Leflunomide

LEFLUNOMIDE- leflunomide tablet
Avera McKennan Hospital

WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY

Embryo-Fetal Toxicity

Leflunomide is contraindicated for use in pregnant women because of the potential for fetal harm. Teratogenicity and embryo-lethality occurred in animals administered leflunomide at doses lower than the human exposure level. Exclude pregnancy before the start of treatment with leflunomide in females of reproductive potential. Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated drug elimination procedure after leflunomide treatment. Stop leflunomide and use an accelerated drug elimination procedure if the patient becomes pregnant [see Contraindications (4), Warnings and Precautions (5.1, 5.3), Use in Special Populations (8.1, 8.3)], and Clinical Pharmacology (12.3)]

Hepatotoxicity

Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide. Leflunomide is contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2xULN before initiating treatment, are at increased risk and should not be treated with leflunomide. Monitor ALT levels at least monthly for six months after starting leflunomide, and thereafter every 6 to 8 weeks. If leflunomide-induced liver injury is suspected, stop leflunomide treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized[see Contraindications (4), Warnings and Precautions (5.2, 5.3), Use in Special Populations (8.6)]

1 INDICATIONS AND USAGE

Leflunomide tablets USP are indicated for the treatment of adults with active rheumatoid arthritis (RA).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of leflunomide is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient???s risk of leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly.

???????????????????????? For patients who are at low risk for leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression the recommended leflunomide loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily.

???????????????????????? For patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomidedosage is 20 mg once daily without a loading dose [ see Warnings and Precautions (5.2 , 5.4)].

The maximum recommended daily dosage is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1).

Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3)]. After stopping leflunomide treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions (5.3)]. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide[see Clinical Pharmacology (12.3)].

2.2 Evaluation and Testing Prior to Starting Leflunomide

Prior to starting leflunomide treatment the following evaluations and tests are recommended:

?????????????????????? Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions (5.4)]

?????????????????????? Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions (5.2, 5.4)]

?????????????????????? For females of reproductive potential, pregnancy testing [see Warnings and Precautions (5.1)]

?????????????????????? ??Check blood pressure [see Warnings and Precautions (5.10)]

3 DOSAGE FORMS AND STRENGTHS

Leflunomide tablets are available in two strengths:

?????????????????????? Tablets: 10 mg, supplied as white to off white, circular, biconvex, film coated tablets debossed with ???L115??? on one side and plain on the other side

?????????????????????? Tablets: 20 mg, supplied as yellow colored, triangular, biconvex, film coated tablets debossed with ???L116??? on one side and plain on the other side

4 CONTRAINDICATIONS


Leflunomide is contraindicated in:

???????????????????????? Pregnant women. Leflunomide may cause fetal harm. If a woman becomes pregnant while taking this drug, stop leflunomide, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see Warnings and Precautions (5.1 and 5.3) and Use in Specific Populations (8.1)].

???????????????????????? Patients with severe hepatic impairment [see Warnings and Precautions (5.2)].

???????????????????????? Patients with known hypersensitivity to leflunomide or any of the other components of leflunomide. Known reactions include anaphylaxis [see Adverse Reactions (6.1)].

???????????????????????? ??Patients being treated with teriflunomide [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

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 non-detectable 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.

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