WARNINGS

See BOXED CONTRAINDICATIONS AND WARNINGS
.
Immunosuppression Potential

ARAVA is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe. uncontrolled infections.

There have been rare reports of pancytopenia in patients receiving ARAVA. In most of these cases, patients received concomitant treatment with methotrexate or other immunosuppressive agents, or they had recently discontinued these therapies; in some cases patients had a prior history of a significant hematologic abnormality. If ARAVA is used in such patients, it should be administered with caution and with frequent clinical and hematologic monitoring. The use of ARAVA in combination therapy with methotrexate has not been adequately studied in a controlled setting.

If evidence of bone marrow suppression occurs in a patient taking ARAVA, treatment with ARAVA should be stopped and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite (see

PRECAUTIONS

: General - Need for Drug Elimination).

In any situation in which the decision is made to switch from ARAVA to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. ARAVA washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to ARAVA treatment.

Skin REACTIONS

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving ARAVA. If a patient taking ARAVA develops any of these conditions, ARAVA therapy should be stopped and a drug elimination procedure is recommended (see

PRECAUTIONS

: General - Need for Drug Elimination).

Hepatotoxicity

In clinical trials, ARAVA treatment 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. The following table shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.

Table 4.Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN)
	US301			MN301			MN302*
	LEF	PL	MTX	LEF	PL	SSZ	LEF	MTX
ALT (SGPT) >3-fold ULN	8	3	5	2	1	2	13	83
(n %)	(4.4)	(2.5)	(2.7)	(1.5)	(1.1)	(1.5)	(2.6)	(16.7)
Reversed to <2-fold ULN:	8	3	5	2	1	2	12	82
Timing of Elevation
0-3 Months	6	1	1	2	1	2	7	27
4-6 Months	1	1	3	-	-	-	1	34
7-9 Months	1	1	1	-	-	-	-	16
10-12 Months	-	-	-	-	-	-	5	6
AST (SGOT) >3-fold ULN	4	2	1	2	0	5	7	29
(n %)	(2.2)	(1.7)	(0.6)	(1.5)	-	(38)	(1.4)	(5.8)
Reversed to 12-fold ULN:	4	2	1	2	-	4	5	29
Timing of Elevation
0-3 Months	2	1	-	2	-	4	3	10
4-6 Months	1	1	1	-	-	1	1	11
7-9 Months	1	-	-	-	-	-	-	8
10-12 Months	-	-	-	-	-	-	3	-

*Only 10% of patients in MN302 received folate. All patents in US301 received folate.

At minimum, ALT (SGPT) should be performed at baseline and monitored initially at monthly intervals then, if stable, at intervals determined by the individual clinical situation.

Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows. For confirmed ALT elevations >2-fold ULN, dose reduction to 10 mg/day may allow continued administration of ARAVA. If elevations >2 but £3-fold ULN persist despite dose reduction, liver biopsy is recommended if continued treatment is desired. If elevations >3-fold ULN persist despite dose reduction. ARAVA should be discontinued and cholestyramine should be administered (see

PRECAUTIONS

: General - Need for Drug Elimination) with dose monitoring including retreatment with cholestyramine as indicated.

Rare elevations of alkaline phosphatase and bilirubin have been observed. Trial US301 used ACR Methotrexate Liver Biopsy Guidelines for monitoring therapy. One of 182 patients receiving leflunomide and 1 of 182 patients receiving methotrexate underwent liver biopsy at 106 and 50 weeks respectively. The biopsy for the leflunomide subject was Roegnik Grade IIIA and for the methotrexate subject Roegnik Grade I.

Pre-existing Hepatic Disease

Given the possible risk of increased hepatotoxicity and the role of the liver in drug activation elimination and recycling, the use of ARAVA is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses.

Malignancy

The risk of malignancy particularly lymphoproliferative disorders is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with ARAVA. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of ARAVA, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with ARAVA.

Use in Women of Childbearing Potential

There are no adequate and well-controlled studies evaluating ARAVA in pregnant women. However based on animal studies leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman (see CONTRAINDICATIONS). Women of childbearing potential must not be started on ARAVA until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with ARAVA, patients must be fully counseled on the potential for serious risk to the fetus.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from ARAVA.

Upon discontinuing ARAVA, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving ARAVA treatment who wish to become pregnant must discontinue ARAVA and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 mg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 mg/mL) are expected to have minimal risk based on available animal data.

Drug Elimination Procedure

The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 mg/mL) after stopping treatment with ARAVA:

1) Administer cholestyramine 8 grams 3 times daily for 11 days. (The 1* days do not need to be consecutive unless there is a need to lower the plasma level rapidly).

2) Verify plasma levels less than 0.02 mg/L (0.02 mg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered.

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.

PRECAUTIONS

General

Need for Drug Elimination

The active metabolite of leflunomide is eliminated slowly from the plasma. In instances of any serious toxicity from ARAVA including hypersensitivity, use of a drug elimination procedure as described in this section is highly recommended to reduce the drug concentration more rapidly after stopping ARAVA therapy. If hypersensitivity is the suspected clinical mechanism, more prolonged cholestyramine or charcoal administration may be necessary to achieve rapid and sufficient clearance. The duration may be modified based on the clinical status of the patient.

Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of M1 by approximately 40% in 24 hours and by 49 to 65% in 48 hours. Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite M1, by 37% in 24 hours and by 48%, in 48 hours.

These drug elimination procedures may be repeated if clinically necessary.

Renal Insufficiency

Single dose studies in dialysis patients show a doubling of the free fraction of M1 in plasma. There is no clinical experience in the use of ARAVA in patients with renal impairment. Caution should be used when administering this drug in this population.

Vaccinations

No clinical data are available on the efficacy and safety of vaccinations during ARAVA treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of ARAVA should be considered when contemplating administration of a live vaccine after stopping ARAVA.

Information for Patients

See PATIENT INFORMATION section.

Laboratory Tests

At minimum, ALT (SGPT) should be performed at baseline and monitored initially at monthly intervals then, if stable, at intervals determined by the individual clinical situation. In patients who are at an increased risk of hematologic toxicity (see

WARNINGS

: Immunosuppression Potential), more vigilant monitoring, including hematologic monitoring, is warranted.

Due to a specific effect on the brush border of the renal proximal tubule, ARAVA has a uricosuric effect. A separate effect of hypophosphaturia is seen in some patients. These effects have not been seen together, nor have there been alterations in renal function.

Carcinogenesis, Mutagenesis and Impairment of Fertility

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human M1 systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (17 times the human M1 exposure based on AUC. Female mice, in the same study exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human M1 exposure based on AUC). The significance of the findings in mice relative to the clinical use of ARAVA is not known.

Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide had no effect on fertility in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human M1 exposure based on AUC).

Pregnancy

Pregnancy Category X. See CONTRAINDICATIONS section. Pregnancy Registry To monitor fetal outcomes of pregnant women exposed to leflunomide, health care providers are encouraged to register such patients by calling 1-877-311-8972.

Nursing Mothers

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.

Use in Males

Available information does not suggest that ARAVA would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimize any possible risk, men wishing to father a child should consider discontinuing use of ARAVA and taking cholestyramine 8 grams 3 times daily for 11 days.

Pediatric Use

The safety and efficacy of ARAVA in the pediatric population have not been studied. Use of ARAVA in patients less than 18 years of age is not recommended.

Geriatric Use

No dosage adjustment is needed in patients over 65.