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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].
In placebo-controlled trials, ALT greater than three times the ULN occurred in 14/429 (3%) and 21/415 (5%) of patients on teriflunomide 7 mg and 14 mg, respectively, and 17/421 (4%) of patients on 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. 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. Teriflunomide-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 teriflunomide and start an accelerated elimination procedure and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide therapy may be considered.
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].
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.
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 and Use In Specific Populations]
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.
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 placebocontrolled trials with 7 mg and 14 mg of AUBAGIO. 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 < 1.5x109/L was observed in 10% and 15% of patients on AUBAGIO 7 mg and 14 mg , respectively, compared with 5% of patients on placebo; lymphocyte count < 0.8x109/L was observed in 7% and 10% of patients on AUBAGIO 7 mg and 14 mg , respectively, compared with 5% of patients on 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 teriflunomide [see CLINICAL PHARMACOLOGY]. 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 teriflunomide 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 teriflunomide 7 mg (1.4%) or 14 mg (2.2%) compared to placebo (2.1%). However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking teriflunomide 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. 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.
No clinical data are available on the efficacy and safety of vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is, however, not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO.
The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with teriflunomide. 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.
In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients taking AUBAGIO than in patients taking placebo. In one 108-week placebo-controlled study in 1086 patients with multiple sclerosis, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.2% (4 patients) and 1.9% (6 patients) on 7 mg and 14 mg of AUBAGIO, respectively, compared with 0% on placebo. Treatment was discontinued in 2 patients with polyneuropathy, one on each dose; one of them recovered following treatment discontinuation. The other cases of peripheral neuropathy did not resolve with continued treatment. There have also been reports of peripheral neuropathy 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.
Acute Renal Failure
In placebo-controlled trials, 10 of 844 (1.2%) of AUBAGIO-treated subjects had transient acute renal failure with a creatinine measurement increased by 100% or more of their baseline serum creatinine value, compared to 0 of 421 placebo-treated subjects. Seven of the 10 subjects had a nadir creatinine clearance less than 30 cc/minute. In each of the 10 subjects, the serum creatinine level was normal on the next reported measurement (6-48 days from the increase in creatinine) with continued teriflunomide use. These increased creatinine measurements occurred between 12 weeks and 2 years after first dose of teriflunomide. Of the 6 subjects with available serum potassium measurements, 3 (50%) had hyperkalemia (measurements of 6.7, > 7.3, and > 7.3 mmol/L). No associated symptoms were documented.
AUBAGIO causes increases in renal uric acid clearance with mean decreases in serum uric acid of 20-30%. Acute uric acid nephropathy is a likely explanation for the cases of transient acute renal failure seen with teriflunomide. Although symptoms associated with acute uric acid nephropathy, such as loin pain or flank pain, were not reported, this information was not systematically collected. No inciting factors, such as dehydration, exercise, or increase in physical activity in the 30 days prior to the adverse event were reported, but this information was not systematically collected.
In placebo-controlled trials, treatment-emergent hyperkalemia > 7.0 mmol/L occurred in 8/829 (1.0%) of teriflunomide-treated subjects, compared to 1/414 (0.2%) of placebo-treated subjects. Two teriflunomide-treated subjects had hyperkalemia > 7.0 mmol/L with acute renal failure. Possible causes in other cases were not documented. Check serum potassium level in AUBAGIO-treated patients with symptoms of hyperkalemia or with acute renal failure.
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 teriflunomide [see CLINICAL PHARMACOLOGY]. If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure.
Blood Pressure Increase
In placebo-controlled studies, mean change from baseline in systolic blood pressure was 2.9 mmHg and 2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -1.3 mmHg for placebo. The change from baseline in diastolic blood pressure was 1.4 mmHg and 1.3 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.9 mmHg for placebo. Hypertension was reported as an adverse reaction in 4% of patients treated with 7 mg or 14 mg of AUBAGIO, compared with 2% on placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO.
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 teriflunomide [see CLINICAL PHARMACOLOGY]. 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.
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 teriflunomide 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.
Patient Counseling Information
See Medication Guide.
