ARAVA (leflunomide)

There are 8 contraindications. Absolute contraindication.

Contraindication List
Acute hepatitis C
Chronic hepatitis C
Disease of liver
Hepatic failure
Lactation
Pregnancy
Severe bone marrow depression
Viral hepatitis B

There are 10 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Active tuberculosis
Hypoproteinemia
Immunosuppression
Impaired wound healing
Inactive tuberculosis
Infection
Interstitial lung disease
Neutropenic disorder
Pancytopenia
Thrombocytopenic disorder

There are 4 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Anemia
Hypertension
Kidney disease with reduction in glomerular filtration rate (GFr)
Peripheral neuropathy

There are 46 severe adverse reactions.

More Frequent	Less Frequent
Bronchitis Hepatitis Hypertension Upper respiratory infection Urinary tract infection	Anemia Chest pain Dyspnea Gastritis Gastroenteritis Palpitations Paresthesia Synovitis Tachycardia Tenosynovitis

Rare/Very Rare

Abnormal hepatic function tests Agranulocytosis Anaphylaxis Angioedema Bacterial sepsis Colitis DRESS syndrome Eosinophilia Epistaxis Erythema multiforme Hepatic failure Hyperbilirubinemia Interstitial lung disease Interstitial pneumonitis Leukopenia Neutropenic disorder Pancreatitis Pancytopenia Peripheral neuropathy Pulmonary fibrosis Pulmonary hypertension Pustular psoriasis Reactivated tuberculosis Retinal detachment Retinal hemorrhage Severe infection Skin ulcer Stevens-johnson syndrome Thrombocytopenic disorder Toxic epidermal necrolysis Vasculitis

There are 37 less severe adverse reactions.

More Frequent	Less Frequent
Abdominal pain with cramps Alopecia Back pain Diarrhea Dizziness Dyspepsia Headache disorder Nausea Skin rash Vomiting Weight loss	Acne vulgaris Anorexia Aphthous stomatitis Conjunctivitis Constipation Fever Flatulence General weakness Malaise Pharyngitis Pruritus of skin Rhinitis Sinusitis Symptoms of anxiety Xerostomia

Rare/Very Rare
Abscess Arthralgia Blurred vision Cough Cramps in legs Drowsy Dry skin Flu-like symptoms Leukocytosis Papilledema Thrombophlebitis

Leflunomide can cause fetal toxicity when administered to pregnant women. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. Leflunomide therapy should not be initiated in a woman of childbearing potential until pregnancy is excluded and it has been confirmed that the woman is using a reliable form of contraception.

Although there are no adequate and controlled studies to date in humans, leflunomide has been shown to increase the risk of fetal death or teratogenic effects in animals. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. The potential for increased risk of birth defects should be discussed with female patients of childbearing potential, and clinicians should advise women that they may be at increased risk of having a child with birth defects if they are pregnant, become pregnant while receiving leflunomide, or do not wait to become pregnant until they have followed a drug elimination procedure following discontinuance of leflunomide.

If leflunomide is administered inadvertently during pregnancy or if the patient becomes pregnant while receiving the drug, leflunomide should be discontinued and the patient informed of the potential hazard to the fetus. Women of childbearing potential should be advised to notify their clinician immediately if they experience a delay in menses or believe they may be pregnant so that pregnancy testing can be done. Use of a drug elimination procedure to rapidly lower plasma concentrations of A77 1726 to undetectable concentrations early in a pregnancy (i.e., at the first delay in menses) may decrease the risk to the fetus.

To monitor fetal outcomes of pregnant women exposed to leflunomide, clinicians are encouraged to register such patients by calling 877-311-8972. The manufacturer recommends that all women of childbearing potential receive an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable concentrations (less than 0.02 mcg/mL) following discontinuance of leflunomide therapy since these concentrations are presumed to be associated with minimal risk based on animal data. Following completion of the cholestyramine regimen, plasma concentrations of A77 1726 should be determined to verify that concentrations are undetectable.

This is especially important in women who wish to become pregnant after discontinuing the drug. Although available information does not indicate that leflunomide therapy is associated with an increased risk of male-mediated fetal toxicity, animal studies to evaluate this specific risk have not been conducted. To minimize risk, men wishing to father a child should consider discontinuing leflunomide therapy and undergoing an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable levels.

Reproduction studies in rats and rabbits using leflunomide oral doses of 1 mg/kg have not revealed evidence of harm to the fetus. However, reproduction studies in rats using oral leflunomide dosages of 15 mg/kg daily during organogenesis (systemic exposure approximately 10% of the human exposure level to A77 1726 based on AUC) have shown teratogenic effects (most notably anophthalmia or microphthalmia and internal hydrocephalus). Under these exposure conditions, leflunomide also caused a decrease in maternal body weight, an increase in embryolethality, and a decrease in fetal body weight for surviving fetuses.

Reproduction studies in rabbits using oral leflunomide dosages of 10 mg/kg daily during organogenesis (exposure equivalent to the maximum human exposure to A77 1726 based on AUC) resulted in fused, dysplastic sternebrae in offspring. In reproduction studies in female rats using leflunomide dosages of 1.25 mg/kg daily (systemic exposure approximately 1% of the human exposure level to A77 1726 based on AUC) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (exceeding 90%) decreases in postnatal survival.

A77 1726 distributes into milk in rats. It is not known whether A77 1726 is distributed into human milk. Because of the potential for serious adverse reactions to leflunomide in nursing infants if it were distributed, a decision should be made whether to proceed with nursing or initiate therapy with leflunomide, taking into account the importance of the drug to the woman.

No enhanced Geriatric Use information available for this drug.