leflunomide (Rx)

Brand and Other Names:Arava
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 10mg
  • 20mg
  • 100mg

Rheumatoid Arthritis

100 mg PO qDay for 3 day initially, THEN 10-20 mg PO qDay

Dosage Modifications

Renal impairment

  • No dosage adjustment provided by the manufacturer; use with caution

Hepatic Impairment

  • Preexisting liver disease: Not recommended
  • Baseline ALT >2 times ULN: Not recommended
  • Severe hepatic impairment: Contraindicated
  • Hepatotoxicity following administration: Discontinue therapy and determine cause; if lefluonamide induced, discontinue treatment and initiate accelerated drug elimination process

Dosing Considerations

Discontinuing leflunomide

  • Drug elimination process recommended to achieve nondetectable plasma levels (ie, <0.02 mg/L) after discontinuation
  • Step 1: Administer cholestyramine 8 g PO TID 11 days; the 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly
  • Step 2: Verify plasma levels <0.02 mg/L by 2 separate tests at least 14 days apart; if plasma levels >0.02 mg/L, consider additional cholestyramine treatment
  • Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels <0.02 mg/L due to individual variation in drug clearance

Safety and efficacy not established

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Interactions

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            Adverse Effects

            >10%

            Diarrhea (17%)

            Respiratory infections (15%)

            1-10% (selected)

            Alopecia (10%)

            Hypertension (10%)

            Rash (10%)

            Nausea (9%)

            Bronchitis (7%)

            Headache (7%)

            Abdominal pain (5%)

            Abnormal LFT's (5%)

            Accidental injury (5%)

            Back pain (5%)

            Dyspepsia (5%)

            UTI (5%)

            Dizziness (4%)

            Infection (4%)

            Joint disorder (4%)

            Pruritus (4%)

            Weight loss (4%)

            Anorexia (3%)

            Cough (3%)

            Gastroenteritis (3%)

            Pharyngitis (3%)

            Stomatitis (3%)

            Tenosynovitis (3%)

            Vomiting (3%)

            Weakness (3%)

            Allergic reaction (2%)

            Chest pain (2%)

            Dry skin (2%)

            Eczema (2%)

            Pain (2%)

            Paresthesia (2%)

            Pneumonia (2%)

            Rhinitis (2%)

            Sinusitis (2%)

            Synovitis (2%)

            Postmarketing Reports

            Body as a whole: Opportunistic infections, severe infections including sepsis that may be fatal

            Gastrointestinal: Pancreatitis; colitis, including microscopic colitis

            Hematologic: Agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia

            Hypersensitivity: Angioedema

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

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

            Nervous system: Peripheral neuropathy

            Skin and appendages: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis; rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS) reported

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            Warnings

            Black Box Warnings

            Contraindicated in pregnancy

            Do not use in pregnant women or in women of childbearing age who do not use reliable contraception

            Avoid pregnancy during treatment and during the drug elimination period following treatment (ie, M1 metabolite <0.02 mcg/mL)

            Severe liver injury

            • 49 cases of severe liver injury identified, including 14 cases of fatal liver failure
            • Do not use with pre-existing liver disease
            • Do not use if elevated liver enzymes (ALT >2 X ULN)
            • Coadministration with other drugs that cause liver injury increases risk
            • Recommend ALT monitoring monthly for 6 months after initiating, and q6-8weeks thereafter
            • If ALT rises to >3X ULN, interrupt therapy while investigating probable cause; if likely leflunomide-induced, initiate cholestyramine washout to speed elimination and conduct follow-up LFTs at least weekly until ALT value within normal range; if not leflunomide-induced ALT elevation, may consider resuming leflunomide

            Contraindications

            Pregnancy

            Hypersensitivity

            Severe hapatic impairment

            Current treatment with teriflunomide

            Cautions

            Hepatotoxicity reported (see Black Box Warnings)

            Vaccination with live vaccines not recommended

            Potential increase risk for malignancy

            Increase in blood pressure reported with therapy; check blood pressure before initiating therapy and periodically thereafter

            Rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS) reported; discontinue therapy; a drug elimination procedure recommended

            Co-administration of teriflunomide with leflunomide not recommended, as leflunomide is parent compound of teriflunomide

            Peripheral neuropathy reported; most recover after discontinuing drug; risk factors include age >60 years, concomitant neurotoxic drugs, and diabetes; if patient develops peripheral neuropathy, consider discontinuing and performing accelerated elimination procedure

            Interstitial lung disease (ILD) reported and has been associated with fatal outcomes; risk increased with prior history of ILD; if pulmonary symptoms worsen in patients with pre-exixting ILD, consider discontinuing therapy and performing accelerated drug elimination procedure

