Leflunomide

Leflunomide is used alone or in combination with other medications to treat rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function). Leflunomide is in a class of medications called disease-modifying antirheumatic drugs (DMARDs). It works by decreasing inflammation and slowing the progress of the condition, which can help improve the physical activity of people with rheumatoid arthritis.

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

Included as part of the PRECAUTIONS section.

Mechanism of Action

Not fully understood

Metabolite inhibits pyrimidine nucleotide synthesis; antiproliferative for T-cells

Absorption

Bioavailability: 80%

Peak plasma time: 6-12 hr

Detectable for up to 2 years

Distribution

Protein bound: >99%

Vd: 0.13 L/kg

Metabolism

GI mucosa, liver

Metabolites: A77 1726 (active)-undergoes hepatic recirculation

Elimination

Half-life: 14-18 days

Clearance: 31 mL/hr

Renal elimination predominant during first 96 hr, thereafter fecal elimination predominates

Excretion: Feces 48%; urine: 43%

Leflunomide may be found in some form under the following brand names:

• Arava

• Taking leflunomide may increase your risk of developing an infection. 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.
• If you are already infected with tuberculosis (TB) leflunomide may make your infection more serious and cause you to develop symptoms, if you don't already have any. 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.
• Severe liver damage, including fatal liver failure, has been reported in some patients treated with leflunomide. Tell your doctor if you experience any signs of liver problems, including:
  • extreme tiredness
  • stomach pain
  • yellowing of the whites of the eyes or skin (jaundice)
• 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 may cause low blood cell counts and anemia.
• Rare cases of severe skin reactions have been reported. Tell your doctor if you experience a skin rash during your treatment.
• Ask your doctor about the safe use of alcoholic beverages while you are taking leflunomide.

Do not take leflunomide if you:

• are allergic to leflunomide or any of its ingredients
• are pregnant
• have liver disease

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Leflunomide falls into category X. 

Do not take leflunomide if you are pregnant or plan to become pregnant. Leflunomide may harm the fetus. You should not begin taking leflunomide until you have taken a pregnancy test with negative results and your doctor tells you that you are not pregnant. You must use an effective method of birth control before you begin taking leflunomide, during your treatment with leflunomide, and for 2 years after treatment. If your period is late or you miss a period during treatment with leflunomide, call your doctor immediately. Talk to your doctor if you plan to become pregnant within 2 years after stopping treatment with leflunomide. Your doctor can prescribe a treatment that will help to remove this medication more quickly from your body.

See FDA Warning.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

The recommended dose of leflunomide is 100 mg tablet per day for 3 days.

The recommended dose of leflunomide is 20 mg/day, thereafter.

If dosing at 20 mg/day is not well tolerated, your doctor may decrease your dose to 10 mg/day.

If you take too much leflunomide call your local Poison Control center or seek emergency medical attention right away.

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

To make sure leflunomide 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 leflunomide, 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 leflunomide.

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.

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).

It is very important that your doctor check your progress at regular visits to make sure that leflunomide is working properly. Blood tests may be needed to check for unwanted effects.

You will need to have your blood pressure measured before starting leflunomide and while you are using it. If you notice any change to your recommended blood pressure, call your doctor right away. If you have questions about this, talk to your doctor.

Using leflunomide while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Leflunomide may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Men taking leflunomide should use condoms as a form of birth control during sexual intercourse. A man intending to father a child should stop taking leflunomide and check with his doctor right away.

Do not use leflunomide if you are also using teriflunomide. Using these medicines together may cause unwanted serious side effects.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Leflunomide can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

leflunomide may cause drug reaction with eosinophilia and systemic reactions (DRESS), including serious skin reactions. Check with your doctor right away if you have any blistering, peeling, or loose skin, chills, itching, joint or muscle pain, red skin lesions, often with a purple center, sores, ulcers, or white spots in the mouth or on the lips, or unusual tiredness or weakness.

You will need to have a skin test for tuberculosis before you start using leflunomide. Tell your doctor if you or anyone in your home has ever had a positive reaction to a tuberculosis test.

Using leflunomide may increase your risk of getting serious infections or cancer. Talk to your doctor if you have concerns about this risk.

Check with your doctor right away if you are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

Check with your doctor right away if you have a cough with or without a fever, shortness of breath, or any difficulty with breathing.

While you are being treated with leflunomide, and after you stop using it, do not have any vaccinations without your doctor's approval. Live virus vaccines should not be given while receiving leflunomide.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• It is used to treat rheumatoid arthritis.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking leflunomide as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about leflunomide, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about leflunomide. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using leflunomide.

Review Date: October 4, 2017

Leflunomide tablets, USP are available in two strengths:

• Leflunomide tablets, USP 10 mg are white, round tablets engraved "LE" over "10" on one side and engraved "APO" on the other side
• Leflunomide tablets, USP 20 mg are white, triangular-shaped tablets engraved "LE" over "20" on one side and engraved "APO" on the other side

Mechanism of Action

Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.

Pharmacokinetics

Following oral administration, Leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of Leflunomide’s in vivo activity. Plasma concentrations of the parent drug, Leflunomide, have been occasionally seen at very low concentrations. Studies of the pharmacokinetics of Leflunomide have primarily examined the plasma concentrations of the active metabolite, teriflunomide.

Absorption
Following oral administration, peak teriflunomide concentrations occurred between 6 to 12 hours after dosing. Due to the very long half-life of teriflunomide (18 to 19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require about two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional.

Effect of Food
Co-administration of Leflunomide tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.

Distribution
Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.

Elimination
Teriflunomide, the active metabolite of Leflunomide, has a median half-life of 18 to 19 days in healthy volunteers. The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal. 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, due to individual variation in drug clearance [see Warnings and Precautions (5.3)]. After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h.

