “drug elimination” procedure.

Arava can cause severe or fatal liver damage. Tell your doctor if you have a history of liver disease or if you also use other medicines such as: pain or arthritis medicine (including aspirin, Tylenol, and Advil/Motrin), medicines to treat tuberculosis or other infections, seizure medication, hormonal birth control or hormone replacement therapy, chemotherapy, cholesterol-lowering medicine, heart medication, or blood pressure medicine.

Your liver function will need to be tested often, and you may need to stop taking Arava based on the results of these tests.

Before taking this medicine

You should not use Arava if you are allergic to leflunomide or teriflunomide, or if:

  • you are pregnant (you will need to have a negative pregnancy test before starting this treatment);

  • you have severe liver disease; or

  • you are also using teriflunomide.

Do not use Arava if you are pregnant or may become pregnant. Avoid getting pregnant until after you stop taking Arava and undergo a “drug elimination” procedure to help rid your body of this medicine. Stop taking Arava and call your doctor right away if you miss a period or think you might be pregnant.

To make sure this medicine is safe for you, tell your doctor if you have:

  • a history of liver disease or hepatitis (leflunomide can cause severe liver problems);

  • a severe or uncontrolled infection;

  • kidney disease;

  • nerve problems, such as neuropathy caused by diabetes;

  • a history of tuberculosis;

  • a weak immune system or bone marrow disorder; or

  • if you are using any drugs that weaken your immune system (such as cancer medicine or steroids).

Use birth control to prevent pregnancy while you are taking this medicine. After you stop taking Arava, continue using birth control until you have received blood tests to make sure the drug has been eliminated from your body.

Ask your doctor if you should use a barrier form of birth control (condom or diaphragm with spermicide). Using hormonal contraception (birth control pills, injections, implants, skin patches, and vaginal rings) may increase your risk of liver damage while taking Arava.

It is not known whether leflunomide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

How should I take Arava?

Before you start treatment with Arava, your doctor may perform tests to make sure you do not have tuberculosis or other infections.

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Your blood pressure will need to be checked often.

Arava can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your Arava treatment may be stopped for a short time based on the results of these tests.

Your liver function will also need to be tested often, and you may need to stop taking Arava based on the results of these tests.

After you stop taking this medicine, you may need to be treated with other medicines to help your body eliminate leflunomide quickly. If you do not undergo this drug elimination procedure, leflunomide could stay in your body for up to 2 years. Follow your doctor’s instructions.

You will also need to go through this drug elimination procedure if you plan to become pregnant after you stop taking Arava.

Arthritis is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor’s advice.

Store at room temperature away from moisture, heat, and light.

Arava dosing information

Usual Adult Dose for Rheumatoid Arthritis:

Loading dose: 100 mg orally once a day for 3 days
Maintenance: 20 mg orally once a day (If not well tolerated, the dose may be decreased to 10 mg orally once a day)
Comment:
-Hematology parameters and liver enzymes should be monitored.
Use:
For the treatment of active rheumatoid arthritis (RA):
-To reduce signs and symptoms
-To inhibit structural damage as evidenced by X-ray erosions and joint space narrowing
-To improve physical function

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include diarrhea, stomach pain, pale skin, easy bruising or bleeding, dark urine, or jaundice (yellowing of the skin or eyes).

What should I avoid while taking Arava?

Avoid being near people who have colds, the flu, or other contagious illnesses. Contact your doctor at once if you develop signs of infection.

Arava side effects

Get emergency medical help if you have signs of an allergic reaction to Arava: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • signs of infection – sudden weakness or ill feeling, fever, chills, sore throat, mouth sores, red or swollen gums, trouble swallowing;

  • sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;

  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

  • numbness, tingling, or burning pain in your hands or feet;

  • liver problems – nausea, upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

  • severe skin reaction – fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common Arava side effects may include:

  • nausea, diarrhea, stomach pain;

  • headache;

  • abnormal liver function tests;

  • thinning hair;

  • back pain;

  • weakness;

  • rash; or

  • high blood pressure.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Arava?

Arava can cause severe or fatal liver damage. This effect is increased when you also use certain other medicines, including:

  • acetaminophen (Tylenol), aspirin, gout or arthritis medication (including gold injections); a NSAID (non-steroidal anti-inflammatory drug) – ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;

  • an antibiotic, antifungal medicine, or sulfa drug; tuberculosis medicine; antiviral or HIV/AIDS medication; medicine to treat mental illness; seizure medication – carbamazepine, phenytoin, valproic acid, and others;

  • birth control pills or hormone replacement therapy; anabolic steroids – methyltestosterone, “performance-enhancing drugs”; cancer medication; or

  • cholesterol-lowering medication – Crestor, Lipitor, Vytorin, Zocor, and others; heart or blood pressure medication.

This list is not complete and many other drugs can interact with leflunomide. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you. Not all possible interactions are listed in this medication guide.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Arava only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2020 Cerner Multum, Inc. Version: 9.01.

  • What are the new drugs for the treatment of rheumatoid arthritis (RA)?

Medical Disclaimer

More about Arava (leflunomide)

  • Side Effects
  • During Pregnancy
  • Dosage Information
  • Drug Images
  • Drug Interactions
  • Pricing & Coupons
  • En Español
  • 25 Reviews
  • Generic Availability
  • Drug class: antirheumatics
  • FDA Alerts (2)
  • Arava
  • Arava (Advanced Reading)
  • Arava (AHFS Monograph)
  • … +1 more
  • Rheumatoid Arthritis

Consumer medicine information

Before you take it

When you must not take it

Do not take Arava if you:

  • have any diseases which reduce your body’s natural defences such as bacterial or viral infections
  • have any diseases of the blood
  • have any serious skin disorders
  • have liver disease
  • have a condition called hypoproteinaemia (when you do not have enough protein in your blood)
  • are pregnant or plan to become pregnant
  • are not using reliable birth control
  • are breastfeeding

You must not become pregnant while taking Arava and for a certain period of time after stopping Arava.

Arava may increase the risk of birth defects.

Women of childbearing potential must use reliable contraception while taking Arava.

Do not take it if you are breastfeeding or planning to breastfeed.

Arava passes into breast milk and therefore there is a possibility that the breastfed baby may be affected.

Do not take Arava if you are allergic to it, teriflunomide or any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Do not give Arava to a child or adolescent.

Arava is not approved for use in children or adolescents under 18 years old.

Do not take it after the expiry date (EXP) printed on the pack.

If you take it after the expiry date has passed, it may not work as well.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any of the ingredients listed at the end of this leaflet
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor immediately if you think you could be pregnant while taking Arava.

Tell your doctor if you intend to become pregnant or father a child.

Arava may increase the risk of birth defects. To reduce any risk to the developing baby, you will need to stop taking Arava and may need to undergo a wash-out procedure. Your doctor will discuss the wash-out procedure with you.

