1.ARAVA HISTORY
(How was Arava discovered?)

Arava is a product of Sanofi-Aventis.

The FDA approved Aravain September 1998.

The Sanofi-Aventis Group is the world's 3rd largest pharmaceutical company, ranking number 1 in Europe. Backed by a world-class R&D organization, Sanofi-Aventis is developing leading positions in seven major therapeutic areas:

• cardiovascular disease,
• thrombosis,
• oncology,
• diabetes,
• central nervous system,
• internal medicine, and
• vaccines.

Note: World-drugs.net sells generic version of Arava

2.ARAVA FACTS

Arava is classified as a disease-modifying antirheumatic drug (DMARD).

Arava helps improve RA symptoms such as joint swelling and tenderness. But unlike many symptom relievers that only help relieve pain and swelling, Arava actually helps slow the progression of joint damage caused by RA. So, while there is no cure for RA, Arava may help prevent RA from getting worse.

3.ABOUT ARAVA MEDICATION

What is Rheumatoid Arthritis?

Rheumatoid arthritis is a chronic disease, mainly characterized by inflammation of the lining, or synovium, of the joints. It can lead to long-term joint damage, resulting in chronic pain, loss of function and disability.

 

Rheumatoid arthritis (RA) progresses in three stages. The first stage is the swelling of the synovial lining, causing pain, warmth, stiffness, redness and swelling around the joint. Second is the rapid division and growth of cells, or pannus, which causes the synovium to thicken. In the third stage, the inflamed cells release enzymes that may digest bone and cartilage, often causing the involved joint to lose its shape and alignment, more pain, and loss of movement.

Because it is a chronic disease, RA continues indefinitely and may not go away. Frequent flares in disease activity can occur. RA is a systemic disease, which means it can affect other organs in the body. Early diagnosis and treatment of RA is critical if you want to continue living a productive lifestyle. Studies have shown that early aggressive treatment of RA can limit joint damage, which in turn limits loss of movement, decreased ability to work, higher medical costs and potential surgery.

RA affects 1 percent of the U.S. population or 2.1 million Americans. Currently, the cause of RA is unknown, although there are several theories. And while there is no cure, it is easier than ever to control RA through the use of new drugs, exercise, joint protection techniques and self-management techniques. While there is no good time to have Rheumatoid arthritis, advancements in research and drug development mean that more people with RA are living happier, healthier and more fulfilling lives. 

Symptoms of Rheumatoid Arthritis

Rheumatoid arthritis can start in any joint, but it most commonly begins in the smaller joints of the fingers, hands and wrists. Joint involvement is usually symmetrical, meaning that if a joint hurts on the left hand, the same joint will hurt on the right hand. In general, more joint erosion indicates more severe disease activity.

Other common physical symptoms include

• Fatigue
• Stiffness, particularly in the morning and when sitting for long periods of time. Typically, the longer the morning stiffness lasts, the more active your disease is.
• Weakness
• Flu-like symptoms, including a low-grade fever
• Pain associated with prolonged sitting
• The occurrence of flares of disease activity followed by remission or disease inactivity
• Rheumatoid nodules, or lumps of tissue under the skin, appear in about one-fifth of people with RA. Typically found on the elbows, they can indicate more severe disease activity.
• Muscle pain
• Loss of appetite, depression, weight loss, anemia, cold and/or sweaty hands and feet
• Involvement of the glands around the eyes and mouth, causing decreased production of tears and saliva

Advanced changes to look out for include damage to cartilage, tendons, ligaments and bone, which causes deformity and instability in the joints. The damage can lead to limited range of motion, resulting in daily tasks (grasping a fork, combing hair, buttoning a shirt) becoming more difficult. You also may see skin ulcers and a general decline in health. People with severe RA are more susceptible to infection.

The effects of Rheumatoid arthritis can vary from person to person. In fact, there is some growing belief that RA isn't one disease, but it may be several different diseases that share commonalities. 

Treatment of Rheumatoid Arthritis

Because Rheumatoid arthritis presents itself on many different fronts and in many different ways, treatment must be tailored to the individual, taking into account the severity of your arthritis, other medical conditions you may have and your individual lifestyle. Current treatment methods focus on relieving pain, reducing inflammation, stopping or slowing joint damage and improving your functioning and sense of well-being. 