            Active metabolite has very long half-life and this should be considered when administering live vaccines or planning pregnancy; all women of childbearing potential are advised to receive cholestyramine 8 g TID x11 days to hasten elimination of metabolite

            If inadvertent pregnancy occurs discontinue immediately and call (877) 311-8972; cholestyramine may reduce risk to fetus

            May cause immunosuppression; not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections; if a serious infection occurs, consider interrupting therapy and initiating accelerated drug elimination procedure

            Cases of tuberculosis reported in clinical studies; prior to initiating therapy, screen all patients for active and inactive (“latent”) tuberculosis infection as per commonly used diagnostic tests; drug not studied in patients with positive tuberculosis screen; safety in individuals with latent tuberculosis infection unknown; treat patients testing positive for tuberculosis with standard medical practice prior to therapy; monitor carefully during treatment for possible reactivation of infection

            Pancytopenia, agranulocytosis and thrombocytopenia reported with therapy; most frequently reported 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

            Perform white blood cell count and hemoglobin or hematocrit at baseline and monthly for six months following initiation of therapy and every 6-to 8 weeks thereafter; monitor monthly if administered concomitantly with methotrexate or other potential immunosuppressive agents; discontinue treatment if bone marrow suppression occurs in patients taking therapy and perform accelerated drug elimination procedure

            When decision is made to switch to another anti-rheumatic agent with potential for hematologic suppression, consider monitoring for hematologic toxicity as systemic exposure to both compounds may overlap

            Stevens-Johnson syndrome and toxic epidermal necrolysis reported (rare); discontinue therapy and perform accelerated drug elimination procedure

            Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate

            Accelerated elimination

            • The active metabolite of leflunomide, teriflunomide, is eliminated slowly from plasma; use of accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and active metabolite, teriflunomide
            • Without use of accelerated drug elimination procedure, 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
            • Consider accelerated elimination procedure at any time after discontinuation of therapy, and in particular, when patient has experienced a severe adverse reaction (eg, hepatotoxicity, serious infection, bone marrow suppression, Steven Johnson Syndrome, toxic epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected hypersensitivity, or has become pregnant
            • All women of childbearing potential recommended to undergo accelerated elimination procedure after stopping treatment
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            Pregnancy & Lactation

            Pregnancy

            A pregnancy exposure registry monitors pregnancy outcomes in women exposed to therapy 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/

            Drug is contraindicated for use in pregnant women because of potential for fetal harm; pregnancy exposure registry data are not available to inform presence or absence of drug-associated risk with use of drug during pregnancy

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

            Advise females to notify healthcare provider immediately if pregnancy occurs or is suspected during treatment; women receiving treatment who wish to become pregnant should discontinue drug and undergo an accelerated drug elimination procedure to achieve plasma teriflunomide concentrations < 0.02 mg/L (0.02 mcg/mL)

            Exclude pregnancy in females of reproductive potential before starting treatment

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

            Animal data

            • In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of and equivalent to maximum recommended human dose (MRHD) based on AUC, respectively in rats and rabbits, caused teratogenicity (rats and rabbits) and embryo-lethality (rats)

            Lactation

            Clinical lactation studies not conducted to assess presence of drug in human milk, effects on breastfed child, or on milk production; because of potential for serious adverse reactions in a breastfed infant, advise a nursing woman to discontinue breastfeeding during therapy

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            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%

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            Images

            BRAND FORM. UNIT PRICE PILL IMAGE
            leflunomide oral
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            10 mg tablet
            leflunomide oral
            -
            20 mg tablet
            leflunomide oral
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            10 mg tablet
            leflunomide oral
            -
            20 mg tablet
            leflunomide oral
            -
            10 mg tablet
            leflunomide oral
            -
            20 mg tablet
            leflunomide oral
            -
            10 mg tablet
            leflunomide oral
            -
            20 mg tablet
            leflunomide oral
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            20 mg tablet
            leflunomide oral
            -
            10 mg tablet
            leflunomide oral
            -
            20 mg tablet
            leflunomide oral
            -
            10 mg tablet
            Arava oral
            -
            20 mg tablet
            Arava oral
            -
            10 mg tablet

            Copyright © 2010 First DataBank, Inc.