Tell your doctor if you are breastfeeding or planning to breastfeed.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • a decrease in the number of white blood cells
  • liver problems
  • kidney problems
  • chronic infections
  • an illness which lowered your body’s resistance to disease
  • tuberculosis
  • lung problems, such as interstitial lung disease (an inflammation of lung tissue) which is a serious and potentially fatal disease

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you take Arava.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Arava. These include:

  • warfarin, a medicine used to stop blood clots
  • some medicines used for diabetes
  • some medicines used to treat epilepsy
  • some medicines used for tuberculosis (TB)
  • some medicines used to lower cholesterol

These medicines may be affected by Arava, or may affect how well it works. You may need to use different amounts of your medicine, or take different medicines. Your doctor or pharmacist will advise you.

In certain situations, for example, if you experience a serious side effect, you change your medication or you want to fall pregnant, your doctor will ask you to take medication that will help your body get rid of Arava faster.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Arava.

Leflunomide

Before taking leflunomide,

  • tell your doctor and pharmacist if you are allergic to leflunomide, teriflunomide (Aubagio), any other medications, or any of the ingredients in leflunomide tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin Jantoven); cholestyramine (Prevalite); gold compounds such as auranofin (Ridaura); medications to treat cancer; other medications that suppress the immune system such as azathioprine (Azasan, Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune), and tacrolimus (Astagraf, Prograf); penicillamine (Cuprimine, Depen), and tolbutamide. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had serious infections or if you frequently get infections, cancer or other conditions affecting the bone marrow or the immune system (including human immunodeficiency virus and acquired immunodeficiency syndrome ), diabetes, or kidney disease.
  • tell your doctor if you are breastfeeding. Do not breastfeed while you are taking leflunomide.
  • if you are planning to father a child, you should talk to your doctor about stopping leflunomide and receiving a treatment to help to remove this medication from your body more quickly.
  • ask your doctor about the safe use of alcoholic beverages while you are taking leflunomide.
  • Taking leflunomide may decrease your ability to fight infection. Tell your doctor if you have an infection now or if you have any signs of infection such as fever, cough, or flu-like symptoms. If you experience any of the following symptoms during your treatment with leflunomide, call your doctor: fever; sore throat; cough; flu-like symptoms; area of warm, red, swollen, or painful skin; painful, difficult, or frequent urination; or other signs of infection. Your treatment with leflunomide may need to be interrupted if you have an infection.
  • You may already be infected with tuberculosis (TB; a serious lung infection) but not have any symptoms of the disease. In this case, leflunomide may make your infection more serious and cause you to develop symptoms. Tell your doctor if you have or have ever had TB, if you have lived in or visited a country where TB is common, or if you have been around someone who has or has ever had TB. Before you begin your treatment with leflunomide, your doctor will perform a skin test to see if you have TB. If you do have TB, your doctor will treat this infection with antibiotics before you begin taking leflunomide.
  • do not have any vaccinations without talking to your doctor.
  • you should know that leflunomide may cause high blood pressure. You should have your blood pressure checked before starting treatment and regularly while you are taking this medication.

Leflunomide is the generic form of the brand-name medicine Arava, which is used to treat rheumatoid arthritis (a condition in which the body attacks its own joints).

This prescription medication is also sometimes used to help treat psoriatic arthritis (a condition that causes joint pain and scaly skin).

Leflunomide belongs to a class of drugs called disease-modifying antirheumatic drugs (DMARDs). It works by suppressing blood cells that cause inflammation.

The U.S. Food and Drug Administration (FDA) approved leflunomide in 1998. It’s marketed as Arava by Sanofi-Aventis.

Leflunomide Warnings

Leflunomide contains a black box warning because it may cause serious liver problems that could potentially lead to death.

Tell your doctor immediately if you experience any of the following symptoms while taking this medicine:

  • Yellowing of the skin or eyes (jaundice)
  • Dark-colored urine
  • Pale-colored stools
  • Pain in the upper right part of the stomach
  • Severe or persistent nausea
  • Loss of appetite
  • Extreme tiredness
  • Unusual bleeding or bruising

Your doctor will monitor your liver function carefully while you take this medicine.

Don’t take leflunomide if you have any type of liver problem.

Drinking alcohol while you’re on leflunomide may increase the risk of liver complications. Tell your doctor if you drink, or have ever drunk large amounts of alcohol.

Also, tell your doctor if you’re taking any of the following medicines before starting on leflunomide:

  • Tylenol (acetaminophen)
  • Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as Advil or Motrin (ibuprofen) and Aleve or Naprosyn (naproxen)
  • Cholesterol-lowering medications (statins)
  • Hydroxychloroquine
  • Iron products
  • Laniazid, Rifamate, or Rifater (isoniazid)
  • Trexall (methotrexate)
  • Niacin
  • Rifadin, Rimactane, Rifamate, or Rifater (rifampin)

Leflunomide may lower your body’s ability to fight infections.

Tell your doctor right away if you experience any of the following symptoms while taking this medicine:

  • Fever
  • Sore throat
  • Cough
  • Flu-like symptoms
  • Red, warm, swollen, or painful skin
  • Difficult, painful, or frequent urination

Don’t receive any vaccines while taking leflunomide without first discussing it with your doctor.

Tell your doctor if you’re prone to getting infections or if you currently have an infection.

It’s possible that you could have tuberculosis (TB — a serious lung infection) and not know it. Your doctor will perform a skin test or do a blood test (quantiferon gold) to determine whether you have an inactive form of TB before you start on leflunomide.

Tell your doctor if you have or have ever had TB, have been around someone with TB, or have traveled to areas where TB is common.

Also, let your doctor know if you have, or have ever had, any of the following before taking leflunomide:

  • Cancer
  • Diabetes
  • Kidney disease
  • Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
  • Hepatitis B or C
  • High blood pressure

Leflunomide may cause high blood pressure. Your healthcare provider will probably want to check your blood pressure before you start on the drug, and frequently throughout your treatment.

Leflunomide may cause birth defects and other serious problems in the offspring of both women and men.

This medicine can stay in your body for up to two years after you stop taking it.

Both women and men who use leflunomide should use effective forms of birth control to prevent pregnancy for as long as your doctor recommends.

If you’re a man who wants to father a child, talk to your doctor about stopping leflunomide and receiving a therapy that helps remove the medicine from your body more quickly.

Pregnancy and Leflunomide

Leflunomide contains a black box warning because it could harm an unborn baby.

Don’t take this medicine if you’re pregnant or plan to become pregnant.

You’ll need to use an effective form of birth control before taking leflunomide, during your treatment, and for two years after your treatment ends.

Call your doctor immediately if you think you might be pregnant while using leflunomide.

Let your doctor know if you want to become pregnant within two years of stopping this medicine. Your healthcare provider may prescribe a treatment that can remove this drug from your body more quickly.

It’s not known whether leflunomide passes into breastmilk or could hurt a breastfeeding baby. Don’t breastfeed while taking this medicine.

