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Generic Name: Teriflunomide
Class: Immunomodulatory Agents
VA Class: IM900
Chemical Name: (2Z)- 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
Molecular Formula: C12H9F3N2O2
CAS Number: 163451-81-8

Warning(s)

  • Hepatotoxicity
  • Severe liver injury, including fatal liver failure, reported with leflunomide (an antirheumatic agent).1 Similar risk expected for teriflunomide (leflunomide's active metabolite) because recommended dosages of teriflunomide and leflunomide produce a similar range of plasma concentrations of teriflunomide.1

  • Concomitant use of other potentially hepatotoxic drugs may increase risk of severe liver injury.1

  • Obtain transaminase and bilirubin concentrations within 6 months before initiating therapy and monitor ALT concentrations at least monthly for first 6 months of therapy.1

  • If drug-induced liver injury suspected, discontinue teriflunomide and start an accelerated elimination procedure.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

  • Contraindicated in patients with severe hepatic impairment.1

  • Patients with preexisting liver disease may be at increased risk of developing elevated transaminase concentrations during teriflunomide therapy.1 (See Hepatotoxicity under Cautions.)

  • Risk of Teratogenicity
  • Based on animal data, teriflunomide may cause major birth defects if used during pregnancy.1

  • Pregnancy must be excluded prior to initiation of therapy.1

  • Contraindicated in pregnant women and women of childbearing potential who are not using reliable contraception.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Pregnancy must be avoided during teriflunomide treatment and prior to completion of an accelerated elimination procedure following treatment with the drug.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

Introduction

Pyrimidine synthesis inhibitor with immunomodulatory and disease-modifying activity in multiple sclerosis.1 4 7

Uses for Aubagio

Multiple Sclerosis (MS)

Used to reduce the frequency of relapses in patients with relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).1 2 3

Clinical experience suggests similar efficacy and improved tolerability when compared with interferon beta in the treatment of RRMS.4 7 8 19 Efficacy compared with other disease-modifying, immunomodulatory MS treatments (e.g., dimethyl fumarate, fingolimod hydrochloride, glatiramer acetate, natalizumab) not fully evaluated.4 7 10

Slideshow: Flashback: FDA Drug Approvals 2013

Concurrent use with antineoplastic or immunosuppressive therapies used in the treatment of MS (e.g., mitoxantrone, natalizumab) not evaluated to date.1 Safety studies in which teriflunomide was used in combination with other immunomodulating therapies (e.g., glatiramer acetate, interferon beta) for up to one year did not reveal any specific safety concerns;1 6 however, longer-term safety of these combinations remains to be established.1 (See Specific Drugs under Interactions.)

Aubagio Dosage and Administration

General

Accelerated Elimination Procedures

  • Eliminated slowly from the plasma.1 Without an accelerated elimination procedure, it takes an average of 8 months to reach plasma concentrations <0.02 mcg/mL and, because of individual variations in clearance, may take up to 2 years.1 An accelerated elimination procedure may be used at any time following teriflunomide discontinuance.1 (See Accelerated Elimination Procedures under Cautions.)

  • May accelerate elimination of teriflunomide from plasma by using either an oral cholestyramine or activated charcoal procedure.1

  • Cholestyramine regimen: Cholestyramine 8 g orally every 8 hours for 11 days.1 If this dosage is not well tolerated, may administer 4 g orally 3 times daily instead.1

  • Activated charcoal regimen:Activated charcoal 50 g orally as suspension every 12 hours for 11 days.1

  • If either elimination procedure is poorly tolerated, the treatment days do not need to be consecutive unless teriflunomide plasma concentrations need to be reduced rapidly.1

  • Following completion of the 11-day accelerated elimination procedures, both regimens successfully accelerated teriflunomide elimination, resulting in >98% decrease in plasma concentrations of the drug.1

  • Use of an accelerated elimination procedure may potentially result in a return of disease activity if the patient had been responding to teriflunomide therapy.1

Administration

Oral Administration

Administer orally once daily without regard to food.1

Dosage

Adults

Multiple Sclerosis
Oral

7 or 14 mg once daily.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with mild or moderate hepatic impairment.1 Not studied in patients with severe hepatic impairment; use is contraindicated.1 (See Hepatotoxicity and also Hepatic Impairment, under Cautions.)

