Arava

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Leflunomide is the generic form of the brand-name medicine Arava, which is used to treat rheumatoid arthritis (a condition in which the body attacks its own joints).

This prescription medication is also sometimes used to help treat psoriatic arthritis (a condition that causes joint pain and scaly skin).

Leflunomide belongs to a class of drugs called disease-modifying antirheumatic drugs (DMARDs). It works by suppressing blood cells that cause inflammation.

The U.S. Food and Drug Administration (FDA) approved leflunomide in 1998. It's marketed as Arava by Sanofi-Aventis.

Leflunomide Warnings

Leflunomide contains a black box warning because it may cause serious liver problems that could potentially lead to death.

Tell your doctor immediately if you experience any of the following symptoms while taking this medicine:

• Yellowing of the skin or eyes (jaundice)
• Dark-colored urine
• Pale-colored stools
• Pain in the upper right part of the stomach
• Severe or persistent nausea
• Loss of appetite
• Extreme tiredness
• Unusual bleeding or bruising

Your doctor will monitor your liver function carefully while you take this medicine.

Don't take leflunomide if you have any type of liver problem.

Drinking alcohol while you're on leflunomide may increase the risk of liver complications. Tell your doctor if you drink, or have ever drunk large amounts of alcohol.

Also, tell your doctor if you're taking any of the following medicines before starting on leflunomide:

• Tylenol (acetaminophen)
• Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as Advil or Motrin (ibuprofen) and Aleve or Naprosyn (naproxen)
• Cholesterol-lowering medications (statins)
• Hydroxychloroquine
• Iron products
• Laniazid, Rifamate, or Rifater (isoniazid)
• Trexall (methotrexate)
• Niacin
• Rifadin, Rimactane, Rifamate, or Rifater (rifampin)

Leflunomide may lower your body's ability to fight infections.

Tell your doctor right away if you experience any of the following symptoms while taking this medicine:

• Fever
• Sore throat
• Cough
• Flu-like symptoms
• Red, warm, swollen, or painful skin
• Difficult, painful, or frequent urination

Don't receive any vaccines while taking leflunomide without first discussing it with your doctor.

Tell your doctor if you're prone to getting infections or if you currently have an infection.

It's possible that you could have tuberculosis (TB — a serious lung infection) and not know it. Your doctor will perform a skin test or do a blood test (quantiferon gold) to determine whether you have an inactive form of TB before you start on leflunomide.

Tell your doctor if you have or have ever had TB, have been around someone with TB, or have traveled to areas where TB is common.

Also, let your doctor know if you have, or have ever had, any of the following before taking leflunomide:

• Cancer
• Diabetes
• Kidney disease
• Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
• Hepatitis B or C
• High blood pressure

Leflunomide may cause high blood pressure. Your healthcare provider will probably want to check your blood pressure before you start on the drug, and frequently throughout your treatment.

Leflunomide may cause birth defects and other serious problems in the offspring of both women and men.

This medicine can stay in your body for up to two years after you stop taking it.

Both women and men who use leflunomide should use effective forms of birth control to prevent pregnancy for as long as your doctor recommends.

If you're a man who wants to father a child, talk to your doctor about stopping leflunomide and receiving a therapy that helps remove the medicine from your body more quickly.

Pregnancy and Leflunomide

Leflunomide contains a black box warning because it could harm an unborn baby.

Don't take this medicine if you're pregnant or plan to become pregnant.

You'll need to use an effective form of birth control before taking leflunomide, during your treatment, and for two years after your treatment ends.

Call your doctor immediately if you think you might be pregnant while using leflunomide.

Let your doctor know if you want to become pregnant within two years of stopping this medicine. Your healthcare provider may prescribe a treatment that can remove this drug from your body more quickly.

It's not known whether leflunomide passes into breastmilk or could hurt a breastfeeding baby. Don't breastfeed while taking this medicine.

ARAVA® (leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:

ARAVA is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only).

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Arava, there are no specific foods that you must exclude from your diet when receiving this medication.

