Teriflunomide
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From MedlinePlus, U.S. National Library of Medicine
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WARNING: HEPATOTOXICITY and EMBRYOFETAL TOXICITY Hepatotoxicity Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with AUBAGIO in the postmarketing setting [see Warnings and Precautions (5.1) ] . Concomitant use of AUBAGIO with other hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1) ].
If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3) ] . AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4) ] . Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Embryofetal Toxicity AUBAGIO is contraindicated for use in pregnant women and in females of reproductive potential who are not using effective contraception because of the potential for fetal harm.
Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with AUBAGIO in females of reproductive potential. Advise females of reproductive potential to use effective contraception during AUBAGIO treatment and during an accelerated drug elimination procedure after AUBAGIO treatment. Stop AUBAGIO and use an accelerated drug elimination procedure if the patient becomes pregnant [see Contraindications (4) , Warnings and Precautions (5.2 , 5.3) , Use in Specific Populations (8.1 , 8.3) , and Clinical Pharmacology (12.3) ] .
WARNING: HEPATOTOXICITY and EMBRYOFETAL TOXICITY See full prescribing information for complete boxed warning. Hepatotoxicity Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with AUBAGIO in the postmarketing setting ( 5.1 ). Concomitant use of AUBAGIO with other hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO and monitor ALT levels at least monthly for six months ( 5.1 ).
If drug induced liver injury is suspected, discontinue AUBAGIO and start accelerated elimination procedure ( 5.3 ). Embryofetal Toxicity Teratogenicity…
Pyrimidine Synthesis Inhibitor
Dosing in kidney impairment
Renal Impairment No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology ] .
Dosing in liver impairment
Hepatic Impairment No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment has not been evaluated. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications , Warnings and Precautions , and Clinical Pharmacology ] .
Drug interactions
Check teriflunomide against a medication listLabel text (5 paragraphs)
Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. ( 7 ) Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. ( 7 ) Warfarin: Monitor INR as teriflunomide may decrease INR. ( 7 ) Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in patients taking AUBAGIO.
( 7 ) Effect of AUBAGIO on CYP2C8 Substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking AUBAGIO, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3) ] . Effect of AUBAGIO on Warfarin Coadministration of AUBAGIO with warfarin requires close monitoring of the international normalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.
Effect of AUBAGIO on Oral Contraceptives AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with AUBAGIO [see Clinical Pharmacology (12.3) ] . Effect of AUBAGIO on CYP1A2 Substrates Teriflunomide may be a weak inducer of CYP1A2 in vivo . In patients taking AUBAGIO, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3) ] .
Effect of AUBAGIO on Organic Anion Transporter 3 (OAT3) Substrates Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking AUBAGIO, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3) ] . Effect of AUBAGIO on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) Substrates Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo .
For a patient taking AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking AUBAGIO [see Clinical Pharmacology (12.3) ] .
Contraindications
Severe hepatic impairment ( 4 , 5.1 ) Pregnancy ( 4 , 5.2 , 8.1 ) Hypersensitivity ( 4 , 5.5 ) Current leflunomide treatment ( 4 ) AUBAGIO is contraindicated in/with: Patients with severe hepatic impairment [see Warnings and Precautions (5.1) ] . Pregnant women and females of reproductive potential not using effective contraception. AUBAGIO may cause fetal harm [see Warnings and Precautions (5.2 , 5.3) and Use in Specific Populations (8.1) ] . Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in AUBAGIO. Reactions have included anaphylaxis, angioedema, and serious skin reactions [see Warnings and Precautions (5.5) ].
Coadministration with leflunomide [see Clinical Pharmacology (12.3) ].
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary AUBAGIO is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of the potential for fetal harm based on animal data [see Contraindications (4) and Warnings and Precautions (5.2) ] . In animal reproduction studies in rat and rabbit, oral administration of teriflunomide during organogenesis caused teratogenicity and embryolethality at plasma exposures (AUC) lower than that at the maximum recommended human dose (MRHD) of 14 mg/day [see Data ].
Available human data from pregnancy registries, clinical trials, pharmacovigilance cases, and published literature are too limited to draw any conclusions, but they do not clearly indicate increased birth defects or miscarriage associated with inadvertent teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure [see Clinical Considerations and Data ] . There are no human data pertaining to exposures later in the first trimester or beyond. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
The background risk of major birth defects and miscarriage in the indicated population is unknown. There is a pregnancy surveillance program for AUBAGIO. If AUBAGIO exposure occurs during pregnancy, or if a patient becomes pregnant within 2 years following the last dose of AUBAGIO, healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2. Clinical Considerations Fetal/Neonatal adverse reactions Lowering the plasma concentration of teriflunomide by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from AUBAGIO.
The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ]. Data Human data Available human data are limited. Prospectively reported data (from clinical trials and postmarketing reports) from >150 pregnancies in patients treated with teriflunomide and >300 pregnancies in patients treated with leflunomide have not demonstrated an increased rate of congenital malformations or miscarriage following teriflunomide exposure in the early first trimester when followed by an accelerated elimination procedure.
Specific patterns of major congenital malformations in humans have not been observed. Limitations of…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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