Renal Impairment

No dosage adjustment necessary for patients with mild, moderate, or severe renal impairment.1 Dose supplementation following hemodialysis or CAPD unlikely to be necessary.13 14 15

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Aubagio

Contraindications

  • Severe hepatic impairment.1

  • Women who are pregnant and women of childbearing potential not using reliable contraception.1

  • Patients receiving leflunomide therapy.1

Warnings/Precautions

Warnings

Hepatotoxicity

Severe liver injury, including fatal liver failure and dysfunction, reported in some patients receiving leflunomide (an antirheumatic agent).1 Similar risk expected for teriflunomide (leflunomide's active metabolite).1 Increased risk of elevated serum transaminases in patients with preexisting liver disease.1 Increased risk of severe liver injury with concomitant use of other potentially hepatotoxic drugs.1

ALT increases reported in teriflunomide-treated patients, usually during the first year of therapy.1 In half of the cases, ALT concentrations returned to normal values despite continued use of the drug.1

Patients with preexisting acute or chronic liver disease and those with ALT concentrations >2 times the ULN before initiating treatment should not normally be treated with teriflunomide.1 The drug is contraindicated in patients with severe hepatic impairment.1

Obtain transaminase and bilirubin concentrations within 6 months prior to initiation of teriflunomide.1 Monitor ALT at least monthly during the initial 6 months of therapy.1 Consider additional liver function monitoring in patients concurrently receiving other potentially hepatotoxic drugs.1 If transaminase concentrations are >3 times the ULN, consider discontinuance of teriflunomide.1

Monitor serum transaminases and bilirubin during teriflunomide therapy, particularly in patients who develop signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine).1

If drug-induced liver injury is suspected, discontinue teriflunomide, initiate an accelerated elimination procedure, and monitor liver function tests weekly until values return to normal.1 20 (See Accelerated Elimination Procedures under Dosage and Administration.) If teriflunomide is considered an unlikely cause of ALT elevation because another probable cause is found, may consider resuming the drug.1 (See Hepatotoxicity under the Boxed Warning.)

Fetal/Neonatal Morbidity and Mortality

Based on animal data, teriflunomide may cause major birth defects and fetal harm (e.g., embryofetal death, skeletal variations, malformations) if administered to pregnant women.1

Do not initiate therapy in women of childbearing potential until pregnancy is excluded and use of a reliable form of contraception is confirmed.1 Contraindicated in pregnant women and in women of childbearing potential who are not using reliable contraception.1

Pregnancy must be avoided during teriflunomide therapy and prior to completion of an accelerated elimination procedure following treatment with the drug.1

If pregnancy does occur during treatment, immediately discontinue teriflunomide and initiate an accelerated elimination procedure.1 Use of an accelerated elimination procedure to rapidly lower plasma concentrations to undetectable concentrations early in a pregnancy (i.e., at the first delay in menses) may decrease risk to fetus.1 20 (See Accelerated Elimination Procedures under Dosage and Administration and also see Advice to Patients.) Clinicians are encouraged to register such patients in the Aubagio pregnancy registry, or pregnant women may enroll themselves in the registry, by telephone at 800-745-4447, option 2.1

Upon discontinuance of teriflunomide therapy, all women of childbearing potential should undergo an accelerated elimination procedure.1 Women receiving teriflunomide who wish to become pregnant must discontinue the drug and undergo an accelerated elimination procedure, including verification of plasma teriflunomide concentrations less than 0.02 mcg/mL; such concentrations are expected to have minimal teratogenic risk.1

Teriflunomide is present in human semen; animal studies to evaluate risk of male-mediated fetal toxicity have not been conducted to date.1 To minimize risk, men receiving teriflunomide not wishing to father a child and their female partners should use reliable contraception.1 Men wishing to father a child should discontinue teriflunomide therapy and undergo an accelerated elimination procedure.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

