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Aubagio

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

Medically reviewed by Drugs.com. Last updated on Nov 18, 2019.

Warning

    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
  • Teratogenicity and embryolethality demonstrated in animals.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Exclude pregnancy prior to initiating therapy.1 (See Contraindications under Cautions.)

  • Females of childbearing potential must use effective contraception during teriflunomide treatment and during an accelerated elimination procedure; if patient becomes pregnant, discontinue drug and initiate an accelerated elimination procedure.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)

Management of relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).1 2 3

Teriflunomide is one of several disease-modifying therapies used in the management of RRMS.76 77 Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing magnetic resonance imaging (MRI) lesions, and disability progression.76 78

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with RRMS who have had recent relapses and/or MRI lesion activity.76 Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.76 77

Clinical experience suggests that teriflunomide has similar efficacy and improved tolerability when compared with interferon beta.4 7 8 19 Efficacy compared with other disease-modifying therapies (e.g., dimethyl fumarate, fingolimod hydrochloride, glatiramer acetate, natalizumab) not fully evaluated.4 7 10

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

  • History of hypersensitivity reaction to teriflunomide, leflunomide, or any ingredient in the formulations.1

Warnings/Precautions

Warnings

Hepatotoxicity

Severe liver injury, including fatal liver failure and dysfunction, reported with leflunomide.1 Similar risk expected for teriflunomide.1 (See Hepatotoxicity under Boxed Warning.) Increased risk of elevated serum transaminases in patients with preexisting liver disease.1

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

Patients with preexisting acute or chronic liver disease and those with ALT concentrations >2 times the ULN generally should not be treated with teriflunomide.1 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 increase to >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 Boxed Warning.)

Fetal/Neonatal Morbidity and Mortality

No human data; however, teratogenicity (e.g., skeletal variations and other malformations) and embryolethality reported in animals.1 (See Pregnancy under Cautions.)

The mechanism of the drug's therapeutic effects is thought to also be involved in the mechanism of developmental toxicity.1

Contraindicated in pregnant women and in women of childbearing potential who are not using reliable contraception.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 either undergo an accelerated elimination procedure or wait until verification received that plasma concentrations have decreased to <0.02 mcg/mL.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 and agranulocytosis reported during postmarketing experience with leflunomide; similar risk expected for teriflunomide.1 Thrombocytopenia (with platelet counts decreasing to <50,000/mm3 in rare cases) reported during postmarketing experience with 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 Screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection 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.)

Blood Pressure Increases

Elevated 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, including acute interstitial pneumonitis, reported during postmarketing experience with teriflunomide.1

Interstitial lung disease and worsening of preexisting interstitial lung disease, sometimes fatal, also reported in patients receiving leflunomide.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.)

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis and angioedema, reported.1

If any manifestations of anaphylaxis or angioedema occur, immediately discontinue drug and perform an accelerated elimination procedure (unless the reaction is clearly not drug related).1 (See Accelerated Elimination Procedures under Dosage and Administration.) Do not re-expose patient to the drug.1

Serious Dermatologic Reactions

Serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, reported; at least 1 fatality occurred.1

If a serious skin reaction occurs, immediately discontinue drug and perform an accelerated elimination procedure (unless the reaction is clearly not drug related).1 (See Accelerated Elimination Procedures under Dosage and Administration.) Do not re-expose patient to the drug.1

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) reported rarely with leflunomide (which is metabolized to teriflunomide).1 Clinical presentation typically includes fever associated with other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction, eosinophilia).1

If manifestations of DRESS occur, immediately discontinue drug and perform an accelerated elimination procedure (unless the reaction is clearly not drug related).1 (See Accelerated Elimination Procedures under Dosage and Administration.) Do not re-expose patient to the drug.1

Specific Populations

Pregnancy

No adequate human data; however, teratogenicity and embryolethality reported in animal studies.1 (See Risk of Teratogenicity under Boxed Warning.)

May cause fetal harm; contraindicated in pregnant women and in women of childbearing potential who are not using effective contraception.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Exclude pregnancy prior to initiating therapy in women of childbearing potential.1 Such women should use effective contraception during and following discontinuance of therapy until plasma concentrations decrease to <0.02 mcg/mL; such concentrations are expected to have minimal embryofetal risk.1

If pregnancy occurs, immediately discontinue therapy and perform an accelerated elimination procedure.1 (See Accelerated Elimination Procedures under Dosage and Administration.) Refer patient to an obstetrician/gynecologist, preferably with experience in reproductive toxicology, for further evaluation and counseling.1

Women who wish to become pregnant must discontinue teriflunomide and undergo an accelerated elimination procedure; advise such women to use effective contraception until verification received that plasma teriflunomide concentrations have decreased to <0.02 mcg/mL.1

Pregnancy registry has been established for teriflunomide.1 Report pregnancies to the registry by calling 800-745-4447, option 2.1

Lactation

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

Consider benefits of breastfeeding along with the woman's clinical need for teriflunomide and any potential adverse effects on the nursing infant from the drug or underlying maternal condition.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.)