Rheumatoid arthritis is a serious disease. It is crucial that you get an early diagnosis and work with your doctor to find the best treatment for you so that you can live well with it. Just a few years ago, your doctor might have only prescribed an over-the-counter pain reliever, like an analgesic or non-steroidal, anti-inflammatory drug (NSAID), until you experienced increased disease progression. Now, with the improvement of available medications, doctors know that they have to be more aggressive early on in order to prevent severe deformity and joint erosion.

Health-Care Professionals

In order to get the proper treatment for RA, you need to make sure you have the proper health-care team. Your primary doctor for treating RA should be a rheumatologist, a physician with special training in arthritis and other disease involving diseases of the bone, muscles and joints. Your rheumatologist will coordinate with your primary care physician. Other team members may include a physical therapist, an occupational therapist, a nurse, a psychologist, an orthopaedic surgeon, a physiatrist, and a social worker. Learn more about these speTadalafilts in the Glossary of Health Professionals.

Medications
The proper medication regimen is important in controlling your RA. You must help your doctor determine the best combination for you. The main categories of drugs used to treat RA are:

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) – These drugs are used to reduce inflammation and relieve pain. These are medications such as aspirin, ibuprofen, indomethacin and COX-2 inhibitors such as valdecoxib and celecoxib.
• Analgesic Drugs – These drugs relieve pain, but don't necessarily have an effect on inflammation. Examples of these medications are acetaminophen, propoxyphene, mepeidine and morphine.
• Glucocorticoids or Prednisone – These are prescribed in low maintenance doses to slow joint damage caused by inflammation.
• Disease Modifying Antirheumatic Drugs (DMARDs) – These are used with NSAIDs and/or prednisone to slow joint destruction caused by RA over time. Examples of these drugs are methotrexate, injectable gold, penicillamine, azathioprine, chloroquine, hydroxychloroquine, sulfasalazine and oral gold.
• Biologic Response Modifiers – These drugs directly modify the immune system by inhibiting proteins called cytokines, which contribute to inflammation. Examples of these are etanercept, infliximab, adaliumumab and anakinra.
• Protein-A Immuoadsorption Therapy – This is not a drug, but a therapy that filters your blood to remove antibodies and immune complexes that promote inflammation.

DMARDs, particularly methotrexate, have been the standard for aggressively treating RA. Recently, studies have shown that the most aggressive treatment for controlling RA may be the combination of methotrexate and another drug, particularly biologic response modifiers. The dual drug treatment seems to create a more effective treatment, especially for people who may not have success with or who have built up a resistance to, methotrexate or another drug alone. Doctors now are prescribing combination drug therapy more often and studies continue. It appears that these combination drug therapies might become the new road to follow in treating RA. Here are some medications your doctor may suggest you combine with methotrexate: lefluonomide (Arava), etanercept (Enbrel), adalimumab (Humira) and infliximab (Remicade).

4.ARAVA EFFECTIVENESS
(When is Arava best taken?)

Following oral administration, Arava dose is metabolized to an active metabolite A77 1726 (referred to as M1) that is responsible for essentially all of its activity in vivo. Plasma levels of Arava are occasionally seen, at very low levels. Studies of the pharmacokinetics of Arava have primarily examined the plasma concentrations of this active metabolite.

Absorption

Following oral administration, peak levels of the active metabolite, M1, occurred between 6 - 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading Arava dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading Arava doses and continued clinical dosing indicate that M1 plasma levels are Arava dose proportional.

Relative to an oral solution, Arava tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.

Distribution

M1 has a low volume of distribution and is extensively bound to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with Rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown. 

Metabolism

Arava is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of Arava metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for Arava; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism.

Elimination

The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. 

5.ARAVA EFFECTS ON SPECIAL POPULATION
(How do different people react to Arava?)

Gender
Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of Arava.

Age
Age has been shown to cause a change in the in vivo pharmacokinetics of Arava.

Pediatrics
The pharmacokinetics following oral administration of Arava have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights =40 kg have a reduced clearance relative to adult Rheumatoid arthritis patients.

6.ARAVA EFFECTS ON MEDICAL CONDITIONS
(How does Arava affect your existing condition/ailment?)

Chronic Renal Insufficiency.
In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination, and without adequate studies of Arava use in subjects with renal insufficiency, caution should be used when Arava is administered to these patients.

Hepatic Insufficiency.
Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. Given the need to metabolize Arava into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of Arava in patients with hepatic insufficiency is not recommended.

7.OTHER/ALTERNATE USES OF ARAVA
(What else does Arava treat?)

Your physician may prescribe Arava for other purposes.

