leflunomide (leflunomide 20 mg) Dailymed

• After stopping leflunomide, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. (5.3)
• Severe infections (including sepsis), pancytopenia, agranulocytosis and thrombocytopenia: Stop leflunomide and use accelerated elimination procedure. Do not start leflunomide in patients with active infection. Monitor CBCs during treatment with leflunomide. (5.4)
• Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS): Stop leflunomide and use accelerated elimination procedure. (5.5)
• Skin ulcers: If skin ulcer is suspected, discontinue leflunomide treatment and consider an accelerated drug elimination procedure. (5.6)
• Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing leflunomide. (5.8)
• Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide and initiation of accelerated elimination procedure. (5.9)
• Increased blood pressure: Monitor and treat. (5.11)

5.1 Embryo-Fetal Toxicity

Leflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level [see Use in Specific Populations (8.1)].

Leflunomide is contraindicated for use in pregnant women [see Contraindications (4)]. Exclude pregnancy before starting treatment with leflunomide in females of reproductive potential [see Dosage and Administration (2.2)]. Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated drug elimination procedure after leflunomide treatment [see Use in Specific Populations (8.3)]. If a woman becomes pregnant while taking leflunomide, stop treatment with leflunomide, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve nondetectable plasma concentrations of teriflunomide, the active metabolite of leflunomide [see Warnings and Precautions (5.3)].

Upon discontinuing leflunomide, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk [see Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.1)].

5.2 Hepatotoxicity

Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) of greater than twice the upper limits of normal (>2xULN) before initiating treatment, should not be treated with leflunomide. Use caution when leflunomide is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting leflunomide, and thereafter every 6 to 8 weeks. If ALT elevation >3-fold ULN occurs, interrupt leflunomide therapy and investigate the cause. If likely leflunomide-induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized [see Warnings and Precautions (5.3)].

If leflunomide-induced liver injury is unlikely because some other cause has been found, resumption of leflunomide therapy may be considered. If leflunomide and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.

5.3 Procedure for Accelerated Elimination of Leflunomide and its Active Metabolite

The active metabolite of leflunomide, teriflunomide, is eliminated slowly from the plasma [see Clinical Pharmacology (12.3)].

Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. Therefore, an accelerated elimination procedure should be considered at any time after discontinuation of leflunomide, and in particular, when a patient has experienced a severe adverse reaction (e.g., hepatotoxicity, serious infection, bone marrow suppression, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected hypersensitivity, or has become pregnant. It is recommended that all women of childbearing potential undergo an accelerated elimination procedure after stopping leflunomide treatment.

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, the plasma concentration not associated with embryo-fetal toxicity in animals.

Elimination can be accelerated by the following procedures:

1. Administer cholestyramine 8 grams orally 3 times daily for 11 days.

2. Alternatively, administer 50 grams of activated charcoal powder (made into a suspension) orally every 12 hours for 11 days.

Verify plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) by two separate tests at least 14 days apart. If plasma teriflunomide concentrations are higher than 0.02 mg/L, repeat cholestyramine and/or activated charcoal treatment.

The duration of accelerated drug elimination treatment may be modified based on the clinical status and tolerability of the elimination procedure. The procedure may be repeated as needed, based on teriflunomide concentrations and clinical status.

Use of the accelerated drug elimination procedure may potentially result in return of disease activity if the patient had been responding to leflunomide treatment.

5.4 Immunosuppression, Bone Marrow Suppression, and Risk of Serious Infections

Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. If a serious infection occurs, consider interrupting leflunomide therapy and initiating the accelerated drug elimination procedure [see Warnings and Precautions (5.3)]. Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jirovecii pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide, especially Pneumocystis jirovecii pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid arthritis, may predispose patients to infection.

Cases of tuberculosis were observed in clinical studies with teriflunomide, the metabolite of leflunomide. Prior to initiating leflunomide, all patients should be screened for active and inactive ("latent") tuberculosis infection as per commonly used diagnostic tests. Leflunomide has not been studied in patients with a positive tuberculosis screen, and the safety of leflunomide in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with leflunomide and monitored carefully during leflunomide treatment for possible reactivation of the infection.

Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.

Patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking leflunomide, stop treatment with leflunomide and perform an accelerated drug elimination procedure to reduce the plasma concentration of the leflunomide active metabolite, teriflunomide [see Warnings and Precautions (5.3)].

In any situation in which the decision is made to switch from leflunomide to another antirheumatic 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.

5.5 Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reactions with Eosinophilia and Systemic Symptoms

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving leflunomide. If a patient taking leflunomide develops any of these conditions, stop leflunomide treatment and perform an accelerated drug elimination procedure [see Warnings and Precautions (5.3)].

5.6 Skin Ulcers

Skin ulcers may occur in patients during therapy with leflunomide. If leflunomide-associated skin ulcer is suspected or if skin ulcers persist despite appropriate therapy, leflunomide discontinuation and an accelerated drug elimination procedure should be considered [see Warnings and Precautions (5.3)]. The decision to resume leflunomide following skin ulcers should be based on clinical judgment of adequate wound healing.