Interactions for Aubagio

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

Inhibits CYP2C8 and weakly induces CYP1A2.1

Inhibitor of the efflux transporter breast cancer resistant protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and 1B3, 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

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

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

Drugs Transported by Organic Anion Transporters and Organic Anion-Transporting Polypeptide

Systemic exposure of OAT3 substrates or OATP substrates may be increased when administered concomitantly with teriflunomide.1 Monitor patients closely for signs of increased exposure; adjust dosage of substrate drug accordingly.1

Drugs Transported by Breast Cancer Resistance Protein

Systemic exposure of BCRP substrates may be increased when administered concomitantly with teriflunomide.1 Monitor patients closely for signs of increased exposure; adjust dosage of substrate drug accordingly.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 patients and adjust dosage of alosetron accordingly1

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

Cefaclor

Possible increased exposure of cefaclor (OAT3 substrate)1

Monitor patients and adjust dosage of cefaclor accordingly1

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

Cimetidine

Possible increased exposure of cimetidine (OAT3 substrate)1

Monitor patients and adjust dosage of cimetidine accordingly1

Ciprofloxacin

Possible increased exposure of ciprofloxacin (OAT3 substrate)1

Monitor patients and adjust dosage of ciprofloxacin accordingly1

Duloxetine

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

Monitor patients and adjust dosage of duloxetine accordingly1

Furosemide

Possible increased exposure of furosemide (OAT3 substrate)1

Monitor patients and adjust dosage of furosemide accordingly1

HMG-CoA reductase inhibitors (e.g., statins)

Possible increased exposure of statins metabolized by OATP (e.g., atorvastatin, pravastatin, simvastatin)1

Monitor patients and adjust dosage of the statin accordingly1

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

Ketoprofen

Possible increased exposure of ketoprofen (OAT3 substrate)1

Monitor patients and adjust dosage of ketoprofen accordingly1

Leflunomide

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

Concurrent use contraindicated1

Methotrexate

Possible increased exposure of methotrexate (OAT3 and OATP substrate)1

Monitor patients and adjust dosage of methotrexate accordingly1

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

Mitoxantrone

Possible increased exposure of mitoxantrone (a BCRP substrate)1

Monitor patients and adjust dosage of mitoxantrone accordingly1

Nateglinide

Possible increased exposure of nateglinide (OATP substrate)1

Monitor patients and adjust dosage of nateglinide accordingly1

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 patients and adjust dosage of paclitaxel accordingly1

Penicillin G

Possible increased exposure of penicillin (OAT3 substrate)1

Monitor patients and adjust dosage of penicillin accordingly1

Pioglitazone

May increase exposure of pioglitazone (a CYP2C8 substrate)1

Monitor patients and adjust dosage of pioglitazone accordingly1

Repaglinide

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

Monitor patients and adjust dosage of repaglinide accordingly1

Rifampin

No substantial effect on pharmacokinetics of teriflunomide1

Possible increased exposure of rifampin (OATP substrate)1

Monitor patients and adjust dosage of rifampin accordingly1

Rosiglitazone

May increase exposure of rosiglitazone (a CYP2C8 substrate)1

Monitor patients and adjust dosage of rosiglitazone accordingly1

Rosuvastatin

Possible increased exposure of rosuvastatin (a BCRP substrate)1

Monitor patients and adjust dosage of rosuvastatin accordingly1

Dosage of rosuvastatin should not exceed 10 mg daily1

Theophylline

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

Monitor patients and adjust dosage of theophylline accordingly1

Tizanidine

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

Monitor patients and adjust dosage of tizanidine accordingly1

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

Zidovudine

Possible increased exposure of zidovudine (OAT3 substrate)1

Monitor patients and adjust dosage of zidovudine accordingly1

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 a 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

  • Risk of serious allergic reactions; importance of advising patients to immediately discontinue the drug and seek medical attention if any manifestations of hypersensitivity reactions occur (e.g., dyspnea, urticaria, angioedema, skin rash).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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Teriflunomide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

7 mg

Aubagio

Genzyme

14 mg

Aubagio

Genzyme

AHFS DI Essentials™. © Copyright 2020, Selected Revisions November 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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; 2016 Nov.

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. http://www.ncbi.nlm.nih.gov/pubmed/21991951?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/16567708?dopt=AbstractPlus

4. Oh J, O'Connor PW. An update of teriflunomide for treatment of multiple sclerosis. Ther Clin Risk Manag. 2013; 9:177-90. http://www.ncbi.nlm.nih.gov/pubmed/23761970?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3673963&blobtype=pdf

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