|indication=patients with relapsing forms of multiple sclerosis
|indication=patients with relapsing forms of multiple sclerosis
|hasBlackBoxWarning=Yes
|hasBlackBoxWarning=Yes
|adverseReactions=
|adverseReactions=headache, diarrhea, nausea, alopecia, increase in ALT
headache, diarrhea, nausea, alopecia, increase in ALT
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<!--Contraindications-->
<!--Contraindications-->
|contraindications=* Condition1
|contraindications=* Severe Hepatic Impairment
<!--Warnings-->
Patients with severe hepatic impairment [see Warnings and Precautions (5.1)].
|warnings=* Description
4.2 Patients Who are Pregnant or Women of Childbearing Potential Not Using Reliable Contraception
AUBAGIO may cause fetal harm when administered to a pregnant woman.
In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically. Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity [see Use in Specific Populations (8.1)].
AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated [see Warnings and Precautions (5.3)]. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling
====Precautions====
Current treatment with leflunomide
* Description
Co-administration of teriflunomide with leflunomide is contraindicated.
<!--Adverse Reactions-->
<!--Warnings-->
|warnings=* Hepatotoxicity
<!--Clinical Trials Experience-->
Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)].
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
In placebo-controlled trials, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving AUBAGIO 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.
One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. AUBAGIO-induced liver injury in this patient could not be ruled out.
Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue AUBAGIO and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If AUBAGIO-induced liver injury is unlikely because some other probable cause has been found, resumption of AUBAGIO therapy may be considered.
5.2 Use in Women of Childbearing Potential
=====Cardiovascular=====
There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman [see Contraindications (4.2)].
Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO [see Warnings and Precautions (5.3)].
Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk [see Contraindications (4.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
5.3 Procedure for Accelerated Elimination of Teriflunomide
=====Digestive=====
Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures:
Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.
If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.
At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.
=====Endocrine=====
Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment.
5.4 Bone Marrow Effects/Immunosuppression Potential/Infections
White Blood Cell (WBC) count decrease
A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO compared to baseline. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 12% and 16% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8×109/L was observed in 10% and 12% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3)]. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.
=====Hematologic and Lymphatic=====
Risk of Infection / Tuberculosis Screening
Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician.
AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like AUBAGIO that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.
In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with AUBAGIO 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%). However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking AUBAGIO 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting 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 disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.
=====Metabolic and Nutritional=====
In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO.
Vaccination
No clinical data are available on the efficacy and safety of live vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO.
Malignancy
=====Musculoskeletal=====
The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with AUBAGIO. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO.
5.5 Peripheral Neuropathy
In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking AUBAGIO than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.4% (13 patients) and 1.9% (17 patients) of patients receiving 7 mg and 14 mg of AUBAGIO, respectively, compared with 0.4% receiving placebo (4 patients). Treatment was discontinued in 0.7% (8 patients) with confirmed peripheral neuropathy (3 patients receiving AUBAGIO 7 mg and 5 patients receiving AUBAGIO 14 mg). Five of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment. Peripheral neuropathy also occurred in patients receiving leflunomide.
Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)].
=====Neurologic=====
5.6 Skin Reactions
Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3)]. If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure [see Warnings and Precautions (5.3)].
5.7 Increased Blood Pressure
In placebo-controlled studies, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with 7 mg or 14 mg of AUBAGIO compared with 1.8% for placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO.
=====Respiratory=====
5.8 Respiratory Effects
Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3)]. Interstitial lung disease may be fatal. Interstitial lung disease 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 the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)].
5.9 Concomitant Use with Immunosuppressive or Immunomodulating Therapies
Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which AUBAGIO was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.