Management Considerations in Cancer Patients With Rheumatoid Arthritis

Rheumatoid arthritis is the most common inflammatory arthritis, affecting 1% of the general population. It is a chronic disease in which inflammation of the synovium leads to bony erosions and joint destruction. The etiology of rheumatoid arthritis remains unclear, but its development likely requires a high-risk genetic background and an environmental trigger, leading to autoimmune dysregulation and an autoinflammatory response; the latter can affect not only the joints, but also other organs and systems. Patients with rheumatoid arthritis usually require treatment for the duration of their lifespan. Drugs used to treat rheumatoid arthritis fall primarily into three general categories: nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirrheumatic drugs (DMARDs); DMARDs can be synthetic drugs or biologic agents targeting specific cytokines or other molecules involved in the regulation of the immune response (Table). DMARDs can suppress the inflammatory response, primarily by downregulating the immune system.

Patients with cancer and concomitant rheumatoid arthritis are at increased risk for morbidity and mortality, in part because of their therapeutic needs. Immunosuppressant drugs used to treat rheumatoid arthritis can increase the risk of infection in patients undergoing surgery, or in those receiving chemotherapy. In addition, there are concerns that chronic immunosuppression from these therapies could result in downregulation of immune antitumor responses. It has been proposed that the use of biologic therapies for rheumatoid arthritis may conceivably increase the risk of malignancy, or of tumor progression in patients with a coexisting cancer. Patients with rheumatoid arthritis already have an increased risk of certain types of cancer, specifically lymphoma and lung cancer, likely as a result of their chronic inflammatory state. There is no evidence so far that rheumatoid arthritis therapies increase the risk of developing non-skin solid tumors. There is some controversy as to whether biologic agents, specifically tumor necrosis factor (TNF) inhibitors, may increase the risk of nonmelanoma skin cancer, melanoma, and lymphoma; any increased risk, however, appears to be small. Whether this class of agents may accelerate tumor progression in patients with pre-existing cancer remains debatable. While in theory this could be possible, the data are scarce, since patients with cancer are typically excluded from clinical trials of these immunosuppressive therapies, and few case series or observational studies have addressed the issue.

Cancer patients may undergo tumor resection, chemotherapy, radiation treatment, or, more recently, immunotherapy—all of which can make their management more challenging if they have concomitant rheumatoid arthritis. Coordination of care with a rheumatologist will be essential, especially if the patient has active rheumatoid arthritis or is receiving concomitant antirrheumatic therapy. Here we present practical approaches to the management of patients with cancer and rheumatoid arthritis at various stages of their malignancy.

Case 1

A 62-year-old man develops abdominal pain and hematochezia. He undergoes colonoscopy and is found to have a nonobstructing adenocarcinoma in his ascending colon. Staging scans do not show evidence of metastatic disease. He is scheduled to undergo a laparoscopic hemicolectomy. The patient has a 15-year history of rheumatoid arthritis, currently well controlled on hydroxychloroquine, methotrexate, and 7.5 mg daily of oral prednisone; he has been treated with this regimen continuously for the last 5 years. He also takes ibuprofen as needed for pain control.

The primary concerns in the management of this patient’s rheumatoid arthritis in the perioperative period include not only the possibility of surgical complications—such as increased systemic and local infections, impaired wound healing, and bleeding—but also problems that more directly involve his rheumatoid arthritis, such as the risk of postoperative arthritis flares, and difficulties in rehabilitation if his antirrheumatic therapies are discontinued.

Nonselective NSAIDs are used by many patients with rheumatoid arthritis as part of their daily drug regimen, or on an as-needed basis. Inhibition of cyclooxygenase (COX)-1 results in decreased production of prostaglandins and thromboxane, ultimately reducing the inflammatory response and platelet aggregation. Because of their antiplatelet effect, bleeding is the most feared side effect of NSAIDs in the perioperative setting, and NSAIDS should be held for a total of 5 half-lives of the drug in question prior to surgery—and in the case of aspirin, for 7 to 10 days, since aspirin binds to COX irreversibly, inactivating platelets for the remainder of their life.

Rheumatoid arthritis patients frequently take glucocorticoids as part of their drug regimen. Chronic glucocorticoid use is associated with surgical site infections and poor wound and bone healing. It is therefore recommended that patients slowly taper their glucocorticoid dose as tolerated throughout the preoperative period. Suppression of the hypothalamic-pituitary-adrenal axis is common in patients receiving long-term glucocorticoid therapy. The axis is considered to be functional if the daily dose of oral prednisone (or equivalent) is ≤ 5 mg. Patients who have been on ≥ 20 mg of prednisone daily for 3 weeks or longer may have significant adrenal suppression. Under normal circumstances, the human body produces 5 to 10 mg of cortisol daily. In the perioperative period, daily cortisol production can range from 50 to 200 mg. It is therefore necessary to give supplemental corticosteroids perioperatively to avoid acute adrenal insufficiency, which can lead to hypotension and shock in patients who are likely to have adrenal suppression as a result of prolonged glucocorticoid therapy.

Although data on hydroxychloroquine use in the perioperative period are limited, a retrospective study of 367 orthopedic surgeries in 204 patients with rheumatoid arthritis found no increased risk of systemic or surgical site infections in patients treated with hydroxychloroquine. This was corroborated in a subsequent study. Due to its low toxicity profile, hydroxychloroquine can be continued throughout the perioperative period.

A number of studies have examined the safety of methotrexate in the postoperative period. A clinical trial evaluated 388 patients with rheumatoid arthritis who were randomized to continuation of methotrexate or to discontinuation from 2 weeks prior to 2 weeks following surgery. The results did not show an increased infection rate in patients who continued methotrexate. Another study retrospectively evaluated 121 patients with rheumatoid arthritis who had undergone total joint arthroplasty; the investigators found no significant differences in postoperative infections or wound healing complications between those who continued on methotrexate and those who did not. Although the evidence would suggest that methotrexate is safe in the perioperative period, most studies included patients undergoing orthopedic surgery, and the results may not be representative of all surgical procedures. Discontinuing methotrexate for just 1 week prior to surgery and 1 week after surgery can minimize the risk of rheumatoid arthritis flares, and seems a reasonable approach in the face of uncertainty for nonorthopedic surgery outcomes.

Data for other DMARDs are scarce. One study showed a decrease in surgical site infections in patients who were taking sulfasalazine throughout the postoperative period. Other researchers have suggested that sulfasalazine be held on the day of surgery because the glomerular filtration rate can decrease during surgery and this drug is primarily excreted by the kidneys. There are limited data regarding the perioperative use of leflunomide, but a study in patients with rheumatoid arthritis who underwent total hip replacement showed no difference with respect to wound healing and infection rate between those who continued leflunomide and those in whom it was held.

There are few data on the use of most biologic agents and Janus kinase (JAK) inhibitors in patients with active cancer, because of concerns of possible suppression of tumor immunity. It is generally recommended that these agents be discontinued in patients with a recent diagnosis of cancer, so most patients will have stopped biologics before surgery.