5.7 Malignancy and Lymphoproliferative Disorders

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

5.8 Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving leflunomide and in clinical studies with teriflunomide, the active metabolite of leflunomide. Most patients recovered after discontinuation of treatment, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking leflunomide develops a peripheral neuropathy, consider discontinuing leflunomide therapy and performing an accelerated drug elimination procedure [see Warnings and Precautions (5.3)].

5.9 Interstitial Lung Disease

Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide and has been associated with fatal outcomes [see Adverse Reactions (6.2)]. The risk of leflunomide-associated interstitial lung disease is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder that may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of leflunomide therapy and for further investigation as appropriate. If discontinuation of leflunomide is necessary, consider performing an accelerated drug elimination procedure [see Warnings and Precautions (5.3)].

5.10 Vaccinations

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

5.11 Blood Pressure Monitoring

In placebo-controlled studies with the active metabolite of leflunomide, teriflunomide, elevations in blood pressure were observed in some subjects. Blood pressure should be checked before starting treatment with leflunomide and monitored periodically thereafter [see Adverse Reactions (6.1)].

6 Adverse Reactions

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)]
• Serious infections [see Warnings and Precautions (5.4)]
• Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms [see Warnings and Precautions (5.5)]
• Skin ulcers [see Warnings and Precautions (5.6)]
• Peripheral neuropathy [see Warnings and Precautions (5.8)]
• Interstitial lung disease [see Warnings and Precautions (5.9)]

• The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 

6.1 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 leflunomide 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 leflunomide 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.

Table 1: Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3*

MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal
*Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate.
	Trial 1			Trial 2			Trial 3*
	Leflunomide 20 mg/day (n= 182)	PL (n=118)	MTX 7.5 to 15 mg/wk (n=182)	Leflunomide 20 mg/day (n= 133)	PL (n=92)	SSZ 2 g/day (n=133)	Leflunomide 20 mg/day (n= 501)	MTX 7.5 to 15 mg/wk (n=498)
ALT (SGPT) >3-fold ULN (n %)	8(4.4)	3(2.5)	5(2.7)	2(1.5)	1(1.1)	2(1.5)	13(2.6)	83 (16.7)
Reversed to ≤2-fold ULN:	8	3	5	2	1	2	12	82
Timing of Elevation
0 to 3 Months	6	1	1	2	1	2	7	27
4 to 6 Months	1	1	3	-	-	-	1	34
7 to 9 Months	1	1	1	-	-	-	-	16
10 to 12 Months	-	-	-	-	-	-	5	6

In a 6-month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide 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 leflunomide-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 leflunomide treatment group).

Table 2: Percentage Of Patients With Adverse Events ≥5% In Any Leflunomide Treated Group in all RA Studies in Patients with RA

MTX = methotrexate, PL = placebo, SSZ = sulfasalazine
* Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate.
†     Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months).
‡      Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials.
	Placebo-Controlled Trials				Active-Controlled Trials		All RA Studies
	Trial 1 and 2				Trial 3 *
	Leflunomide 20 mg/day (n=315)	PL (n=210)	SSZ 2 g/day (n=133)	MTX 7.5 to 15 mg/wk (n=182)	Leflunomide 20 mg/day (n=501)	MTX 7.5 to 15 mg/wk (n=498)	Leflunomide (n=1339) â€
Diarrhea	27%	12%	10%	20%	22%	10%	17%
Headache	13%	11%	12%	21%	10%	8%	7%
Nausea	13%	11%	19%	18%	13%	18%	9%
Rash	12%	7%	11%	9%	11%	10%	10%
Abnormal Liver Enzymes	10%	2%	4%	10%	6%	17%	5%
Alopecia	9%	1%	6%	6%	17%	10%	10%
Hypertension‡	9%	4%	4%	3%	10%	4%	10%
Asthenia	6%	4%	5%	6%	3%	3%	3%
Back Pain	6%	3%	4%	9%	8%	7%	5%
GI/Abdominal Pain	6%	4%	7%	8%	8%	8%	5%
Abdominal Pain	5%	4%	4%	8%	6%	4%	6%
Allergic Reaction	5%	2%	0%	6%	1%	2%	2%
Bronchitis	5%	2%	4%	7%	8%	7%	7%
Dizziness	5%	3%	6%	5%	7%	6%	4%
Mouth Ulcer	5%	4%	3%	10%	3%	6%	3%
Pruritus	5%	2%	3%	2%	6%	2%	4%
Rhinitis	5%	2%	4%	3%	2%	2%	2%
Vomiting	5%	4%	4%	3%	3%	3%	3%
Tenosynovitis	2%	0%	1%	2%	5%	1%	3%

Adverse events during a second year of treatment with leflunomide 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 leflunomide 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

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of leflunomide. 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, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis