Leflunomide

All patients in Trial 1 received folate. 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.

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. 5–15 mg/wk (N=498) LEF (N=1339) 2 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 3 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% LEF = leflunomide, MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 1 Only 10% of patients in Trial3 received folate.

All patients in Trial 1 received folate; none in Trial 2 received folate. 2 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 3 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials.

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. 2 Post Marketing 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 microscpic 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.

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.

3) ]. Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. , hepatotoxicity, serious infection, bone marrow suppression, Steven 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. 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. 02 µg/mL) by two separate tests at least 14 days apart. 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. 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.

3) ]. Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci 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 jiroveci 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.

3) ]. In any situation in which the decision is made to switch from leflunomide 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.

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.

3) ]. 6 Malignancy and Lymphoproliferative Disorder 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.

7 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. 3 )]. 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.

3) ]. 9 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.

10 Blood Pressure Monitoring In placebo-controlled studies with the active metabolite of leflunomide, teriflunomide, elevations in blood pressure were observed in some subjects. 1) ].