Other Warnings and Precautions

Accelerated Elimination Procedures

From 8 months to 2 years may be required for plasma concentrations to decrease to undetectable levels (<0.02 mcg/mL) following discontinuance of teriflunomide.1 Manufacturer recommends an accelerated elimination procedure when more rapid elimination is required or desirable.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

An accelerated elimination procedure is recommended in all women of childbearing potential upon teriflunomide discontinuance and in men who wish to father a child after discontinuance of the drug.1

An accelerated elimination procedure is also recommended in patients with potentially serious drug-related adverse effects (e.g., suspected liver injury, serious infection, peripheral neuropathy, severe dermatologic reactions, new onset or worsening pulmonary symptoms).1

If the patient responded to teriflunomide treatment, an accelerated elimination procedure may result in return of disease activity.1

Hematologic Effects

Decreases in WBC and platelet counts reported; WBC decreases generally occurred during first 6 weeks of therapy and remained low during treatment.1

No cases of serious pancytopenia reported with teriflunomide.1 Rare cases of pancytopenia, agranulocytosis, and thrombocytopenia reported with leflunomide; similar risk expected for teriflunomide.1

Obtain CBC within 6 months prior to initiation of treatment.1 Base further hematologic monitoring on signs and symptoms suggestive of bone marrow suppression.1

Risk of Infection/Tuberculosis Screening

Do not initiate teriflunomide in patients with active acute or chronic infections until the infection is resolved.1 If a serious infection develops, consider interruption of therapy and initiation of an accelerated elimination procedure.1 (See Accelerated Elimination Procedures under Dosage and Administration and also see Advice to Patients.) Reassess risks and benefits of teriflunomide prior to reinitiating the drug.1

No overall increase in the risk of serious infection was observed in teriflunomide-treated patients in clinical studies; however, one fatal case of Klebsiella pneumoniae sepsis occurred in a patient receiving teriflunomide 14 mg daily for 1.7 years.1 Reactivation of cytomegalovirus hepatitis also reported.1 Fatal infections, including Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia and aspergillosis, reported with leflunomide; most were confounded by concomitant immunosuppressant therapy and/or comorbidities, in addition to rheumatoid disease, that may predispose patients to infection.1

Not recommended in patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections.1 Drugs with an immunosuppressive potential, including teriflunomide, may increase susceptibility to infection, including opportunistic infections.1

Cases of tuberculosis observed.1 Not evaluated in patients with latent tuberculosis infection; safety of the drug in such patients is unknown.1 Evaluate all patients for latent tuberculosis infection with a tuberculin skin test prior to initiation of therapy.1 When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to teriflunomide therapy.1

Vaccination

Limited clinical data are available regarding efficacy and safety of vaccination in patients receiving teriflunomide.1 11 Vaccination with live vaccines not recommended.1 Consider the long half-life of teriflunomide when contemplating administration of a live vaccine after discontinuing the drug.1 (See Specific Drugs under Interactions.)

Malignancy

Increased risk of malignancy, particularly lymphoproliferative disorders, in patients receiving some immunosuppressant drugs.1 While an increased incidence of malignancies and lymphoproliferative disorders has not been observed in patients receiving teriflunomide in clinical studies, larger and longer-term studies are needed to determine whether there is an increased risk of malignancy with the drug.1

Peripheral Neuropathy

Peripheral neuropathy, including polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), reported; most cases were mild or moderate in severity.1 10

Possible increased risk for peripheral neuropathy in patients ≥60 years of age, patients concomitantly receiving other neurotoxic medications, and those with diabetes.1 Consider discontinuance of teriflunomide and use of an accelerated elimination procedure if a patient develops symptoms consistent with peripheral neuropathy (e.g., bilateral numbness or tingling of hands or feet).1 (See Accelerated Elimination Procedures under Dosage and Administration.)

Acute Renal Failure

Transient acute renal failure, including Scr increased by ≥100% of their baseline value, reported.1 Acute uric acid nephropathy is the most likely cause.1 Increased Scr measurements typically occurred between 12 weeks and 2 years following the first dose and normalized with continued teriflunomide use.1 Hyperkalemia also occurred in some of the cases.1 (See Hyperkalemia under Cautions.)

