Leflunomide - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS After stopping leflunomide, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide.

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.

Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS): Stop leflunomide and use accelerated elimination procedure.

Skin ulcers: If skin ulcer is suspected, discontinue leflunomide treatment and consider an accelerated drug elimination procedure.

Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing leflunomide.

Interstitial lung disease: May be fatal.

New onset or worsening symptoms may necessitate discontinuation of leflunomide and initiation of accelerated elimination procedure.

Increased blood pressure: Monitor and treat.

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 ].

Leflunomide is contraindicated for use in pregnant women [see Contraindications ] .

Exclude pregnancy before starting treatment with leflunomide in females of reproductive potential [see Dosage and Administration ] .

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 ] .

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 ].

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 , Warnings and Precautions , and Use in Specific Populations ] .

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 ].