=====Skin and Hypersensitivy Reactions=====
In any situation in which the decision is made to switch from AUBAGIO to another 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. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=The following serious adverse reactions are described elsewhere in the prescribing information:
Hepatotoxicity [see Contraindications (4.1) and Warnings and Precautions (5.1)]
Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4)]
Peripheral Neuropathy [see Warnings and Precautions (5.5)]
Skin Reactions [see Warnings and Precautions (5.6)]
Increased Blood Pressure [see Warnings and Precautions (5.7)]
Respiratory Effects [see Warnings and Precautions (5.8)]
=====Special Senses=====
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
A total of 2047 patients receiving AUBAGIO (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years.
Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo treatment arms, respectively).
=====Urogenital=====
: [[File:Teriflunomide Adv.png|none|500px]]
Cardiovascular deaths
Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between AUBAGIO and cardiovascular death has not been established.
Acute Renal Failure
=====Miscellaneous=====
In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients in the 14 mg AUBAGIO group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. AUBAGIO may cause acute uric acid nephropathy with transient acute renal failure because AUBAGIO increases renal uric acid clearance.
Hypophosphatemia
In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
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<!--Drug Interactions-->
<!--Drug Interactions-->
|drugInteractions=* Drug
|drugInteractions=* Effect of AUBAGIO on CYP2C8 substrates
:* Description
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
<!--Use in Specific Populations-->
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|FDAPregCat=X
|useInPregnancyFDA=* When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).
Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD.
In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD.
In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.
Use in Males
AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].
Pregnancy Registry
Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447 FREE
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInNursing=* Teriflunomide was detected in rat milk following a single oral dose of teriflunomide. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInPed=* Safety and effectiveness in pediatric patients have not been established.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGeri=* Clinical studies of AUBAGIO did not include patients over 65 years old.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInRenalImpair=* No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInHepaticImpair=* No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated. AUBAGIO is contraindicated in patients with severe hepatic impairment
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
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|administration=* Oral
|administration=* Oral
* Intravenous
|monitoring=* 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)].
|monitoring=* 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)].
Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].
Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].
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<!--Overdosage-->
<!--Overdosage-->
|overdose====Acute Overdose===
|overdose=* There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects.
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
<!--Pharmacology-->
<!--Drug box 2-->
In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination
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Black Box Warning
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
Hepatotoxicity
Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially 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 (4.1)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO.
Risk of Teratogenicity
Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment
Overview
Teriflunomide is a pyrimidine synthesis inhibitor that is FDA approved for the treatment of patients with relapsing forms of multiple sclerosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, diarrhea, nausea, alopecia, increase in ALT.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
Dosage
The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.
DOSAGE FORMS AND STRENGTHS
AUBAGIO is available as 7 mg and 14 mg tablets.
The 14 mg tablet is a pale blue to pastel blue, pentagonal film-coated tablet with the dose strength, "14" imprinted on one side and engraved with the corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.
The 7 mg tablet is a very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with the corporate logo on other side. Each tablet contains 7 mg of teriflunomide.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriflunomide in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriflunomide in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Teriflunomide in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriflunomide in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriflunomide in pediatric patients.
Contraindications
Severe Hepatic Impairment
Patients with severe hepatic impairment [see Warnings and Precautions (5.1)].
4.2 Patients Who are Pregnant or Women of Childbearing Potential Not Using Reliable Contraception
AUBAGIO may cause fetal harm when administered to a pregnant woman.
In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically. Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity [see Use in Specific Populations (8.1)].
AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated [see Warnings and Precautions (5.3)]. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling
Current treatment with leflunomide
Co-administration of teriflunomide with leflunomide is contraindicated.
Warnings
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY
Hepatotoxicity
Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially 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 (4.1)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO.
Risk of Teratogenicity
Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment
Hepatotoxicity
Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)].
In placebo-controlled trials, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving AUBAGIO 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.
One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. AUBAGIO-induced liver injury in this patient could not be ruled out.
Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue AUBAGIO and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If AUBAGIO-induced liver injury is unlikely because some other probable cause has been found, resumption of AUBAGIO therapy may be considered.
