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

Interaction Checker

and leflunomide

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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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            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.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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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.