Monitor renal function and potassium concentrations in patients with symptoms of acute renal failure or hyperkalemia.1 (See Hyperkalemia under Cautions.)

Hyperkalemia

Treatment-emergent hyperkalemia reported.1 Two cases of hyperkalemia exceeding 7 mmol/L with accompanying acute renal failure reported; possible causes of hyperkalemia not documented in the other cases.1

Monitor potassium concentrations and renal function in patients with symptoms of hyperkalemia or with acute renal failure.1 (See Acute Renal Failure under Cautions.)

Dermatologic Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, reported rarely in patients receiving leflunomide; similar risk expected for teriflunomide (leflunomide's main active metabolite).1

If a severe dermatologic reaction occurs, discontinue teriflunomide and perform an accelerated elimination procedure.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

Blood Pressure Increases

Increased BP and hypertension reported.1

Measure BP at baseline and monitor periodically during therapy.1 Manage elevated BP appropriately.1

Interstitial Lung Disease

Interstitial lung disease and worsened preexisting interstitial lung disease, sometimes fatal, reported in patients receiving leflunomide; similar risk expected for teriflunomide (its main active metabolite).1 May occur acutely at any time during therapy, with a variable clinical presentation.1

In patients experiencing new or worsening pulmonary symptoms (e.g., cough, dyspnea) with or without fever, consider discontinuing teriflunomide.1 If discontinuance is warranted, consider use of an accelerated elimination procedure.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

Specific Populations

Pregnancy

Category X.1

Aubagio pregnancy registry (for clinicians and patients) at 800-745-4447, option 2.1 (See Risk of Teratogenicity under the Boxed Warning and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Teriflunomide distributes into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Clinical studies did not include patients >65 years of age.1

Hepatic Impairment

Mild and moderate hepatic impairment had no impact on pharmacokinetics.1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

Because of possible increased risk of hepatotoxicity, use not normally recommended in patients with preexisting acute or chronic liver disease or baseline serum ALT concentrations >2 times the ULN.1 Contraindicated in patients with severe hepatic impairment.1 (See Hepatotoxicity under the Boxed Warning and also under Cautions and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Severe renal impairment had no clinically important effect on pharmacokinetics.1 (See Special Populations under Dosage and Administration and also under Pharmacokinetics.)

Common Adverse Effects

Increased ALT concentrations,1 2 3 alopecia (e.g., hair loss, hair thinning),1 2 3 10 diarrhea,1 2 3 influenza,1 2 nausea,1 2 3 paresthesia.1 3

If discontinuance of teriflunomide therapy is necessary due to a serious adverse effect (e.g., hepatotoxicity, serious skin reactions), can clear the drug more rapidly from the body by use of an accelerated elimination procedure.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

Not metabolized by CYP-450 or flavin monoamine oxidase enzymes.1

Inhibits CYP2C8 and weakly induces CYP1A2.1

Substrate of the efflux transporter breast cancer resistant protein (BCRP).1 Inhibitor of BCRP, organic anion transport protein (OATP) 1B1, and organic anion transporter 3 (OAT3).1

Drug interactions may continue to occur after patient no longer is receiving teriflunomide.1 17 18 May reduce risk by using an accelerated elimination procedure after discontinuance of therapy.1 (See Accelerated Elimination Procedures under Dosage and Administration.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2C8 substrates: Possible increased AUC and peak plasma concentrations of substrate; monitor patients during concurrent therapy.1

CYP1A2 substrates: Possible reduced AUC and peak plasma concentrations of substrate resulting in reduced efficacy; monitor patients during concurrent therapy.1

Hepatotoxic Agents

Possible increased risk of serious hepatotoxicity during concurrent use.1 Consider additional monitoring of liver function (see Hepatotoxicity under the Boxed Warning and also under Cautions).1

Neurotoxic Agents

Possible increased risk of peripheral neuropathy.1 (See Peripheral Neuropathy under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Alosetron