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            Patient Handout

            Patient Education
            leflunomide oral

            LEFLUNOMIDE - ORAL

            (leh-FLEW-no-mide)

            COMMON BRAND NAME(S): Arava

            WARNING: Leflunomide must not be used during pregnancy because it may cause serious harm (possibly death) to an unborn baby. Women of childbearing age must have a negative pregnancy test before starting this medication. They must also use reliable forms of birth control before starting leflunomide, while taking it, and after stopping it until they have finished taking another drug that helps leflunomide leave the body and confirmed through 2 blood tests that the leflunomide levels are very low (see How to Use section). If you become pregnant or think you may be pregnant, inform your doctor right away (see Precautions section).This drug may rarely cause serious (possibly fatal) liver disease. Most cases occur within 6 months of taking this drug. If you already have liver disease (such as hepatitis B or C), leflunomide should not be used. Liver function (blood) tests must be performed periodically while taking leflunomide. Tell your doctor right away if you notice nausea/vomiting that doesn't stop, dark urine, light-colored stools, stomach/abdominal pain, yellowing eyes/skin. See Drug Interactions section.

            USES: This medication is used to treat rheumatoid arthritis, a condition in which the body's defense system (immune system) fails to recognize the body as itself and attacks the healthy tissues around the joints. Leflunomide helps to reduce the joint damage/pain/swelling and helps you to move better. It works by weakening your immune system and decreasing swelling (inflammation).

            HOW TO USE: Take this medication by mouth with or without food, usually once daily or as directed by your doctor. Take this medication exactly as prescribed. You may be instructed to take a higher dose for the first 3 days of treatment.Dosage is based on your medical condition and response to therapy.Take this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time each day.After treatment is stopped, a different drug (cholestyramine) may be given as directed to help remove leflunomide from your body. This procedure is used if you need a rapid removal of the drug from your system (for example, if you are a female/male planning to have children, or suffering from severe side effects). Without the procedure, the drug may stay in your body for up to 2 years. Consult your doctor or pharmacist for more details.Tell your doctor if your symptoms last or get worse.

            SIDE EFFECTS: Diarrhea, nausea, and dizziness may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: cough, numbness/tingling of hands/feet, hair loss, chest pain, fast/pounding heartbeat, increased thirst/urination, muscle cramp/pain, mental/mood changes, vision changes, easy bruising/bleeding, unusual growths/lumps, unexplained weight loss, unusual tiredness.This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high.This medication may lower your ability to fight infections. This may make you more likely to get a serious (rarely fatal) infection or make any infection you have worse. Get medical help right away if you have any signs of infection (such as sore throat that doesn't go away, fever, swollen lymph nodes, chills).A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.Leflunomide can commonly cause a mild rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Get medical help right away if you develop any rash.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

            PRECAUTIONS: Before taking leflunomide, tell your doctor or pharmacist if you are allergic to it; or to teriflunomide; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: immune system disorder (such as HIV infection), current/recent infection (such as tuberculosis), cancer, bone marrow/blood disorder, kidney disease, liver disease (such as hepatitis B or C), alcohol abuse, heart disease (such as congestive heart failure), high blood pressure, lung disease.This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis). Alcohol may also cause liver disease.Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.Leflunomide can make you more likely to get infections or may worsen any current infections. Avoid contact with people who have infections that may spread to others (such as chickenpox, measles, flu). Consult your doctor if you have been exposed to an infection or for more details.This medication must not be used during pregnancy. It may harm an unborn baby. Before starting this medication, women of childbearing age must have a negative pregnancy test before starting this medication. Men and women must use effective forms of birth control (such as condoms and birth control pills) while taking this medication. Consult your doctor for more details and to discuss reliable forms of birth control. (See also Warning section.)It is not known whether this medication affects the sperm. To minimize any possible risk, the manufacturer recommends that men wishing to father a child should consider stopping the medication and using another drug (cholestyramine) as directed to help this drug leave the body before attempting to father a child. (See How to Use section.) Consult your doctor for more details.This drug may pass into breast milk and could have undesirable effects on a nursing infant. Breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

            DRUG INTERACTIONS: See also How to Use Section.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: warfarin, rifamycins (such as rifampin), drugs affecting the liver (such as methotrexate), cholestyramine, other drugs that weaken the immune system (such as tacrolimus, cyclosporine).Because teriflunomide (used to treat multiple sclerosis) is very similar to this medication, do not take it while you are taking leflunomide.

            OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

            NOTES: Do not share this medication with others.A skin test to check for tuberculosis should be performed before you start this medication. Lab and/or medical tests (such as liver function, blood counts, blood pressure) should be done while you are taking this medication. Keep all medical and lab appointments. Consult your doctor for more details.

            MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

            STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

            MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

            Information last revised December 2022. Copyright(c) 2022 First Databank, Inc.

            IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.