Teriflunomide

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# Black Box Warning

# 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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Teriflunomide in pediatric patients.

# Contraindications
- Patients with severe hepatic impairment .
- 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.
- 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. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling
- Co-administration of teriflunomide with leflunomide is contraindicated.

# Warnings
- 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 .
- 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. 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 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.
- 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.
- 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.
- 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:
- 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.
- 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 < 1.5109/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 <0.8109/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. 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.
- 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.
- 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.
- 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.
- 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.
- 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 . If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure.
- 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.
- 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. 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.
- 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:
- 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).
- 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.
- 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.
- 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.

# Drug Interactions
- 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 .
- Coadministration of AUBAGIO with warfarin requires close monitoring of the international normalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.
- 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.
- 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 .
- 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 .
- 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

### Pregnancy
Pregnancy Category (FDA): X
- 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.
- 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).
- 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.
- 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.
- Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection.
- 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

## Mechanism of Action
- Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.

## Structure
- AUBAGIO (teriflunomide) is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme, with the chemical name (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide. Its molecular weight is 270.21, and the empirical formula is C12H9F3N2O2 with the following chemical structure:

## Pharmacodynamics
- In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

## Pharmacokinetics
- Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity in vivo. At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.
- Based on a population analysis of teriflunomide in healthy volunteers and MS patients, median t1/2 was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg.
- Median time to reach maximum plasma concentrations is between 1 to 4 hours post-dose following oral administration of teriflunomide.
- Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.
- Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.
- Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.
- Teriflunomide is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.
- Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes.
- The Potential Effect of AUBAGIO on Other Drugs
- CYP2C8 Substrates
- There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose .
- CYP1A2 Substrates
- Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.
- OAT3 Substrates
- There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo.
- BCRP and OATP1B1/1B3 Substrates
- There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide , suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3).
- Oral Contraceptives
- There was an increase in mean ethinylestradiol Cmax and AUC024 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC024 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide .
- Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate).
- The Potential Effect of Other Drugs on AUBAGIO
- Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.
- Hepatic Impairment
- Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated.
- Renal Impairment
- Severe renal impairment had no impact on the pharmacokinetics of teriflunomide .
- Gender
- In a population analysis, the clearance rate for teriflunomide is 23% less in females than in males.
- Race
- Effect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to a low number of non-white patients in the clinical trials.

## Nonclinical Toxicology
- 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 95104 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 97104 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.
- 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.

# Clinical Studies
- Four randomized, controlled, double-blind clinical trials established the efficacy of AUBAGIO in patients with relapsing forms of multiple sclerosis.
- Study 1 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 26 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course, with or without progression, and to have experienced at least one relapse over the year preceding the trial or at least two relapses over the two years preceding the trial. Patients were required not to have received interferon-beta for at least four months, or any other multiple sclerosis medication for at least six months before entering the study, nor were these medications permitted during the study. Neurological evaluations were to be performed at screening, every 12 weeks until week 108, and after suspected relapses. MRI was to be performed at screening, and at Week 24, 48, 72, and 108. The primary endpoint was the annualized relapse rate (ARR).
- In Study 1, 1088 patients were randomized to receive AUBAGIO 7 mg (n=366), AUBAGIO 14 mg (n=359), or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score 5.5. Patients had a mean age of 38 years, mean disease duration of 5 years, and mean EDSS at baseline of 2.7. A total of 91% of patients had relapsing remitting multiple sclerosis, and 9% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 635, 627, and 631 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.
- There was a statistically significant reduction in ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg, compared to patients who received placebo (see Table 2). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.
- There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS  5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (see Table 2 and Figure 1).
- The effect of AUBAGIO on several magnetic resonance imaging (MRI) variables including the total lesion volume of T2 and hypointense T1 lesions, was assessed in Study 1. The change in total lesion volume from baseline was significantly lower in the AUBAGIO 7 mg and AUBAGIO 14 mg groups than in the placebo group. Patients in both AUBAGIO groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (see Table 2).
- Study 2 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 40 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course and to have experienced at least one relapse over the year preceding the trial, or at least two relapses over the two years preceding the trial. Patients were required not to have received any multiple sclerosis medication for at least three months before entering the trial, nor were these medications permitted during the trial. Neurological evaluations were to be performed at screening, every 12 weeks until completion, and after every suspected relapse. The primary end point was the ARR.
- A total of 1165 patients received AUBAGIO 7 mg (n=407), AUBAGIO 14 mg (n=370), or placebo (n=388). Patients had a mean age of 38 years, a mean disease duration of 5 years, and a mean EDSS at baseline of 2.7. A total of 98% of patients had relapsing remitting multiple sclerosis, and 2% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 552, 567, and 571 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.
- There was a statistically significant reduction in the ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg compared to patients who received placebo (see Table 3). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.
- There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS  5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (See Table 3 and Figure 2).
- Study 3 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 108 weeks in patients with relapsing multiple sclerosis. Patients were required to have had a first clinical event consistent with acute demyelination occurring within 90 days of randomization with 2 or more T2 lesions at least 3 mm in diameter that were characteristic of multiple sclerosis. A total of 614 patients received AUBAGIO 7 mg (n=203), AUBAGIO 14 mg (n=214), or placebo (n=197). Patients had a mean age of 32 years, EDSS at baseline of 1.7, and mean disease duration of two months. The proportion of patients free of relapse was greater in the AUBAGIO 7 mg (70.5%, p < 0.05) and AUBAGIO 14 mg (72.2%, p < 0.05) groups than in the placebo group (61.7%).
- The effect of AUBAGIO on MRI activity was also demonstrated in Study 4, a randomized, double-blind, placebo-controlled clinical trial of multiple sclerosis patients with relapse. In Study 4, MRI was to be performed at baseline, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, and 36 weeks after treatment initiation. A total of 179 patients were randomized to AUBAGIO 7 mg (n=61), AUBAGIO 14 mg (n=57), or placebo (n= 61). Baseline demographics were consistent across treatment groups. The primary endpoint was the average number of unique active lesions/MRI scan during treatment. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with AUBAGIO 7 mg (1.06) and AUBAGIO 14 mg (0.98) as compared to placebo (2.69), the difference being statistically significant for both (p=0.0234 and p=0.0052, respectively).