Case 2

A 44-year-old woman with seropositive rheumatoid arthritis, on triple-DMARD therapy (methotrexate, sulfasalazine, and hydroxychloroquine), presents with a 1.5-cm nodule on her right breast, and no suspicious regional lymph nodes. Biopsy confirms an estrogen receptor–positive, progesterone receptor–positive, human epidermal growth factor receptor 2–negative ductal carcinoma. Her rheumatoid arthritis medications are stopped. The patient would like to undergo lumpectomy followed by radiation therapy but is concerned about the possible adverse effects of radiotherapy in women with rheumatoid arthritis.

A few studies have evaluated the risk of radiation therapy in patients with cancer and connective tissue diseases, especially scleroderma and lupus erythematosus. The evidence is limited; still, while some studies show an increase in the incidence of early and late adverse events in patients with rheumatoid arthritis, this risk appears to be small, and the majority of patients do not have any major complications.

The patient decides to undergo lumpectomy followed by radiation therapy, and she experiences no complications. She declines adjuvant chemotherapy and starts treatment with oral tamoxifen, returning to her full-time job. Two months later, she develops severe polyarthritis of her hands, elbows, and knees, which has a major impact on her quality of life. She starts treatment with oral prednisone. Six weeks later she starts triple-DMARD therapy, which had been an effective treatment before her cancer diagnosis. After 4 months, she shows no improvement and is obliged to take a temporary leave from her job; she would like to discuss an alternative therapy for her rheumatoid arthritis.

Decision making about antirrheumatic therapy in patients with concomitant rheumatoid arthritis and cancer requires careful risk stratification with respect to the cancer type, its stage, and its prognosis; patient preferences with regard to risk and outcome uncertainty must also be considered. In this situation, had this patient not had a recent diagnosis of cancer, it would be appropriate to consider a biologic therapy for her rheumatoid arthritis, according to recommendations from the American College of Rheumatology (ACR). However, this woman is young and has a recent cancer diagnosis with an excellent prognosis; thus, it would be desirable to choose an agent with a low likelihood of affecting tumor immunity. This is particularly important because the patient declined adjuvant chemotherapy, which can be effective in eliminating micrometastases.

Most commonly, patients with rheumatoid arthritis in whom traditional DMARD therapy fails are treated with TNF inhibitors. However, there is insufficient evidence regarding the safety of these agents in patients with cancer, primarily because they are typically excluded from clinical trials. Two observational studies assessed the risk of cancer recurrence in patients with rheumatoid arthritis treated with TNF inhibitors compared with traditional DMARDs and found no differences in recurrence rates; however, the numbers were small, and these studies did not include any patients who were within 5 years of their cancer diagnosis. Another case series reported that 8 of the included patients received TNF inhibitors within 5 years of cancer diagnosis, with no recurrences. A recent larger observational study showed that patients with rheumatoid arthritis who started therapy with TNF inhibitors after a diagnosis of breast cancer were not at increased risk for recurrence, but the median time from diagnosis to therapy initiation was 9 years (more than 5 years for 85% of the patients). These results are reassuring in that in selected patients with a history of treated cancer and no recurrence, TNF inhibitors appear to be safe when used several years after completion of therapy. However, for patients with a more recent cancer diagnosis, uncertainty remains.

Several factors should be taken into consideration when making decisions about rheumatoid arthritis therapy in patients with a history of cancer. The baseline risk of recurrence varies depending on how aggressive the original cancer was. Moreover, although the risk of recurrence decreases over time, for some cancer types, such as breast cancer, there is a risk even decades later. No study has examined the likelihood of cancer recurrence for specific rheumatoid arthritis therapies. However, most of the concerns have centered on TNF inhibitors, primarily because of their mode of action and limited evidence showing an increase in the risk of lymphoma, melanoma, and nonmelanoma skin cancers with these agents.

Because this patient has failed to respond to therapy with combination DMARDs, it is appropriate to initiate treatment with a biologic agent, but TNF inhibitors would not be the best choice. An appropriate alternative would be rituximab, which is an effective therapy for rheumatoid arthritis, and which has been used for many years in the treatment of lymphoma, with no evidence of increased recurrence in patients with prior solid tumors. Other biologic agents and JAK inhibitors have not been sufficiently evaluated in this setting to offer a recommendation.

Leflunomide 10mg Tablets

2. What you need to know before you take Leflunomide Winthrop

Do not take Leflunomide Winthrop

  • if you have ever had an allergic reaction to leflunomide (especially a serious skin reaction, often accompanied by fever, joint pain, red skin stains, or blisters e.g. Stevens-Johnson syndrome) or to any of the other ingredients of this medicine (listed in section 6),
  • if you have any liver problems,
  • if you have moderate to severe kidney problems,
  • if you have severely low numbers of proteins in your blood (hypoproteinaemia),
  • if you suffer from any problem which affects your immune system (e.g. AIDS),
  • if you have any problem with your bone marrow, or if you have low numbers of red or white cells in your blood or a reduced number of blood platelets,
  • if you are suffering from a serious infection,
  • if you are pregnant, think you may be pregnant, or are breast-feeding.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Leflunomide Winthrop

  • if you have ever suffered from tuberculosis or interstitial lung disease (lung disease),
  • if you are male and wish to father a child. As it can not be excluded that Leflunomide Winthrop passes into semen, reliable contraception should be used during treatment with Leflunomide Winthrop. Men wishing to father a child should contact their doctor who may advise them to stop taking Leflunomide Winthrop and take certain medicines to remove Leflunomide Winthrop rapidly and sufficiently from their body. You will then need a blood test to make sure that Leflunomide Winthrop has been sufficiently removed from your body, and you should then wait for at least another 3 months before attempting to father a child.

Leflunomide Winthrop can occasionally cause some problems with your blood, liver, lungs, or nerves in your arms or legs. It may also cause some serious allergic reactions (including Drug Reaction with Eosinophilia and Systemic Symptoms ), or increase the chance of a severe infection. For more information on these, please read section 4 (Possible side effects).

DRESS appears initially as flu like symptoms and a rash on the face then an extended rash with a high temperature, increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia) and enlarged lymph nodes.

Your doctor will carry out blood tests at regular intervals, before and during treatment with Leflunomide Winthrop, to monitor your blood cells and liver. Your doctor will also check your blood pressure regularly as Leflunomide Winthrop can cause an increase in blood pressure.

Children and adolescents

Leflunomide Winthrop is not recommended for use in children and adolescents below 18 years of age.

Other medicines and Leflunomide Winthrop

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

This is especially important if you are taking:

  • other medicines for rheumatoid arthritis such as antimalarials (e.g. chloroquine and hydroxychloroquine), intramuscular or oral gold, D penicillamine, azathioprine and other immunosuppressive drugs (e.g. methotrexate) as these combinations are not advisable,
  • a medicine called colestyramine (used to reduce high cholesterol) or activated charcoal as these medicines can reduce the amount of Leflunomide Winthrop which is absorbed by the body,
  • phenytoin (used to treat epilepsy), warfarin or phenprocoumon (used to thin the blood) or tolbutamide (used to treat type 2 diabetes) as these medicines may increase the risk of side effects.