Possible decreased AUC and peak plasma concentrations and reduced efficacy of alosetron (a CYP1A2 substrate)1

Monitor patients1

Bupropion

Pharmacokinetics of bupropion (a CYP2B6 substrate) not affected1

Caffeine

Repeated doses of teriflunomide decreased mean peak plasma concentrations and AUC of caffeine (a CYP1A2 substrate and probe)1

Charcoal, activated

Decreases plasma concentrations and hastens elimination of teriflunomide1

Used for accelerated elimination procedures1

Cholestyramine

Decreases plasma concentrations and hastens elimination of teriflunomide1

Used for accelerated elimination procedures1

Cyclosporine

Cyclosporine (a BCRP inhibitor) may increase exposure of teriflunomide1

Duloxetine

Possible decreased AUC and peak plasma concentrations and reduced efficacy of duloxetine (a CYP1A2 substrate)1

Monitor patients1

Eltrombopag

Eltrombopag (a BCRP inhibitor) may increase exposure of teriflunomide1

Gefitinib (not commercially available in the US)

Gefitinib (a BCRP inhibitor) may increase exposure of teriflunomide1

Immunosuppressive and immunomodulating agents (e.g., glatiramer acetate, interferon beta, mitoxantrone, natalizumab)

Safety of combined use in MS not fully evaluated; possible increased risk of hematologic effects with certain drugs1

When switching from teriflunomide to another agent with a known potential for hematologic suppression, monitor for hematologic toxicity; use of an accelerated elimination procedure may decrease this risk, but may result in a return of disease activity in responding patients1

Leflunomide

Teriflunomide is the main active metabolite of leflunomide; risk of additive toxicity with combined use1

Concurrent use contraindicated1

Metoprolol

Concomitant use of teriflunomide did not affect pharmacokinetics of metoprolol (a CYP2D6 substrate)1

Midazolam

Concomitant use of teriflunomide did not affect pharmacokinetics of midazolam (a CYP3A4 substrate)1

Omeprazole

Concurrent administration of teriflunomide did not affect pharmacokinetics of omeprazole (a CYP2C19 substrate)1

Oral contraceptives

Increased peak concentrations and AUC of ethinyl estradiol (1.58- and 1.54-fold, respectively) and levonorgestrel (1.33- and 1.41-fold, respectively)1

Consider type or dosage of oral contraceptives used concurrently with teriflunomide1

Paclitaxel

May increase exposure of paclitaxel (a CYP2C8 substrate)1

Monitor patients1

Pioglitazone

May increase exposure of pioglitazone (a CYP2C8 substrate)1

Monitor patients1

Repaglinide

Increased peak concentrations and AUC by 1.7- and 2.4-fold, respectively, of repaglinide (a CYP2C8 substrate)1

Monitor patients1

Rifampin

No substantial effect on pharmacokinetics of teriflunomide1

Rosiglitazone

May increase exposure of rosiglitazone (a CYP2C8 substrate)1

Monitor patients1

Theophylline

Possible decreased AUC and peak plasma concentrations and reduced efficacy of theophylline (a CYP1A2 substrate)1

Monitor patients1

Tizanidine

Possible decreased AUC and peak plasma concentrations and reduced efficacy of tizanidine (a CYP1A2 substrate)1

Monitor patients1

Vaccines

Limited data available concerning efficacy and safety of vaccination in teriflunomide-treated patients1 11

Teriflunomide does not appear to interfere with the antibody response to influenza virus vaccine inactivated11

Avoid live vaccines during therapy and for ≥6 months following discontinuance of the drug; consider long half-life of teriflunomide when contemplating administration of a live vaccine following discontinuance of the drug1

Warfarin

Does not affect pharmacokinetics of R- and S-warfarin (a CYP2C9 substrate); however, INR decreased by 25%1 12

Close INR follow-up and monitoring recommended1

Aubagio Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma teriflunomide concentrations ranged from 1–4 hours after oral administration.1