Leflunomide can cause severe or fatal liver damage. This effect is increased when you also use certain other medicines, including:

• acetaminophen (Tylenol), aspirin, gout or arthritis medication (including gold injections); an NSAID (non-steroidal anti-inflammatory drug)--ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;

• an antibiotic, antifungal medicine, or sulfa drug; tuberculosis medicine; antiviral or HIV/AIDS medication; medicine to treat mental illness; seizure medication--carbamazepine, phenytoin, valproic acid, and others;

• birth control pills or hormone replacement therapy; anabolic steroids--methyltestosterone, "performance-enhancing drugs"; cancer medication; or

• cholesterol-lowering medication--Crestor, Lipitor, Vytorin, Zocor, and others; heart or blood pressure medication.

This list is not complete and many other drugs can interact with leflunomide. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you. Not all possible interactions are listed in this medication guide.

• A pharmacologically active metabolite (A77 1726; commercially available as teriflunomide) is responsible for essentially all of leflunomide’s activity in vivo.1 2 3 4 8 12 13 14 15 72

• Mechanism of action in rheumatoid arthritis appears to principally involve regulation of autoimmune lymphocytes.2 5 8 12 14 15 18

• Reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase.1 2 3 4 5 6 7 8 12 13 14 15 17 18 Inhibition of dihydroorotate dehydrogenase prevents production of ribonucleotide uridine monophosphate (rUMP) by the de novo pathway, which leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest.2 12 15 Thus, leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells.12 18

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• High blood pressure has happened with Arava. Have your blood pressure checked as you have been told by your doctor.
• Talk with your doctor before getting any vaccines while you take this medicine and after you stop taking it. Vaccine use with Arava may either raise the chance of an infection or make the vaccine not work as well. Talk with your doctor.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• This medicine may lower the ability of your bone marrow to make blood cells that your body needs. This can lead to very bad and sometimes deadly bleeding problems or infections. Tell your doctor right away if you have signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, a wound that will not heal; any bruising or bleeding; or if you feel very tired or weak.
• You will need a TB (tuberculosis) test before starting this medicine.
• This medicine will stay in your body for some time after you stop taking it. Sometimes, your doctor may give you other drugs to get rid of this drug faster. Talk with your doctor.
• This medicine may add to the chance of getting some types of cancer. Talk with the doctor.
• Nerve problems have happened with Arava. Most of the time, these nerve problems went away after this medicine was stopped. Sometimes, people had nerve problems that did not go away even after Arava (leflunomide) was stopped. Talk with the doctor.
• If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
• If you are 60 or older, use Arava with care. You could have more side effects.
• If you are a man and have sex with a female who could get pregnant or you wish to father a child, talk with your doctor.
• If you are a woman and you miss a period, have unprotected sex, or think that your birth control has not worked, call your doctor right away.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

The following serious adverse reactions are described elsewhere in the labeling:

• Hepatotoxicity [see Warnings and Precautions (5.2)]
• Immunosuppression [see Warnings and Precautions (5.4)]
• Bone marrow suppression [see Warnings and Precautions (5.4)]
• Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.5)]
• Peripheral neuropathy [see Warnings and Precautions (5.7)]
• Interstitial lung disease [see Warnings and Precautions (5.8)]

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with Arava administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years.

Elevation of Liver Enzymes

Treatment with Arava was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.

In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, Arava was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo.

Most Common Adverse Reactions

The most common adverse reactions in Arava-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year (≥ 5% in any Arava treatment group).

Adverse events during a second year of treatment with Arava in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.

Less Common Adverse Reactions

In addition, in controlled clinical trials, the following adverse events in the Arava treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug.

Blood and Lymphatic System: leukocytosis, thrombocytopenia;

Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein;

Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage;

Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth;

General Disorders: malaise;

Immune System: anaphylactic reaction;

Infection: abscess, flu syndrome, vaginal moniliasis;

Nervous System: dizziness, headache, somnolence;

Respiratory System: dyspnea;

Post Marketing Experience

The following additional adverse reactions have been identified during postapproval use of Arava. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia;

Infection: opportunistic infections, severe infections including sepsis;

Gastrointestinal: acute hepatic necrosis, colitis, including microscopic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure

Immune System: angioedema;

Nervous system: peripheral neuropathy;

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

Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.

Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.

Effect of potent CYP and transporter inducers

Leflunomide is metabolized by CYP450 metabolizing enzymes. Concomitant use of Arava and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when co-administered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for Arava when coadministered with rifampin. Because of the potential for Arava concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both Arava and rifampin [see Clinical Pharmacology (12.3)].

