leflunomide

Absorption: 80% absorbed following oral administration.

Distribution: Well distributed to tissues.

Protein Binding: 99%.

Metabolism/Excretion: Extensively metabolized in the liver to teriflunomide, which is responsible for pharmacologic activity; metabolites excreted in urine (43%) and feces (48%). Also undergoes biliary recycling.

Half-Life: 14–18 days.

Time/Action Profile ⬆ ⬇

(antirheumatic effect)

ROUTE	ONSET	PEAK	DURATION
PO	1 mo	3–6 mo	wk–mos‡

‡Due to persistence of active metabolite.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity to leflunomide or teriflunomide;
Compromised immune function, including bone marrow dysplasia or severe uncontrolled infection;
Concurrent vaccination with live vaccines;
Hepatic impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Renal impairment;
History of interstitial lung disease (ILD);
Patients >60 yr, with diabetes, or taking neurotoxic medications (↑ risk of peripheral neuropathy);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Exercise Extreme Caution in:

Concurrent use of other hepatotoxic agents (↑ risk of hepatotoxicity).

Adv. Reactions/Side Effects ⬆ ⬇

CV: chest pain, hypertension

Derm: alopecia, rash, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), dry skin, eczema, pruritus, skin ulcers, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

EENT: pharyngitis, rhinitis, sinusitis

F and E: hypokalemia

GI: diarrhea, nausea, ↑liver enzymes, abdominal pain, anorexia, dyspepsia, gastroenteritis, HEPATOTOXICITY, HEPATOTOXICITY, mouth ulcers, vomiting

GU: urinary tract infection

Metab: weight loss

MS: arthralgia, back pain, joint disorder, leg cramps, synovitis, tenosynovitis

Neuro: headache, dizziness, paresthesia, peripheral neuropathy, weakness

Resp: bronchitis, cough, ILD, pneumonia

Misc: INFECTION (INCLUDING SEPSIS AND TUBERCULOSIS [TB] REACTIVATION)

Interactions ⬆ ⬇

Drug-drug:

Cholestyramine and activated charcoal cause a rapid and significant ↓ in levels of the active metabolite.
Methotrexate and other hepatotoxic drugs↑ risk of hepatotoxicity.
Rifampin↑ levels of the active metabolite.
May ↑ risk of bleeding with warfarin.

Route/Dosage ⬆ ⬇

PO (Adults ): Loading dose: 100 mg once daily for 3 days; Maintenance dose: 20 mg once daily (if intolerance occurs, may ↓ to 10 mg once daily).

Availability ⬆ ⬇

(Generic available)

Tablets: 10 mg; 20 mg

Assessment ⬆ ⬇

Obtain baseline BP. Monitor throughout therapy.
Assess for skin ulcers. If ulcers do not resolve, consider discontinuing therapy and use drug elimination procedure.
Assess range of motion and degree of swelling and pain in affected joints before and periodically during therapy.
Monitor for signs and symptoms of ILD (new onset or worsening cough or dyspnea, associated with fever). May require discontinuation of therapy; consider drug elimination procedure if needed.
Assess for rash periodically during therapy. May cause SJS or TEN. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.
Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, facial swelling), associated with involvement of other organ systems (hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) during therapy. May resemble an acute viral infection. Eosinophilia is often present. Discontinue therapy if signs occur.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
Monitor liver function throughout therapy. Assess ALT at baseline, then monthly during initial 6 mo of therapy, then every 6–8 wk. If given concurrently with methotrexate, monitor ALT, AST, and serum albumin monthly. May cause ↑ ALT and AST, which are usually reversible with ↓ in dose or discontinuation, but may be fatal. If ALT is 2–3 times the upper limit of normal (ULN),↓ dose to 10 mg/day and continue therapy. Monitor closely after dose reduction; plasma concentrations may not ↓ for several wk due to long half-life. If ALT ↑ of 2–3 × ULN persists despite dose reduction or if ALT >3 × ULN occurs, discontinue leflunomide and administer cholestyramine (see Toxicity and Overdose). Monitor closely and readminister cholestyramine as indicated.
- Monitor CBC with platelets monthly for 6 mo following initiation of therapy and every 6–8 wk thereafter. If used with methotrexate or other immunosuppressive therapy, continue monitoring monthly. If bone marrow depression occurs, discontinue leflunomide and begin ↓ levels with cholestyramine (see Implementation).
- May rarely cause ↑ of alkaline phosphatase and bilirubin.

Toxicity and Overdose:

If overdose or significant toxicity occurs, cholestyramine 8 g 3 times a day for 24 hr, or activated charcoal orally or via nasogastric tube, 50 g every 6 hr for 24 hr, is recommended to accelerate elimination.

Implementation ⬆ ⬇

Administer a tuberculin skin test prior to administration of leflunomide. Patients with active latent TB should be treated for TB prior to therapy.
PO: Initiate therapy with loading dose of 100 mg/day for 3 days, followed by 20 mg/day dose. May ↓ to 10 mg/day if not well tolerated.
Drug Elimination Procedure: Recommended to achieve nondetectable plasma teriflunomide concentrations <0.02 mg/L after stopping treatment with leflunomide. Administer cholestyramine 8 g 3 times daily for 11 days (days do not need to be consecutive unless rapid lowering of levels is desired). Verify plasma teriflunomide concentrations <0.02 mg/L by two separate tests ≥14 days apart. If plasma teriflunomide concentrations >0.02 mg/L, consider additional cholestyramine treatment. Plasma teriflunomide concentrations may take up to 2 yr to reach nondetectable levels without drug elimination procedure.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other medications. Aspirin, NSAIDs, or low-dose corticosteroids may be continued during therapy, but other agents for treatment of rheumatoid arthritis may require discontinuation.
Advise patient if a dose is missed to take as soon as remembered. Do not take two doses at the same time.
May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
Discuss the possibility of hair loss with patient. Explore methods of coping.
Advise patient to notify health care professional if rash, mucous membrane lesions, unusual tiredness, abdominal pain, jaundice, or symptoms of ILD occur.
Instruct patient to avoid vaccinations with live vaccines during and following therapy without consulting health care professional.
Emphasize the importance of routine lab tests to monitor for side effects.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception. Women wishing to become pregnant must undergo the drug elimination procedure (see Implementation) and verify that the plasma teriflunomide concentrations are <0.02 mg/L.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