# How Supplied
- AUBAGIO is available as 7 mg and 14 mg tablets.
- The 14 mg tablet is pale blue to pastel blue, pentagonal film-coated tablet with dose strength "14" imprinted on one side and engraved with corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.
- The 7 mg tablet is very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with corporate logo on other side. Each tablet contains 7 mg of teriflunomide.

## Storage
- Store at 68F to 77F (20C to 25C) with excursions permitted between 59F and 86F (15C and 30C).

# Images

## Drug Images

## Package and Label Display Panel

### PRINCIPAL DISPLAY PANEL
NDC 58468-0210-2
Aubagio 
(teriflunomide)
Tablets
14 mg per Tablet
Rx only
Dispense with enclosed Medication Guide
28 tablets
genzyme
A SANOFI COMPANY
NDC 58468-0211-1
Aubagio 
(teriflunomide)
Tablets
7 mg per Tablet
Rx only
Dispense with enclosed Medication Guide
28 tablets
genzyme
A SANOFI COMPANY

### Ingredients and Appearance

# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- A Medication Guide is required for distribution with AUBAGIO.
- 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.
- 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.
- 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.
- 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.

### MEDICATION GUIDE
- Read this Medication Guide before you start using AUBAGIO and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.
- AUBAGIO may cause serious side effects, including:
- Liver problems: AUBAGIO may cause serious liver problems that may lead to death. Your risk of liver problems may be higher if you take other medicines that also affect your liver. Your doctor should do blood tests to check your liver:
- within 6 months before you start taking AUBAGIO
- 1 time a month for 6 months after you start taking AUBAGIO
- Call your doctor right away if you have any of the following symptoms of liver problems:
- nausea
- vomiting
- stomach pain
- loss of appetite
- tiredness
- your skin or the whites of your eyes turn yellow
- dark urine
- Harm to your unborn baby: AUBAGIO may cause harm to your unborn baby. Do not take AUBAGIO if you are pregnant. Do not take AUBAGIO unless you are using effective birth control.
- If you are a female, you should have a pregnancy test before you start taking AUBAGIO. Use effective birth control during your treatment with AUBAGIO.
- After stopping AUBAGIO, continue using effective birth control until you have blood tests to make sure your blood levels of AUBAGIO are low enough. If you become pregnant while taking AUBAGIO or within 2 years after you stop taking it, tell your doctor right away.
- AUBAGIO Pregnancy Registry. If you become pregnant while taking AUBAGIO or during the 2 years after you stop taking AUBAGIO, talk to your doctor about enrolling in the AUBAGIO Pregnancy Registry at 1-800-745-4447 FREE, option 2. The purpose of this registry is to collect information about your health and your baby's health.
- For men taking AUBAGIO:
- If your female partner plans to become pregnant, you should stop taking AUBAGIO and ask your doctor how to quickly lower the levels of AUBAGIO in your blood.
- If your female partner does not plan to become pregnant, you and your female partner should use effective birth control during your treatment with AUBAGIO. AUBAGIO remains in your blood after you stop taking it, so continue using effective birth control until AUBAGIO blood levels have been checked and they are low enough.
- AUBAGIO may stay in your blood for up to 2 years after you stop taking it. Your doctor can prescribe a medicine to help lower your blood levels of AUBAGIO more quickly. Talk to your doctor if you want more information about this.
- AUBAGIO is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS). AUBAGIO can decrease the number of MS flare-ups (relapses). AUBAGIO does not cure MS, but it can help slow down the physical problems that MS causes.
- It is not known if AUBAGIO is safe and effective in children.
- Do not take AUBAGIO if you:
- have severe liver problems
- are pregnant or are of childbearing age and not using effective birth control
- take a medicine called leflunomide
