Arava

Name: Arava

Do I need a prescription for leflunomide?

Yes

Which drugs or supplements interact with leflunomide?

Cholestyramine (Questran, Questran Light) and charcoal decrease the concentration of the active form of leflunomide in the blood probably by preventing absorption. Rifampin increases the blood concentration of the active form of leflunomide by 40% probably by increasing the conversion of leflunomide to its active form. This may increase the side effects of leflunomide. Increased activity of warfarin (Coumadin) by leflunomide has been reported rarely. Leflunomide also may increase the blood concentration of tolbutamide.

What else should I know about leflunomide?

What preparations of leflunomide are available?

10 and 20 mg tablets

How should I keep leflunomide stored?

Leflunomide should be stored at room temperature 15 C - 30 C (59 F - 86 F).

US Brand Name

  1. Arava

Arava Interactions

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • acetaminophen (Tylenol)
  • anticoagulants ('blood thinners') such as warfarin (Coumadin, Jantoven)
  • aspirin and other nonsteroidal anti-inflammatory medications (NSAIDs such as ibuprofen [Advil, Motrin] and naproxen [Aleve, Naprosyn]
  • cholesterol-lowering medications (statins)
  • cholestyramine (Prevalite, Questran)
  • colestipol (Colestid)
  • etanercept (Enbrel)
  • gold compounds such as auranofin (Ridaura) and aurothioglucose (Aurolate, Solganol)
  • hydroxychloroquine
  • iron products
  • isoniazid (INH, Nydrazid, in Rifamate)
  • medications to treat cancer
  • methotrexate (Rheumatrex, Trexall)
  • niacin (nicotinic acid)
  • other medications that suppress the immune system such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), sirolimus (Rapamune), and tacrolimus (Prograf)
  • rifampin (Rifadin, Rimactane, in Rifamate, in Rifater)

 This is not a complete list of Arava drug interactions. Ask your doctor or pharmacist for more information.

Arava and Lactation

Arava should not be used by nursing mothers. It is not known whether Arava 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 Arava. Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with Arava, taking into account the importance of the drug to the mother.

Arava Dosage

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 Arava is 100 mg tablet per day for 3 days.

The recommended dose of Arava 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.

Patient Handout

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What is leflunomide?

Leflunomide affects the immune system and reduces swelling and inflammation in the body.

Leflunomide is used to treat the symptoms of rheumatoid arthritis.

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

What is the most important information I should know about leflunomide?

Do not use leflunomide 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 leflunomide, and until you complete a "drug elimination" procedure.

Leflunomide 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 leflunomide based on the results of these tests.

Introduction

Immunomodulating agent and disease-modifying antirheumatic drug (DMARD).1 2 3 4 5 6 7 8 12 13 14 15 17 Considered a prodrug since it is rapidly and almost completed metabolized to an active metabolite (A77 1726; commercially available as teriflunomide).2 3 4 8 12 13 14 15 72

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Leflunomide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

10 mg*

Arava

Sanofi-Aventis

Leflunomide Tablets

20 mg*

Arava

Sanofi-Aventis

Leflunomide Tablets

100 mg

Arava

Sanofi-Aventis

Dosage Forms and Strengths

Arava Tablets are available in three strengths:

  • Tablets: 10 mg, supplied as white, round film-coated tablet embossed with "ZBN" on one side
  • Tablets: 20 mg, supplied as light yellow, triangular film-coated tablet embossed with "ZBO" on one side
  • Tablets: 100 mg, supplied as white, round film-coated tablet embossed with "ZBP" on one side

Arava - Clinical Pharmacology

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 –12 hours after dosing. Due to the very long half-life of teriflunomide (18–19 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 18–19 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 Arava (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

The Potential Effect of Other Drugs on Arava

  • Potent CYP and transporter inducers:

Following concomitant administration of a single dose of Arava to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when Arava was given alone [see Drug Interactions (7)].

  • An in vivo interaction study with Arava and cimetidine (non-specific weak CYP inhibitor) has demonstrated a lack of a significant impact on teriflunomide exposure.

The Potential Effect of Arava 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).

Patient Counseling Information

Embryo-Fetal Toxicity

Advise females of reproductive potential

  • Of the potential for fetal harm if Arava is taken during pregnancy.
  • To notify their healthcare provider immediately if a pregnancy occurs or is suspected.
  • To use effective contraception during treatment with Arava and until the active metabolite (teriflunomide) plasma concentration is verified to be less than 0.02 mg/L [see Warnings and Precautions (5.1, 5.3), Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.3)].