5.2 Use in Women of Childbearing Potential
There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman [see Contraindications (4.2)].
Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO [see Warnings and Precautions (5.3)].
Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk [see Contraindications (4.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
5.3 Procedure for Accelerated Elimination of Teriflunomide
Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures:
Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.
Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.
If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.
At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.
Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment.
5.4 Bone Marrow Effects/Immunosuppression Potential/Infections
White Blood Cell (WBC) count decrease
A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO compared to baseline. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 12% and 16% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8×109/L was observed in 10% and 12% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3)]. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.
Risk of Infection / Tuberculosis Screening
Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician.
AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like AUBAGIO that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.
In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with AUBAGIO 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%). However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking AUBAGIO 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting 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 disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.
In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO.
Vaccination
No clinical data are available on the efficacy and safety of live vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO.
Malignancy
The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with AUBAGIO. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO.
5.5 Peripheral Neuropathy
In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking AUBAGIO than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.4% (13 patients) and 1.9% (17 patients) of patients receiving 7 mg and 14 mg of AUBAGIO, respectively, compared with 0.4% receiving placebo (4 patients). Treatment was discontinued in 0.7% (8 patients) with confirmed peripheral neuropathy (3 patients receiving AUBAGIO 7 mg and 5 patients receiving AUBAGIO 14 mg). Five of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment. Peripheral neuropathy also occurred in patients receiving leflunomide.
Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)].
5.6 Skin Reactions
Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3)]. If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure [see Warnings and Precautions (5.3)].
5.7 Increased Blood Pressure
In placebo-controlled studies, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with 7 mg or 14 mg of AUBAGIO compared with 1.8% for placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO.
5.8 Respiratory Effects
Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3)]. Interstitial lung disease may be fatal. Interstitial lung disease 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 the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)].
5.9 Concomitant Use with Immunosuppressive or Immunomodulating Therapies
Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which AUBAGIO was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.
In any situation in which the decision is made to switch from AUBAGIO to another 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. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactions are described elsewhere in the prescribing information:
Hepatotoxicity [see Contraindications (4.1) and Warnings and Precautions (5.1)]
Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4)]
Peripheral Neuropathy [see Warnings and Precautions (5.5)]
Skin Reactions [see Warnings and Precautions (5.6)]
Increased Blood Pressure [see Warnings and Precautions (5.7)]
Respiratory Effects [see Warnings and Precautions (5.8)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
A total of 2047 patients receiving AUBAGIO (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years.
Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo treatment arms, respectively).
Cardiovascular deaths
Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between AUBAGIO and cardiovascular death has not been established.
Acute Renal Failure
In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients in the 14 mg AUBAGIO group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. AUBAGIO may cause acute uric acid nephropathy with transient acute renal failure because AUBAGIO increases renal uric acid clearance.
Hypophosphatemia
In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Teriflunomide in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Drug Interactions
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
When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).
Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD.
In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD.
In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.
Use in Males
AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].
Pregnancy Registry
Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447 FREE
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Teriflunomide in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Teriflunomide during labor and delivery.
Nursing Mothers
Teriflunomide was detected in rat milk following a single oral dose of teriflunomide. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic Use
Clinical studies of AUBAGIO did not include patients over 65 years old.
Gender
There is no FDA guidance on the use of Teriflunomide with respect to specific gender populations.
Race
There is no FDA guidance on the use of Teriflunomide with respect to specific racial populations.
Renal Impairment
No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment
Hepatic Impairment
No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated. AUBAGIO is contraindicated in patients with severe hepatic impairment
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Teriflunomide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Teriflunomide in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
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)].
Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].
Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection [see Warnings and Precautions (5.4)].
Check blood pressure before start of AUBAGIO treatment and periodically thereafter
IV Compatibility
There is limited information regarding IV Compatibility of Teriflunomide in the drug label.
Overdosage
There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects.
In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination
Pharmacology
There is limited information regarding Teriflunomide Pharmacology in the drug label.