- Before you take AUBAGIO, tell your doctor if you:
- have liver or kidney problems
- have a fever or infection, or you are unable to fight infections
- have numbness or tingling in your hands or feet that is different from your MS symptoms
- have diabetes
- have had serious skin problems when taking other medicines
- have breathing problems
- have high blood pressure
- are breastfeeding or plan to breastfeed. It is not known if AUBAGIO passes into your breast milk. You and your doctor should decide if you will take AUBAGIO or breastfeed. You should not do both at the same time.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Using AUBAGIO and other medicines may affect each other causing serious side effects. AUBAGIO may affect the way other medicines work, and other medicines may affect how AUBAGIO works.
- Especially tell your doctor if you take medicines that could raise your chance of getting infections, including medicines used to treat cancer or to control your immune system.
- Ask your doctor or pharmacist for a list of these medicines if you are not sure.
- Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.
- Take AUBAGIO exactly as your doctor tells you to take it.
- Take AUBAGIO 1 time each day.
- Take AUBAGIO with or without food.
- AUBAGIO may cause serious side effects, including:
- See "What is the most important information I should know about AUBAGIO?"
- decreases in your white blood cell count. Your white blood cell counts should be checked before you start taking AUBAGIO. When you have a low white blood cell count you:
- may have more frequent infections. You should have a skin test for TB (Tuberculosis) before you start taking AUBAGIO. Tell your doctor if you have any of these symptoms of an infection:
- fever
- tiredness
- body aches
- chills
- nausea
- vomiting
- should not receive certain vaccinations during your treatment with AUBAGIO and for 6 months after your treatment with AUBAGIO ends.
- numbness or tingling in your hands or feet that is different from your MS symptoms. You have a greater chance of getting peripheral neuropathy if you:
- are over 60 years of age
- take certain medicines that affect your nervous system
- have diabetes
- Tell your doctor if you have numbness or tingling in your hands or feet that is different from your MS.
- serious skin problems. Tell your doctor if you have any skin problems such as redness and peeling.
- new or worsening breathing problems. Tell your doctor if you have shortness of breath or coughing with or without fever.
- high blood pressure. Your doctor should check your blood pressure before you start taking AUBAGIO and while you are taking AUBAGIO.
- The most common side effects of AUBAGIO include:
- headache
- diarrhea
- nausea
- hair thinning or loss (alopecia)
- increases in the results of blood tests to check your liver function
- Tell your doctor if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of AUBAGIO. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-332-1088 FREE.
- Store AUBAGIO at room temperature between 68F to 77F (20C to 25C).
- Keep AUBAGIO and all medicines out of reach of children.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUBAGIO for a condition for which it was not prescribed. Do not give AUBAGIO to other people, even if they have the same symptoms you have. It may harm them.
- This Medication Guide summarizes the most important information about AUBAGIO. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AUBAGIO that is written for healthcare professionals.
- For more information, go to www.aubagio.com or call Genzyme Medical Information Services at 1-800-745-4447 FREE, option 2.
- Active ingredient: teriflunomide
- Inactive ingredients in 7 mg and 14 mg tablets: lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake.
- In addition, the 7 mg tablets also contain iron oxide yellow.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.

# Precautions with Alcohol
- Alcohol-Teriflunomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Aubagio

# Look-Alike Drug Names
There is limited information regarding Teriflunomide Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price