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Arava during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise nursing women to discontinue breastfeeding during treatment with Arava [see Use in Specific Populations (8.2)].

Advise patients of the possibility of rare, serious skin reactions. Instruct patients to promptly report if they develop a skin rash or mucous membrane lesions.

Advise patients of the potential hepatotoxic effects of Arava and of the need for monitoring liver enzymes. Instruct patients to report if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.

Advise patients that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with Arava, who have recently discontinued such therapy before starting treatment with Arava, or who have had a history of a significant hematologic abnormality. Instruct patients to promptly report if they notice symptoms consistent with pancytopenia, such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness.

Inform patients about the early warning signs of interstitial lung disease and ask them to contact their physician promptly if these symptoms appear or worsen during therapy.

Release date: February 2016

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2016 sanofi-aventis U.S. LLC

What happens if i miss a dose (arava)?

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.

For Healthcare Professionals

Applies to leflunomide: oral tablet

Gastrointestinal

Very common (10% or more): Diarrhea (up to 22%), dyspepsia (up to 13%)
Common (1% to 10%): Abdominal pain, anorexia, gastroenteritis, nausea, gastrointestinal/abdominal pain, mouth ulcer, vomiting, cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder, dry mouth
Frequency not reported: Pancreatitis[Ref]

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.[Ref]

Respiratory

A 54-year-old female with rheumatoid arthritis experienced acute respiratory failure coincident with leflunomide (the active ingredient contained in Arava) 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.[Ref]

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[Ref]

Cardiovascular

Common (1% to 10%): Hypertension, chest pain
Postmarketing reports: Angina pectoris, migraine, palpitation, tachycardia, vasculitis, vasodilation, varicose vein[Ref]

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 (the active ingredient contained in Arava) 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.[Ref]

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[Ref]

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[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection, albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, arthralgia, leg cramps, joint disorder, synovitis, tenosynovitis, arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture[Ref]

Metabolic

Common (1% to 10%): Hypokalemia, weight loss, creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema[Ref]

Hypersensitivity

A 69-year-old male with a 19-year history of rheumatoid arthritis experienced hypersensitivity pneumonitis coincident with leflunomide (the active ingredient contained in Arava) 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.[Ref]

Common (1% to 10%): Allergic reaction[Ref]

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[Ref]

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

Endocrine

Frequency not reported: Hyperthyroidism[Ref]

Ocular

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

Renal

Frequency not reported: Renal failure[Ref]

Hepatic

A 69-year-old male with stable rheumatoid arthritis experienced liver tuberculosis coincident with leflunomide (the active ingredient contained in Arava) 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.[Ref]

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[Ref]

Other

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

Immunologic

Common (1% to 10%): Flu Syndrome
Postmarketing reports: Opportunistic infections, severe infections including sepsis that may be fatal[Ref]

Psychiatric

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

Some side effects of Arava may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Leflunomide Pregnancy Warnings

-Animal studies have revealed signs of teratogenicity and embryolethality. There are no controlled data in human pregnancy. -The active metabolite of this drug, A771726 is suspected to cause serious birth defects when administered during pregnancy. -Women should wait to become pregnant for at least 2 years after discontinuation of treatment and plasma levels of A771726 should be less than 0.02 mg/L. If this is not feasible, the manufacturer suggests a washout. Following discontinuation of leflunomide, all women of childbearing potential should undergo the following drug elimination procedure: 1) Administer cholestyramine 8 grams, 3 times daily for 11 days. (The 11 days only need to be consecutive when there is a need (such as pregnancy) to lower the cholesterol levels rapidly.) 2) Verify plasma levels less than 0.02 mg/L by 2 separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. -Human plasma levels less than 0.02 mg/L are expected to have minimal risk based on available animal data. Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance. AU TGA pregnancy category X: Drugs which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy. US FDA pregnancy category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. US: To monitor fetal outcomes of pregnant women exposed to leflunomide, health care providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Use is contraindicated. AU TGA pregnancy category: X US FDA pregnancy category: X Comments: -This drug can cause fetal harm when administered to a pregnant woman. -Pregnancy should be excluded before starting therapy. -This drug should not be used in women who are or may become pregnant, or prior to the completion of the drug elimination procedure after treatment. -Patients should be notified to contact their doctor immediately if they suspect they may be pregnant.

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