Steady-state concentrations achieved in approximately 3 months.1

Food

No clinically relevant effect on pharmacokinetics.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Highly bound (>99%) to plasma proteins and mainly distributed in plasma.1 8 9

Elimination

Metabolism

Teriflunomide is the major circulating moiety in plasma.1 8 Primary biotransformation pathway to minor metabolites is hydrolysis; oxidation is a minor pathway.1 Secondary pathways include oxidation, N-acetylation, and sulfate conjugation.1

Elimination Route

Eliminated in feces (37.5%; mainly through direct biliary excretion of unchanged drug) and in urine (22.6%; mainly as metabolites) within 21 days.1 8

Half-life

Median half-life of 18 and 19 days after chronic dosing of 7 and 14 mg daily, respectively.1

Special Populations

Mild and moderate hepatic impairment: No effect on pharmacokinetics.1 Severe hepatic impairment: Pharmacokinetics not evaluated.1

Severe renal impairment had no clinically important effect on pharmacokinetics.1 Appears to be negligibly removed by peritoneal dialysis and hemodialysis.13 14 15

In a population analysis, clearance was decreased by 23% in females compared with males.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Teriflunomide is the principal active metabolite of leflunomide (an antirheumatic agent) and is responsible for essentially all of leflunomide's pharmacologic activity in vivo.1 4 7

  • Exact mechanism of action of teriflunomide in MS is unknown; may involve, at least in part, a reduction in the number of activated lymphocytes in the CNS.1 4 7

  • Inhibits pyrimidine synthesis through reversible inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase.1 4 7 9

Advice to Patients

  • Importance of providing a copy of the teriflunomide medication guide to the patient each time the drug is dispensed; importance of patient reading the medication guide prior to initiating teriflunomide therapy and each time the prescription is refilled.1

  • Importance of patients being counseled on and understanding the benefits and potential risks of treatment with teriflunomide.1 Importance of advising patients not to discontinue teriflunomide without first talking with their clinician.1

  • Importance of informing patients of the potential for hepatotoxic effects and the need for monitoring of liver enzymes prior to initiating teriflunomide and for at least 6 months while they are receiving the drug.1 Importance of reporting possible signs or symptoms (e.g., unexplained nausea, vomiting, fatigue, anorexia, jaundice, dark urine) to their clinician.1

  • Risk of fetal harm.1 Importance of advising women of childbearing potential of the need for effective contraception during teriflunomide treatment and until completion of an accelerated elimination procedure.1 Women of childbearing potential should also be informed that an accelerated elimination procedure can be used at any time after discontinuance of teriflunomide.1 Women of childbearing potential should be advised to notify their clinician immediately if they experience any delay in menses or believe they may be pregnant.1 Importance of informing women who become pregnant while taking teriflunomide about the existence of the Aubagio pregnancy registry.1 Importance of instructing men who are taking teriflunomide and wish to father a child to discontinue teriflunomide and use an accelerated elimination procedure.1 Importance of instructing men taking teriflunomide who do not wish to father a child that they and their female partners should use reliable contraception.1 (See Fetal/Neonatal Morbidity and Mortality and also see Pregnancy under Cautions.)

  • Importance of women informing clinicians if they plan to breast-feed.1

  • Importance of informing patients that teriflunomide may stay in the blood for up to 2 years following the last dose and that an accelerated elimination procedure may be used if needed.1

  • Possible increased risk of infections.1 Importance of informing patients that teriflunomide may decrease WBCs and that their clinician may check their blood counts before initiating teriflunomide therapy.1 Importance of advising patients to contact their clinician if they develop any symptoms of infection (e.g., fever, tiredness, body aches, chills, nausea, vomiting), particularly if they develop fever.1

  • Advise patients that some vaccines should be avoided during treatment with teriflunomide and for at least 6 months after discontinuing the drug.1

  • Risk of peripheral neuropathy.1 Patients should be advised to contact their clinician if they develop symptoms of peripheral neuropathy (e.g., numbness or tingling of the hands or feet) that are different from their MS symptoms.1

  • Importance of informing patients that teriflunomide may increase BP.1

  • Risk of acute renal failure.1 Importance of advising patients to contact their clinician if they experience pain in their side (i.e., flank pain).1