If you are already taking a nonsteroidal anti-inflammatory drug (NSAID) and/or corticosteroids, you may continue to take them after starting Leflunomide Winthrop.

Vaccinations

If you have to be vaccinated, ask your doctor for advice. Certain vaccinations should not be given while taking Leflunomide Winthrop, and for a certain amount of time after stopping treatment.

Leflunomide Winthrop with food, drink and alcohol

Leflunomide Winthrop may be taken with or without food.

It is not recommended to drink alcohol during treatment with Leflunomide Winthrop. Drinking alcohol while taking Leflunomide Winthrop may increase the chance of liver damage.

Pregnancy and breast-feeding

Do not take Leflunomide Winthrop if you are, or think you may be pregnant. If you are pregnant or become pregnant while taking Leflunomide Winthrop, the risk of having a baby with serious birth defects is increased. Women of childbearing potential must not take Leflunomide Winthrop without using reliable contraceptive measures.

Tell your doctor if you plan to become pregnant after stopping treatment with Leflunomide Winthrop, as you need to ensure that all traces of Leflunomide Winthrop have left your body before trying to become pregnant. This may take up to 2 years. This may be reduced to a few weeks by taking certain medicines which speed up removal of Leflunomide Winthrop from your body.

In either case it should be confirmed by a blood test that Leflunomide Winthrop has been sufficiently removed from your body and you should then wait for at least another month before you become pregnant.

For further information on the laboratory testing please contact your doctor.

If you suspect that you are pregnant while taking Leflunomide Winthrop or in the two years after you have stopped treatment, you must contact your doctor immediately for a pregnancy test. If the test confirms that you are pregnant, your doctor may suggest treatment with certain medicines to remove Leflunomide Winthrop rapidly and sufficiently from your body, as this may decrease the risk to your baby.

Do not take Leflunomide Winthrop when you are breast-feeding, as leflunomide passes into the breast milk.

Driving and using machines

Leflunomide Winthrop can make you feel dizzy which may impair your ability to concentrate and react. If you are affected, do not drive, or use machines.

Leflunomide Winthrop contains lactose.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Embryo-Fetal Toxicity

ARAVA may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level .

ARAVA is contraindicated for use in pregnant women . Exclude pregnancy before starting treatment with ARAVA in females of reproductive potential . Advise females of reproductive potential to use effective contraception during ARAVA treatment and during an accelerated drug elimination procedure after ARAVA treatment . If a woman becomes pregnant while taking ARAVA, stop treatment with ARAVA, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide .

Upon discontinuing ARAVA, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving ARAVA treatment who wish to become pregnant must discontinue ARAVA and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk .

Hepatotoxicity

Severe liver injury, including fatal liver failure, has been reported in some patients treated with ARAVA. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) of greater than twice the upper limits of normal ( > 2xULN) before initiating treatment, should not be treated with ARAVA. Use caution when ARAVA is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting ARAVA, and thereafter every 6-8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt ARAVA therapy and investigate the cause. If likely ARAVA-induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized If ARAVA-induced liver injury is unlikely because some other cause has been found, resumption of ARAVA therapy may be considered.

If ARAVA and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.

Procedure For Accelerated Elimination Of ARAVA And Its Active Metabolite

The active metabolite of leflunomide, teriflunomide, is eliminated slowly from the plasma .

Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. Therefore, an accelerated elimination procedure should be considered at any time after discontinuation of ARAVA, and in particular, when a patient has experienced a severe adverse reaction (e.g., hepatotoxicity, serious infection, bone marrow suppression, Steven Johnson Syndrome, toxic epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected hypersensitivity, or has become pregnant. It is recommended that all women of childbearing potential undergo an accelerated elimination procedure after stopping ARAVA treatment.

Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, the plasma concentration not associated with embryo-fetal toxicity in animals.

Elimination can be accelerated by the following procedures:

  1. Administer cholestyramine 8 grams orally 3 times daily for 11 days.
  2. Alternatively, administer 50 grams of activated charcoal powder (made into a suspension) orally every 12 hours for 11 days.

Verify plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 μg/mL) by two separate tests at least 14 days apart. If plasma teriflunomide concentrations are higher than 0.02 mg/L, repeat cholestyramine and/or activated charcoal treatment.

The duration of accelerated drug elimination treatment may be modified based on the clinical status and tolerability of the elimination procedure. The procedure may be repeated as needed, based on teriflunomide concentrations and clinical status.

Use of the accelerated drug elimination procedure may potentially result in return of disease activity if the patient had been responding to ARAVA treatment.

Immunosuppression, Bone Marrow Suppression, And Risk Of Serious Infections

ARAVA is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. If a serious infection occurs, consider interrupting ARAVA therapy and initiating the accelerated drug elimination procedure . Medications like ARAVA that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving ARAVA, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid arthritis, may predispose patients to infection.

Cases of tuberculosis were observed in clinical studies with teriflunomide, the metabolite of ARAVA. Prior to initiating ARAVA, all patients should be screened for active and inactive (“latent”) tuberculosis infection as per commonly used diagnostic tests. ARAVA has not been studied in patients with a positive tuberculosis screen, and the safety of ARAVA in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ARAVA and monitored carefully during ARAVA treatment for possible reactivation of the infection.

Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving ARAVA alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.

Patients taking ARAVA should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6- to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking ARAVA, stop treatment with ARAVA, and perform an accelerated drug elimination procedure to reduce the plasma concentration of the ARAVA active metabolite, teriflunomide .

In any situation in which the decision is made to switch from ARAVA to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds.

Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, And Drug Reactions With Eosinophilia And Systemic Symptoms

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving ARAVA. If a patient taking ARAVA develops any of these conditions, stop ARAVA treatment and perform an accelerated drug elimination procedure .

Malignancy And Lymphoproliferative Disorders

The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with ARAVA. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of ARAVA, but larger dosages and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with ARAVA.

Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving ARAVA and in clinical studies with teriflunomide, the active metabolite of leflunomide. Most patients recovered after discontinuation of treatment, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking ARAVA develops a peripheral neuropathy, consider discontinuing ARAVA therapy and performing an accelerated drug elimination procedure .

Interstitial Lung Disease

Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with ARAVA and has been associated with fatal outcomes . The risk of ARAVA-associated interstitial lung disease is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder that may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of ARAVA therapy and for further investigation as appropriate. If discontinuation of ARAVA is necessary, consider performing an accelerated drug elimination procedure .

Vaccinations

No clinical data are available on the efficacy and safety of vaccinations during ARAVA treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of the active metabolite of ARAVA should be considered when contemplating administration of a live vaccine after stopping ARAVA.