Effect on CYP2C8 substrates

Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking Arava, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3)].

Effect on warfarin

Coadministration of Arava with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of Arava, may decrease peak INR by approximately 25%.

Effect on oral contraceptives

Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with Arava [see Clinical Pharmacology (12.3)].

Effect on CYP1A2 substrates

Teriflunomide, the active metabolite of Arava, may be a weak inducer of CYP1A2 in vivo. In patients taking Arava, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3)].

Effect on organic anion transporter 3 (OAT3) substrates

Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking Arava, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3)].

Effect on BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) substrates

Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking Arava, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking Arava [see Clinical Pharmacology (12.3)].

NDC 0088-2161-30

Arava®
Tablets

leflunomide

20mg

OVERSIZED CONTAINER
FOR EASE OF PATIENT USE

30 Tablets

sanofi aventis

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

Leflunomide is used to treat the symptoms of rheumatoid arthritis. Leflunomide also helps reduce joint damage and improves physical functioning.

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

• Ankylosing Spondylitis
• Psoriatic Arthritis
• Rheumatoid Arthritis (RA)
• Rheumatoid Arthritis (RA) Medications

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

Arava 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 Arava based on the results of these tests.

Before you start treatment with Arava, your doctor may perform tests to make sure you do not have tuberculosis or other infections.

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Your blood pressure will need to be checked often.

Arava can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your Arava treatment may be stopped for a short time based on the results of these tests.

Your liver function will also need to be tested often, and you may need to stop taking Arava based on the results of these tests.

After you stop taking this medicine, you may need to be treated with other medicines to help your body eliminate leflunomide quickly. If you do not undergo this drug elimination procedure, leflunomide could stay in your body for up to 2 years. Follow your doctor's instructions.

You will also need to go through this drug elimination procedure if you plan to become pregnant after you stop taking Arava.

Arthritis is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Store at room temperature away from moisture, heat, and light.

Get emergency medical help if you have signs of an allergic reaction to Arava: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• signs of infection - sudden weakness or ill feeling, fever, chills, sore throat, mouth sores, red or swollen gums, trouble swallowing;

• sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• numbness, tingling, or burning pain in your hands or feet;

• liver problems - nausea, upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• severe skin reaction - fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common Arava side effects may include:

• nausea, diarrhea, stomach pain;

• headache;

• abnormal liver function tests;

• thinning hair;

• back pain;

• weakness;

• rash; or

• high blood pressure.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to leflunomide: oral tablet

Along with its needed effects, leflunomide (the active ingredient contained in Arava) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking leflunomide:

• Bloody or cloudy urine
• cough
• difficult or painful breathing
• difficult, burning, or painful urination
• dizziness
• fever
• frequent urge to urinate
• headache
• loss of appetite
• nausea or vomiting
• sneezing
• sore throat
• tightness in the chest
• yellow eyes or skin

• Burning feeling in the chest or stomach
• burning, prickling, or tingling sensation in the fingers or toes
• chest pain
• diarrhea
• fast or pounding heartbeat
• indigestion
• joint or muscle pain or stiffness
• severe stomach pain
• tenderness in the stomach area
• unusual tiredness or weakness

• Area rash
• black or tarry stools
• bleeding gums
• blistering, peeling, or loosening of the skin
• bloating
• blood in the stools
• burning, numbness, tingling, or painful sensations
• chills
• clay-colored stools
• confusion
• constipation
• continuing vomiting
• cough or hoarseness
• dark urine
• fainting
• fever with or without chills
• general feeling of tiredness or weakness
• high fever
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• lightheadedness
• lower back or side pain
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• pinpoint red spots on the skin
• rapid, shallow breathing
• red skin lesions, often with a purple center
• red, irritated eyes
• sores, ulcers, or white spots in the mouth or on the lips
• swollen glands
• unexplained bleeding or bruising
• unpleasant breath odor
• unsteadiness or awkwardness
• unusual bleeding or bruising
• upper right abdominal or stomach pain
• vomiting of blood
• weakness in the arms, hands, legs, or feet

Some side effects of leflunomide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• hair loss
• heartburn
• skin rash
• stomach pain
• weight loss (unexplained)

• Acne
• anxiety
• decreased appetite
• dry mouth
• gas
• irritation or soreness of the mouth
• itching of the skin
• pain or burning in the throat
• runny nose