A Medication Guide is required for distribution with AUBAGIO. Encourage patients to read the AUBAGIO Medication Guide. The complete text of the Medication Guide is reprinted at the end of this document.
Benefits and Risks
Summarize for patients the benefits and potential risks of treatment with AUBAGIO. Tell patients to take AUBAGIO once daily as prescribed. Tell patients not to discontinue AUBAGIO without first discussing with the prescribing physician.
Inform patients that AUBAGIO may increase liver enzymes and that their liver enzymes will be checked before starting AUBAGIO and for at least 6 months while they are taking AUBAGIO. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.
Importance of Preventing Pregnancy
- Inform patients that based on animal studies, AUBAGIO may cause fetal harm.
- Advise women of childbearing potential of the need for effective contraception during AUBAGIO treatment and until completion of an accelerated elimination procedure. Advise them that an accelerated elimination procedure can be used at any time after the discontinuation of AUBAGIO.
- Instruct the patient that if she suspects or confirms pregnancy, she should immediately inform her physician. Inform the patients that an AUBAGIO pregnancy registry is available.
- Instruct men who are taking AUBAGIO and wish to father a child to discontinue AUBAGIO and use an accelerated elimination procedure. Instruct men taking AUBAGIO who do not wish to father a child that they and their female partners should use reliable contraception.
Availability of an Accelerated Elimination Procedure
Advise patients that AUBAGIO may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed.
Risk of Infections
Inform patients that they may develop a lowering of their white blood cell counts and that their blood counts will be checked before starting AUBAGIO.
Inform patients that they may be more likely to get infections when taking AUBAGIO and that they should contact their physician if they develop symptoms of infection, particularly in case of fever.
Advise patients that the use of some vaccines should be avoided during treatment with AUBAGIO and for at least 6 months after discontinuation.
Inform patients that they may develop peripheral neuropathy. Advise patients that they should contact their physician if they develop symptoms of peripheral neuropathy, such as numbness or tingling of hands or feet.
Blood Pressure Effects
Inform patients that AUBAGIO may increase blood pressure.
Inform patients that it is not known whether this drug is present in human milk. Advise patients to discontinue breastfeeding or discontinue the drug.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was observed in lifetime carcinogenicity bioassays in mouse and rat. In mouse, teriflunomide was administered orally at doses up to 12 mg/kg/day for up to 95-104 weeks; plasma teriflunomide exposures (AUC) at the highest dose tested are approximately 3 times that in humans at the maximum recommended human dose (MRHD, 14 mg /day). In rat, teriflunomide was administered orally at doses up to 4 mg/kg/day for up to 97-104 weeks; plasma teriflunomide AUCs at the highest doses tested are less than that in humans at the MRHD.
Teriflunomide was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and in in vivo micronucleus and chromosomal aberration assays. Teriflunomide was positive in an in vitro chromosomal aberration assay in human lymphocytes, with and without metabolic activation. Addition of uridine (to supplement the pyrimidine pool) reduced the magnitude of the clastogenic effect; however, teriflunomide was positive in the in vitro chromosomal aberration assay, even in the presence of uridine.
4-Trifluoromethylaniline (4-TFMA), a minor metabolite of teriflunomide, was positive in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and the in vitro chromosomal aberration assay in mammalian cells. 4-TFMA was negative in in vivo micronucleus and chromosomal aberration assays.
Impairment of fertility: Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a mg/m² basis.
Oral administration of teriflunomide (0, 0.84, 2.6, 8.6 mg/kg/day) to female rats, prior to and during mating (to untreated males) and continuing to gestation day 6, resulted in embryolethality, reduced fetal body weight, and/or malformations at all doses tested. Due to marked embryolethality at the highest dose tested, no fetuses were available for evaluation. The lowest dose tested is less than the MRHD on a mg/m² basis.
Use In Specific Populations
Pregnancy Category X
[see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
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 noeffect 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 malemediated 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]
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, option 2.
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.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of AUBAGIO did not include patients over 65 years old.
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. Teriflunomide is contraindicated in patients with severe hepatic impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 9/21/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Aubagio Information
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