Blood Pressure Monitoring

In placebo-controlled studies with the active metabolite of ARAVA, teriflunomide, elevations in blood pressure were observed in some subjects. Blood pressure should be checked before starting treatment with ARAVA and monitored periodically thereafter .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human teriflunomide systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human teriflunomide exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human teriflunomide exposure based on AUC). The significance of the findings in mice relative to the clinical use of ARAVA is not known.

Leflunomide was not mutagenic in the Ames assay, the unscheduled DNA synthesis assay, or in the HGPRT gene mutation assay. In addition, leflunomide was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames assay and in the HGPRT gene mutation assay, and was clastogenic in the in vitro Chinese hamster cell chromosomal aberration assay. TFMA was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test.

Leflunomide had no effect on fertility or reproductive performance in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human teriflunomide exposure based on AUC) .

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-ina-study/.

Risk Summary

ARAVA is contraindicated for use in pregnant women because of the potential for fetal harm. In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of and equivalent to the maximum recommended human dose (MRHD) based on AUC, respectively in rats and rabbits, caused teratogenicity (rats and rabbits) and embryo-lethality (rats) . Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of ARAVA during pregnancy. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with ARAVA, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) .

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from ARAVA. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L. .

Data

Animal Data

In an embryofetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microophthalmia and internal hydrocephalus, were observed. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In an embryofetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. Leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in both rats and rabbits).

In a pre- and post-natal development study, when female rats were treated leflunomide at a dose that was approximately 1/100 of the MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival.

Lactation

Clinical lactation studies have not been conducted to assess the presence of ARAVA in human milk, the effects of ARAVA on the breastfed child, or the effects of ARAVA on milk production. Because of the potential for serious adverse reactions in a breastfed infant from ARAVA, advise a nursing woman to discontinue breastfeeding during treatment with ARAVA.

Females And Males Of Reproductive Potential

ARAVA may cause fetal harm when administered during pregnancy. Advise females of the potential risk to the fetus. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment . Women receiving ARAVA treatment who wish to become pregnant should discontinue ARAVA and undergo an accelerated drug elimination procedure to achieve plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) .

Pregnancy Testing

Exclude pregnancy in females of reproductive potential before starting treatment with ARAVA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ARAVA and while undergoing a drug elimination procedure until verification that the plasma teriflunomide concentration is less than 0.02 mg/L .

Pediatric Use

The safety and effectiveness of ARAVA in pediatric patients have not been established.

The safety and effectiveness of ARAVA in the treatment of polyarticular course juvenile idiopathic arthritis (JIA) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (JIA) as defined by the American College of Rheumatology (ACR). In this population, ARAVA treatment was found not to be effective.

The safety of ARAVA was studied in 74 patients with polyarticular course JIA ranging in age from 3-17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between 3 and 8-fold the upper limit of normal.

Geriatric Use

Of the total number of subjects in controlled clinical trials (Trials 1, 2, and 3) of ARAVA, 234 subjects were 65 years and over . No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in patients over 65.

Hepatic Impairment

Dedicated studies of the effect of hepatic impairment on leflunomide pharmacokinetics have not been conducted. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of ARAVA in patients with hepatic impairment is not recommended.

Renal Impairment

Dedicated studies of the effect of renal impairment on leflunomide pharmacokinetics have not been conducted. Given that the kidney plays an important role in drug elimination, caution should be used when ARAVA is administered to these patients.

Identification

Are you a new drug developer? Contact us to learn more about our customized products and solutions. Stay in the know! As part of our commitment to providing the most up-to-date drug information, we will be releasing #DrugBankUpdates with our newly added curated drug pages. #DrugBankUpdates Name Leflunomide Accession Number DB01097 (APRD00205) Type Small Molecule Groups Approved, Investigational Description

Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999.

Structure 3D Download Similar Structures

Structure for Leflunomide (DB01097)

× Close Synonyms External IDs SU-101 / SU101 Product Images Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End
Unlock Additional Data
Arava Tablet, film coated 20 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 10 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 10 mg/1 Oral sanofi-aventis U.S. LLC 1998-09-10 Not applicable US
Arava Tablet, film coated 20 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 20 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 100 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 10 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 20 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 10 mg Oral Sanofi Aventis Deutschland Gmb H 1999-09-02 Not applicable EU
Arava Tablet, film coated 100 mg/1 Oral sanofi-aventis U.S. LLC 1998-09-19 Not applicable US

Additional Data Available

  • Application Number Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more

  • Product Code Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

Generic Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End
Unlock Additional Data
Accel-leflunomide Tablet Oral Accel Pharma Inc 2019-09-19 Not applicable Canada
Accel-leflunomide Tablet Oral Accel Pharma Inc 2019-09-19 Not applicable Canada
Apo-leflunomide Tablet Oral Apotex Corporation 2004-09-14 Not applicable Canada
Apo-leflunomide Tablet Oral Apotex Corporation 2004-09-14 Not applicable Canada
Dom-leflunomide Tablet Oral Dominion Pharmacal Not applicable Not applicable Canada
Dom-leflunomide Tablet Oral Dominion Pharmacal Not applicable Not applicable Canada
Leflunomide Tablet, film coated 10 mg/1 Oral Barr Laboratories 2005-09-14 2011-09-30 US
Leflunomide Tablet 10 mg/1 Oral KVK-Tech, Inc. 2019-06-03 Not applicable US
Leflunomide Tablet 20 mg/1 Oral Apotex Corp. 2005-09-13 Not applicable US
Leflunomide Tablet, film coated 10 mg/1 Oral Prasco, Laboratories 1998-09-10 2014-10-31 US

Additional Data Available

  • Application Number Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more

  • Product Code Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

Categories UNII G162GK9U4W CAS number 75706-12-6 Weight Average: 270.2073
Monoisotopic: 270.061612157 Chemical Formula C12H9F3N2O2 InChI Key VHOGYURTWQBHIL-UHFFFAOYSA-N InChI InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18) IUPAC Name 5-methyl-N–1,2-oxazole-4-carboxamide SMILES CC1=C(C=NO1)C(=O)NC1=CC=C(C=C1)C(F)(F)F

Pharmacology

Indication

For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease. Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use.

Associated Conditions

  • Juvenile Idiopathic Arthritis (JIA)
  • Rheumatoid Arthritis

Pharmacodynamics

Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide’s inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.

Mechanism of action

Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug’s activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells.

Target Actions Organism
ADihydroorotate dehydrogenase (quinone), mitochondrial inhibitor Humans
UAryl hydrocarbon receptor agonist Humans
UProtein-tyrosine kinase 2-beta antagonist Humans

Unlock Additional Data Additional Data Available Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

Learn more Additional Data Available Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

Learn more Additional Data Available Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Learn more Absorption

Well absorbed, peak plasma concentrations appear 6-12 hours after dosing

Volume of distribution

  • 0.13 L/kg

Protein binding

>99.3%

Metabolism

Primarily hepatic. Leflunomide is converted to its active form following oral intake.