Metabolism
In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in Leflunomide metabolism. In vivo, Leflunomide is metabolized to one primary (teriflunomide) and many minor metabolites. In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes. The parent compound is rarely detectable in plasma.

Excretion
Teriflunomide, the active metabolite of Leflunomide, is eliminated by direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).

Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialyzable.

Specific Populations
Gender. Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide.

Smoking. A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.

Drug Interaction Studies
Drug interaction studies have been conducted with both Leflunomide (Leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

The Potential Effect of Other Drugs on Leflunomide

• Potent CYP and transporter inducers:
  Following concomitant administration of a single dose of Leflunomide to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when Leflunomide was given alone [see Drug Interactions (7)].
• An in vivo interaction study with Leflunomide and cimetidine (non-specific weak CYP inhibitor) has demonstrated a lack of a significant impact on teriflunomide exposure.

The Potential Effect of Leflunomide on Other Drugs

• CYP2C8 Substrates
  There was an increase in mean repaglinide Cmax and AUC (1.7-and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose [see Drug Interactions (7)].
• CYP1A2 Substrates
  Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.
• OAT3 Substrates
  There was an increase in mean cefaclor Cmax and AUC (1.43-and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo [see Drug Interactions (7)].
• BCRP and OATP1B1/1B3 Substrates
  There was an increase in mean rosuvastatin Cmax and AUC (2.65-and 2.51-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) [see Drug Interactions (7)].
• Oral Contraceptives
  There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58-and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0-24 (1.33-and 1.41-fold, respectively) following repeated doses of teriflunomide [see Drug Interactions (7)].
• Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate).

APOTEX CORP. NDC 60505-2502-1

Leflunomide Tablets, USP

10 mg

Rx

30 bottle count

• Antirheumatic, Disease Modifying

Juvenile idiopathic arthritis

Data from a limited number of clinical trials suggest that leflunomide may be beneficial for the treatment of juvenile idiopathic arthritis (JIA) [Foeldvari 2010], [Jahan 2012], [Silverman 2005]. Additional data may be necessary to further define the role of leflunomide in this condition.

Based on the American College of Rheumatology guidelines for the treatment of JIA (Ringold 2014), leflunomide is effective and is recommended as adjunct therapy in the management of patients with JIA with systemic features and who require additional therapy due to continued disease activity and as initial therapy in patients without systemic features who have an active joint count >4.

Additional Off-Label Uses

Acute and chronic rejection in recipients of solid organ transplants (prevention); Cytomegalovirus (CMV) disease in transplant recipients resistant to standard antivirals

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bendamustine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Bendamustine. Concentrations of active metabolites may be increased. Monitor therapy

Bile Acid Sequestrants: May decrease serum concentrations of the active metabolite(s) of Leflunomide. Management: Unless using this combination to intentionally enhance leflunomide elimination, consider an alternative to the bile acid sequestrants when possible. Separating drug administration is not likely to be effective at avoiding this interaction. Consider therapy modification

Charcoal, Activated: May decrease serum concentrations of the active metabolite(s) of Leflunomide. Management: Unless using this combination to intentionally enhance leflunomide elimination, consider an alternative to charcoal when possible. Separating drug administration is not likely to be effective at avoiding this interaction. Consider therapy modification

CloZAPine: CYP1A2 Inducers may decrease the serum concentration of CloZAPine. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP1A2 Substrates: CYP1A2 Inducers (Moderate) may decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erlotinib: Leflunomide may decrease the serum concentration of Erlotinib. Management: Avoid the concomitant use of erlotinib and leflunomide if possible. If concomitant use is unavoidable, increase the erlotinib dose by 50 mg increments at 2-week intervals to a maximum of 300 mg. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Immunosuppressants: May enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Exceptions: Cytarabine (Liposomal). Consider therapy modification

Methotrexate: May enhance the adverse/toxic effect of Leflunomide. Particular concerns are an increased risk of pancytopenia and/or hepatotoxicity. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pirfenidone: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Pirfenidone. Monitor therapy

Repaglinide: Leflunomide may increase the serum concentration of Repaglinide. Specifically, the active metabolite of leflunomide may increase repaglinide concentrations. Monitor therapy

RifAMPin: May increase serum concentrations of the active metabolite(s) of Leflunomide. Monitor therapy

Riluzole: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Riluzole. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Selexipag. Management: If initiating selexipag in a patient on a moderate CYP2C8 inhibitor, consider a less frequent dosing regimen (ie, once daily). If initiating a moderate CYP2C8 inhibitor in a patient on selexipag, consider a selexipag dose reduction. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Teriflunomide: Leflunomide may enhance the adverse/toxic effect of Teriflunomide. Leflunomide may increase the serum concentration of Teriflunomide. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

TOLBUTamide: Leflunomide may increase the serum concentration of TOLBUTamide. Specifically, the active metabolite of leflunomide (teriflunomide) may both increase total tolbutamide concentrations and increase the free fraction (i.e., non-protein bound) of tolbutamide. TOLBUTamide may increase the serum concentration of Leflunomide. Specifically, tolbutamide may increase the proportion of non-protein-bound (i.e., free fraction) teriflunomide. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Leflunomide may enhance the adverse/toxic effect of Vaccines (Live). Leflunomide may diminish the therapeutic effect of Vaccines (Live). Management: The ACIP guidelines state that live-attenuated vaccines should generally be avoided for at least 3 months after cessation of immunosuppressant therapy. However, the ACR does not recommend avoiding live vaccines in patients being treated with leflunomide. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Leflunomide may enhance the anticoagulant effect of Vitamin K Antagonists. Leflunomide may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Caution is recommended