8.ADVERSE/SIDE EFFECTS of ARAVA
(What are the side effects of Arava?)

Adverse reactions associated with the use of Arava in RA include diarrhea, elevated liver enzymes, alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality.

Percentage Of Patients With Adverse Events 3% In Any Leflunomide Treated Group
	All RA Studies	Placebo-Controlled Trials				Active-Controlled Trials
(N=1339)	(N=315)	(N=210)	(N=133)	(N=182)	(N=501)	(N=498)
BODY AS A WHOLE
Allergic Reaction	2%	5%	2%	0%	6%	1%	2%
Asthenia	3%	6%	4%	5%	6%	3%	3%
Flu Syndrome	2%	4%	2%	0%	7%	0%	0%
Infection, upper respiratory	4%	0%	0%	0%	0%	0%	0%
Injury Accident	5%	7%	5%	3%	11%	6%	7%
Pain	2%	4%	2%	2%	5%	1%	<1%
Abdominal Pain	6%	5%	4%	4%	8%	6%	4%
Back Pain	5%	6%	3%	4%	9%	8%	7%
CARDIOVASCULAR
Hypertension	10%	9%	4%	4%	3%	10%	4%
-New onset of hypertension		1%	<1%	0%	2%	2%	<1%
Chest Pain	2%	4%	2%	2%	4%	1%	2%
GASTROINTESTINAL
Anorexia	3%	3%	2%	5%	2%	3%	3%
Diarrhea	17%	27%	12%	10%	20%	22%	10%
Dyspepsia	5%	10%	10%	9%	13%	6%	7%
Gastroenteritis	3%	1%	1%	0%	6%	3%	3%
Abnormal Liver Enzymes	5%	10%	2%	4%	10%	6%	17%
Nausea	9%	13%	11%	19%	18%	13%	18%
GI/Abdominal Pain	5%	6%	4%	7%	8%	8%	8%
Mouth Ulcer	3%	5%	4%	3%	10%	3%	6%
Vomiting	3%	5%	4%	4%	3%	3%	3%
METABOLIC AND NUTRITIONAL
Hypokalemia	1%	3%	1%	1%	1%	1%	<1%
Weight Loss	4%	2%	1%	2%	0%	2%	2%
MUSCULO-SKELETAL SYSTEM
Arthralgia	1%	4%	3%	0%	9%	<1%	1%
Leg Cramps	1%	4%	2%	2%	6%	0%	0%
Joint Disorder	4%	2%	2%	2%	2%	8%	6%
Synovitis	2%	<1%	1%	0%	2%	4%	2%
Tenosynovitis	3%	2%	0%	1%	2%	5%	1%
NERVOUS SYSTEM
Dizziness	4%	5%	3%	6%	5%	7%	6%
Headache	7%	13%	11%	12%	21%	10%	8%
Paresthesia	2%	3%	1%	1%	2%	4%	3%
RESPIRATORY SYSTEM
Bronchitis	7%	5%	2%	4%	7%	8%	7%
Increased Cough	3%	4%	5%	3%	6%	5%	7%
Respiratory Infection	15%	21%	21%	20%	32%	27%	25%
Pharyngitis	3%	2%	1%	2%	1%	3%	3%
Pneumonia	2%	3%	0%	0%	1%	2%	2%
Rhinitis	2%	5%	2%	4%	3%	2%	2%
Sinusitis	2%	5%	5%	0%	10%	1%	1%
SKIN AND APPENDAGES
Alopecia	10%	9%	1%	6%	6%	17%	10%
Eczema	2%	1%	1%	1%	1%	3%	2%
Pruritus	4%	5%	2%	3%	2%	6%	2%
Rash	10%	12%	7%	11%	9%	11%	10%
Dry Skin	2%	3%	2%	2%	0%	3%	1%
UROGENITAL SYSTEM
Urinary Tract Infection	5%	5%	7%	4%	2%	5%	6%

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.

In addition, the following adverse events have been reported in 1% to <3% of the RA patients in the Arava treatment group in controlled clinical trials.

Body as a Whole : abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain;

Cardiovascular : angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation;

Gastrointestinal : cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder;

Endocrine : diabetes mellitus, hyperthyroidism;

Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis;

Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema;

Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture;

Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo;

Respiratory System : asthma, dyspnea, epistaxis, lung disorder;

Skin and Appendages : 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; 

Special Senses : blurred vision, cataract, conjunctivitis, eye disorder, taste perversion;

Urogenital System : albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis.

Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia (rare).