  • Leflunomide A771726

Route of elimination

The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide.

Half life

2 weeks

Clearance Not Available Toxicity

LD50=100-250 mg/kg (acute oral toxicity)

Affected organisms

  • Humans and other mammals

Pathways Not Available Pharmacogenomic Effects/ADRs

Interacting Gene/Enzyme Allele name Genotype(s) Defining Change(s) Type(s) Description Details
Cytochrome P450 1A2 (C;C) C allele ADR Directly Studied The presence of this genotype in CYP1A2 may be associated with an increased risk of drug-related toxicity from leflunomide therapy. Details

Interactions

Drug Interactions This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

  • All Drugs
  • Approved
  • Vet approved
  • Nutraceutical
  • Illicit
  • Withdrawn
  • Investigational
  • Experimental
Drug Interaction
Unlock Additional Data
(R)-warfarin The serum concentration of (R)-warfarin can be decreased when it is combined with Leflunomide.
(S)-Warfarin The metabolism of (S)-Warfarin can be decreased when combined with Leflunomide.
2-Methoxyethanol The risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Leflunomide.
4-hydroxycoumarin The therapeutic efficacy of 4-hydroxycoumarin can be increased when used in combination with Leflunomide.
6-O-benzylguanine The serum concentration of 6-O-benzylguanine can be decreased when it is combined with Leflunomide.
8-azaguanine The serum concentration of 8-azaguanine can be decreased when it is combined with Leflunomide.
8-chlorotheophylline The serum concentration of 8-chlorotheophylline can be decreased when it is combined with Leflunomide.
9-(N-methyl-L-isoleucine)-cyclosporin A The risk or severity of adverse effects can be increased when 9-(N-methyl-L-isoleucine)-cyclosporin A is combined with Leflunomide.
9-Deazaguanine The serum concentration of 9-Deazaguanine can be decreased when it is combined with Leflunomide.
9-Methylguanine The serum concentration of 9-Methylguanine can be decreased when it is combined with Leflunomide.

Additional Data Available

  • Extended Description Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more

  • Severity Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more

  • Evidence Level Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more

  • Action Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more

Food Interactions

  • Take without regard to meals.

Synthesis Reference US20010031878 General References External Links Human Metabolome Database HMDB0015229 KEGG Drug D00749 KEGG Compound C07905 PubChem Compound 3899 PubChem Substance 46506013 ChemSpider 3762 BindingDB 50054601 ChEBI 6402 ChEMBL CHEMBL960 Therapeutic Targets Database DAP000636 PharmGKB PA450192 RxList RxList Drug Page Drugs.com Drugs.com Drug Page Wikipedia Leflunomide ATC Codes L04AA13 — Leflunomide

  • L04AA — Selective immunosuppressants
  • L04A — IMMUNOSUPPRESSANTS
  • L04 — IMMUNOSUPPRESSANTS
  • L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

AHFS Codes

  • 92:36.00 — Disease-modifying Antirheumatic Agents

FDA label (1.23 MB) MSDS (105 KB)

Clinical Trials

Clinical Trials

Phase Status Purpose Conditions Count
1 Completed Not Available Healthy Volunteers 2
1 Completed Not Available To Determine the Bioequivalence Study Under Fasting 1
1 Completed Other To Determine Bioequivalence Under Fed Conditions 1
1 Completed Treatment Gliomas / Sarcomas 1
1 Completed Treatment Human Immunodeficiency Virus (HIV) Infections 1
1 Completed Treatment Psoriatic Arthritis / Rheumatoid Arthritis 1
1 Not Yet Recruiting Treatment Chronic Graft Versus Host Disease / Steroid Refractory Graft Versus Host Disease 1
1 Terminated Treatment Melanoma 1
1, 2 Active Not Recruiting Treatment Recurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma 1
1, 2 Recruiting Treatment Breast Diseases / Metastatic Triple Negative Breast Cancer / Neoplasms, Breast 1
2 Completed Treatment Adult-Onset Still’s Disease 1
2 Completed Treatment Brain and Central Nervous System Tumors 1
2 Completed Treatment Rheumatoid Arthritis 1
2 Completed Treatment Systemic Lupus Erythematosus (SLE) 1
2 Completed Treatment Uveitis 1
2 Recruiting Treatment Henoch-Schoenlein Purpura Nephritis 1
2 Terminated Prevention Viral sepsis / Viruria 1
2 Unknown Status Treatment Bullous Pemphigoid (BP) 1
2 Withdrawn Treatment Smoldering Plasma Cell Myeloma 1
2 Withdrawn Treatment Systemic Lupus Erythematosus (SLE) 1
2, 3 Completed Treatment Nephritis, Lupus 1
2, 3 Completed Treatment Prostate Cancer 1
3 Completed Treatment Brain and Central Nervous System Tumors 1
3 Completed Treatment Rheumatoid Arthritis 7
3 Recruiting Treatment Myasthenia Gravis 1
3 Recruiting Treatment Polymyalgia Rheumatica 1
3 Terminated Treatment Nephritis, Lupus 1
3 Terminated Treatment Rheumatoid Arthritis 2
4 Completed Treatment Immunoglobulin G4 Related Sclerosing Disease 1
4 Completed Treatment Rheumatoid Arthritis 7
4 Enrolling by Invitation Basic Science Rheumatoid Arthritis 1
4 Not Yet Recruiting Treatment IgA Glomerulonephritis / Renal Insufficiency,Chronic 1
4 Not Yet Recruiting Treatment Psoriatic Arthritis 2
4 Recruiting Treatment Rheumatoid Arthritis 1
4 Terminated Treatment Rheumatoid Arthritis 1
4 Unknown Status Treatment Juvenile Idiopathic Arthritis (JIA) 1
4 Unknown Status Treatment Rheumatoid Arthritis 1
Not Available Active Not Recruiting Not Available Rheumatoid Arthritis / The Polymorphisms Associated With Efficacy or Adverse Reactions to the Drug 1
Not Available Completed Basic Science Rheumatoid Arthritis 1
Not Available Completed Treatment Rheumatoid Arthritis 1
Not Available Recruiting Not Available Mechanisms, Defense / Outcomes / Pregnancy Related / Takayasu’s Disease / Treatment Refusal 1
Not Available Recruiting Treatment Autoimmune Diseases 1
Not Available Recruiting Treatment Lupus / Nephritis 1
Not Available Recruiting Treatment Takayasu’s Disease 1
Not Available Unknown Status Treatment BK Virus Infection / Terminal Renal Failure 1
Not Available Unknown Status Treatment Rheumatoid Arthritis 1

Pharmacoeconomics

Manufacturers Not Available Packagers

  • Apotex Inc.
  • Barr Pharmaceuticals
  • Diversified Healthcare Services Inc.
  • Heritage Pharmaceuticals
  • Kali Laboratories Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Physicians Total Care Inc.
  • Prasco Labs
  • Sandoz
  • Sanofi-Aventis Inc.
  • Teva Pharmaceutical Industries Ltd.