  • Risk of hyperkalemia.1 Importance of advising patients to contact their clinician if they experience persistent nausea or an increase in heart rate.1

  • Risk of interstitial lung disease.1 Importance of advising patients to contact their clinician if they experience shortness of breath or coughing with or without fever.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Teriflunomide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

7 mg

Aubagio

Genzyme

14 mg

Aubagio

Genzyme

AHFS Drug Information. © Copyright, 1959-2014, Selected Revisions January 2, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Genzyme Corporation. Aubagio (teriflunomide) tablets prescribing information. Cambridge, MA; 2012 Sep.

2. O'Connor P, Wolinsky JS, Confavreux C et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011; 365:1293-303. [PubMed 21991951]

3. O'Connor PW, Li D, Freedman MS et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006; 66:894-900. [PubMed 16567708]

4. Oh J, O'Connor PW. An update of teriflunomide for treatment of multiple sclerosis. Ther Clin Risk Manag. 2013; 9:177-90. [PubMed 23761970]

5. Miller AE, O'Connor P, Wolinsky JS et al. Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Mult Scler. 2012; 18:1625-32. [PubMed 22723573]

6. Freedman MS, Wolinsky JS, Wamil B et al. Teriflunomide added to interferon-β in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012; 78:1877-85. [PubMed 22622860]

7. Tanasescu R, Evangelou N, Constantinescu CS. Role of oral teriflunomide in the management of multiple sclerosis. Neuropsychiatr Dis Treat. 2013; 9:539-53. [PubMed 23637535]

8. Wiese MD, Rowland A, Polasek TM et al. Pharmacokinetic evaluation of teriflunomide for the treatment of multiple sclerosis. Expert Opin Drug Metab Toxicol. 2013; 9:1025-35. [PubMed 23682862]

9. Rakhila H, Rozek T, Hopkins A et al. Quantitation of total and free teriflunomide (A77 1726) in human plasma by LC-MS/MS. J Pharm Biomed Anal. 2011; 55:325-31. [PubMed 21349677]

10. Freedman MS. Teriflunomide in relapsing multiple sclerosis: therapeutic utility. Ther Adv Chronic Dis. 2013; 4:192-205. [PubMed 23997924]

11. Bar-Or A, Freedman MS, Kremenchutsky M et al. Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. Neurology. 2013; 81:552-8. [PubMed 23851964]

12. Turpault S, Mair S, Meng Z et al. Effect of teriflunomide on the pharmacodynamic and pharmacokinetic profiles of warfarin in healthy male subjects. Paper presented at 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. Lyon, France: 2012 Oct 11.

13. Beaman JM, Hackett LP, Luxton G et al. Effect of hemodialysis on leflunomide plasma concentrations. Ann Pharmacother. 2002; 36:75-7. [IDIS 475291] [PubMed 11816264]

14. Bergner R, Peters L, Schmitt V et al. Leflunomide in dialysis patients with rheumatoid arthritis--a pharmacokinetic study. Clin Rheumatol. 2013; 32:267-70. [PubMed 23179005]

15. Russo PA, Wiese MD, Smith MD et al. Leflunomide for inflammatory arthritis in end-stage renal disease on peritoneal dialysis: a pharmacokinetic and pharmacogenetic study. Ann Pharmacother. 2013; 47:e15. [PubMed 23447478]

16. Weimer LH, Sachdev N. Update on medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep. 2009; 9:69-75. [PubMed 19080756]

17. Aventis Pharmaceuticals, Kansas City, MO. Personal communication.

18. Reviewers’ comments on leflunomide (personal observations).

19. Vermersch P, Czlonkowska A, Grimaldi LM et al. A multicenter, randomized, parallel-group, rater-blinded study comparing the effectiveness and safety of teriflunomide and subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis. Paper presented at 4th Cooperative Meeting of CMSC and ACTRIMS. San Diego, CA; 2012 May 30 - Jun 2. Abstract.

20. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202992Orig1s000: Medical Reviews. From FDA website.

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