Dosage forms

Form Route Strength
Tablet, film coated Oral 10 mg
Tablet, film coated Oral 100 mg
Tablet, film coated Oral 100 mg/1
Tablet, film coated Oral 20 mg
Tablet Oral
Tablet Oral 10 mg
Tablet Oral 10 mg/1
Tablet Oral 20 mg
Tablet Oral 20 mg/1
Tablet, film coated Oral 10 mg/1
Tablet, film coated Oral 20 mg/1
Tablet, film coated Oral 15 mg

Prices

Unit description Cost Unit
Arava 10 mg tablet 24.76USD tablet
Arava 20 mg tablet 24.76USD tablet
Leflunomide 10 mg tablet 16.75USD tablet
Leflunomide 20 mg tablet 16.75USD tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only. Patents Not Available

Properties

State Solid Experimental Properties

Property Value Source
melting point (°C) 165-166 °C Not Available
water solubility 21 mg/L (poorly soluble) Not Available
logP 2.8 Not Available

Predicted Properties

Property Value Source
Water Solubility 0.0844 mg/mL ALOGPS
logP 2.52 ALOGPS
logP 2.51 ChemAxon
logS -3.5 ALOGPS
pKa (Strongest Acidic) 10.41 ChemAxon
pKa (Strongest Basic) -0.45 ChemAxon
Physiological Charge 0 ChemAxon
Hydrogen Acceptor Count 2 ChemAxon
Hydrogen Donor Count 1 ChemAxon
Polar Surface Area 55.13 Å2 ChemAxon
Rotatable Bond Count 3 ChemAxon
Refractivity 64.16 m3·mol-1 ChemAxon
Polarizability 23.11 Å3 ChemAxon
Number of Rings 2 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five Yes ChemAxon
Ghose Filter Yes ChemAxon
Veber’s Rule No ChemAxon
MDDR-like Rule No ChemAxon

Predicted ADMET features

Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9949
Caco-2 permeable + 0.5069
P-glycoprotein substrate Non-substrate 0.909
P-glycoprotein inhibitor I Non-inhibitor 0.7822
P-glycoprotein inhibitor II Non-inhibitor 0.8889
Renal organic cation transporter Non-inhibitor 0.9154
CYP450 2C9 substrate Non-substrate 0.8548
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.5211
CYP450 1A2 substrate Inhibitor 0.9189
CYP450 2C9 inhibitor Non-inhibitor 0.9071
CYP450 2D6 inhibitor Non-inhibitor 0.9231
CYP450 2C19 inhibitor Non-inhibitor 0.9026
CYP450 3A4 inhibitor Non-inhibitor 0.5117
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5622
Ames test Non AMES toxic 0.5504
Carcinogenicity Non-carcinogens 0.7067
Biodegradation Not ready biodegradable 0.9836
Rat acute toxicity 3.0297 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9879
hERG inhibition (predictor II) Non-inhibitor 0.9068

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST) Not Available Spectra

Taxonomy

Description This compound belongs to the class of organic compounds known as aromatic anilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with an aromatic group. They have the general structure RNC(=O)R’, where R= benzene, and R = aryl group. Kingdom Organic compounds Super Class Benzenoids Class Benzene and substituted derivatives Sub Class Anilides Direct Parent Aromatic anilides Alternative Parents Trifluoromethylbenzenes / Isoxazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / OrganofluoridesOrganic oxides / Hydrocarbon derivatives / Alkyl fluorides show 3 more Substituents Aromatic anilide / Trifluoromethylbenzene / Azole / Isoxazole / Heteroaromatic compound / Carboxamide group / Secondary carboxylic acid amide / Carboxylic acid derivative / Organoheterocyclic compound / AzacycleOxacycle / Organic oxide / Organooxygen compound / Organonitrogen compound / Organofluoride / Organohalogen compound / Organopnictogen compound / Alkyl fluoride / Organic oxygen compound / Alkyl halide / Organic nitrogen compound / Hydrocarbon derivative / Aromatic heteromonocyclic compound show 13 more Molecular Framework Aromatic heteromonocyclic compounds External Descriptors monocarboxylic acid amide, isoxazoles, (trifluoromethyl)benzenes (CHEBI:6402)

Targets

Binding Properties

×

Property Measurement pH Temperature (°C)
IC 50 (nM) 10000 N/A N/A 9873513
IC 50 (nM) 13000 N/A N/A 9719606

Details Binding Properties1. Dihydroorotate dehydrogenase (quinone), mitochondrial Kind Protein Organism Humans Pharmacological action Yes Actions Inhibitor General Function Ubiquinone binding Specific Function Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Gene Name DHODH Uniprot ID Q02127 Uniprot Name Dihydroorotate dehydrogenase (quinone), mitochondrial Molecular Weight 42866.93 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Agonist General Function Transcription regulatory region dna binding Specific Function Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes… Gene Name AHR Uniprot ID P35869 Uniprot Name Aryl hydrocarbon receptor Molecular Weight 96146.705 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Antagonist General Function Signal transducer activity Specific Function Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulat… Gene Name PTK2B Uniprot ID Q14289 Uniprot Name Protein-tyrosine kinase 2-beta Molecular Weight 115873.62 Da

  1. Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I: Tyrosine kinase blockers: new hope for successful cancer therapy. Anticancer Agents Med Chem. 2009 Jan;9(1):66-76.
  2. Fukushima R, Kanamori S, Hirashiba M, Hishikawa A, Muranaka RI, Kaneto M, Nakamura K, Kato I: Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reprod Toxicol. 2007 Nov-Dec;24(3-4):310-6. Epub 2007 May 18.
  3. Steeghs N, Nortier JW, Gelderblom H: Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol. 2007 Feb;14(2):942-53. Epub 2006 Nov 14.

Enzymes

Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate Inhibitor General Function Steroid hydroxylase activity Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP2C9 Uniprot ID P11712 Uniprot Name Cytochrome P450 2C9 Molecular Weight 55627.365 Da Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un… Gene Name CYP1A2 Uniprot ID P05177 Uniprot Name Cytochrome P450 1A2 Molecular Weight 58293.76 Da

  1. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218.
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1.

Transporters

Kind Protein Organism Humans Pharmacological action Unknown Actions Substrate General Function Xenobiotic-transporting atpase activity Specific Function High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro… Gene Name ABCG2 Uniprot ID Q9UNQ0 Uniprot Name ATP-binding cassette sub-family G member 2 Molecular Weight 72313.47 Da ×Unlock Data

There is additional data available for commercial users including Adverse Effects, Contraindications, and Blackbox Warnings. Contact us to learn more about these and other features.

Learn more

Drug created on June 13, 2005 07:24 / Updated on February 02, 2020 00:24

About the author

Leave a Reply

Your email address will not be published. Required fields are marked *