Aubagio

Name: Aubagio

What is teriflunomide, and how does it work (mechanism of action)?

Teriflunomide is an oral immunomodulatory agent used for the treatment of patients with relapsing forms of multiple sclerosis (MS). It inhibits dihydroorotate dehydrogenase, an enzyme used to make pyrimidine which is used to build DNA. The exact mechanism of action of teriflunomide in the treatment of MS is unknown. However, it is thought to reduce the over activation of the immune system by decreasing the number of white blood cells (T and B lymphocytes) in the central nervous system. Teriflunomide decreases the number of MS relapses. The FDA approved teriflunomide in September 2013.

Do I need a prescription for teriflunomide?

Yes

What are the side effects of teriflunomide?

The most common side effects associated with teriflunomide treatment are

  • alopecia (hair thinning or loss),
  • diarrhea,
  • influenza,
  • paresthesia (tingling, burning, prickling or pricking sensations of the skin),
  • and increase in liver enzymes.

Serious liver injury, kidney problems, decrease in white blood cell counts, risk for serious infections such as

  • tuberculosis, increase in blood potassium levels (hyperkalemia),
  • increase in blood pressure, breathing problems,
  • and serious skin problems were also reported in clinical studies.

Aubagio Overview

Aubagio is a prescription medication used to treat relapsing forms of multiple sclerosis (MS). Aubagio belongs to a group of drugs called immunomodulatory agents. These are believed to work by reducing inflammation and decreasing the action of immune cells that may cause nerve damage.

This medication comes in tablet form and is taken once a day, with or without food.

Common side effects of Aubagio include increases in liver blood test results, hair thinning or loss (alopecia), and diarrhea.

Aubagio Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • medications that stop an enzyme called BCRP such as cyclosporine (Gengraf, Neoral, Sandimmune), eltrombopag (Promacta), gefitinib (Iressa)
  • ethinylestradiol and levonorgestrel (such as Climara, Daysee, Seasonique, Quartette, Seasonale)
  • medications that use an enzyme CYP2C8 such as amiodarone (Cordarone), cabazitaxel (Jevtana), carbamazepine (Tegretol), chloroquine (Aralen), diclofenac (Voltaren), ibuprofen (Advil), paclitaxel (Taxol), rosiglitazone (Avandia), repaglinide (Prandin), treprostinil (Tyvaso)
  • medications that use the enzyme CYP1A2 such as alosetron (Lotronex), caffeine, clozapine (Clozaril), flutamide (Eulexin), frovatriptan (Frova), melatonin, mexiletine (Mexitil),  mirtazapine (Remeron), olanzapine (Zyprexa), ramelteon (Rozerem), rasagiline (Azilect), ropinirole (Requip), tacrine (Cognex), theophylline, tizanidine (Zanaflex), triamterene (Dyrenium), zolmitriptan (Zomig)
  • warfarin (Jantoven, Coumadin)

This is not a complete list of Aubagio drug interactions. Ask your doctor or pharmacist for more information.

Aubagio Dosage

Take Aubagio exactly as your doctor tells you to take it.

The usual dosage for Aubagio is 7 mg or 14 mg by mouth once daily, with or without food.

 

Dosing & Uses

Dosage Forms and Strengths

tablet

  • 7mg
  • 14mg

Multiple Sclerosis

Indicated for treatment of relapsing forms of multiple sclerosis

7 mg or 14 mg PO qDay

Dosing Considerations

Gender: Drug clearance decreased by 23% in females compared with males

Requires regular monitoring to assess safety (see Cautions)

Administration

May be taken with or without food

Safety and efficacy not established

Warnings

Black Box Warnings

Hepatotoxicity: severe liver injury including fatal liver failure has been reported with other drugs in class; monitor liver enzymes monthly for 6 months and discontinue if liver injury is suspected

Risk of teratogenicity: animal data shows major birth defects if used during pregnancy; exclude pregnancy before the start of therapy in females of reproductive potential; advise females of reproductive potential to use effective contraception during therapy and during an accelerated drug elimination procedure after therapy; stop therapy and use an accelerated drug elimination procedure if patient becomes pregnant contraindicated in women of child bearing potential who are not using reliable contraception

Contraindications

Hypersensitivity to drug or any of the inactive ingredients

Severe hepatic impairment

Pregnancy

Females of reproductive potential not using effective contraception

Current leflunomide treatment

Cautions

Severe liver injury including fatal liver failure and dysfunction have been reported in patients treated with leflunomide; similar risk to be expected

Use with caution in patients with pre-existing liver dysfunction; monitor liver enzymes routinely

May take an average of 8 months to clear drug from plasma; consider accelerated elimination with cholestyramine or activated charcoal

Decreases in white blood cell count and platelet count have been observed

Not recommended for patients with serious immunodeficiency; do not initiate treatment in patients with active acute or chronic infections

Peripheral neuropathy, including polyneuropathy and mononeuropathy have been reported; evaluate patient and consider discontinuing therapy

May cause an increases in renal uric acid clearance and decreases in serum uric acid

Use caution in hyperkalemia

Anaphylaxis and severe allergic reactions reported; signs and symptoms have included dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue.

Cases of serious skin reactions, including cases of Stevens-Johnson syndrome (SJS) and a fatal case of toxic epidermal necrolysis (TEN), reported

Very rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) reported in patients treated with leflunomide, the parent compound

May increase blood pressure; measure blood pressure at treatment initiation and monitor blood pressure during treatment

Interstitial lung disease, including acute interstitial pneumonitis, reported; use with caution in patients with pre-existing respiratory conditions; monitor for new or worsening respiratory symptoms

May decrease WBC; a recent CBC should be available before starting teriflunomide; monitor for signs and symptoms of infection; consider suspending treatment with teriflunomide in case of serious infection; do not start teriflunomide in patients with active infections

Teriflunomide side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using teriflunomide and call your doctor at once if you have:

  • fever, chills, swollen glands, easy bruising or bleeding, muscle weakness, nausea, vomiting, tired feeling;

  • skin redness or peeling;

  • numbness, tingling, or burning pain in your hands or feet;

  • chest pain, new or worsening cough with fever, trouble breathing;

  • high blood pressure--severe headache, blurred vision, pounding in your neck or ears, nosebleed, anxiety, irregular heartbeats;

  • liver problems--upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes); or

  • severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

  • nausea, diarrhea;

  • thinning hair; or

  • abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Interactions for Aubagio

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

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

Before Using Aubagio

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of teriflunomide in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies have not been performed on the relationship of age to the effects of teriflunomide in patients over the age of 65 years. Safety and efficacy have not been established.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Leflunomide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Adenovirus Vaccine Type 4, Live
  • Adenovirus Vaccine Type 7, Live
  • Bacillus of Calmette and Guerin Vaccine, Live
  • Influenza Virus Vaccine, Live
  • Measles Virus Vaccine, Live
  • Methotrexate
  • Mumps Virus Vaccine, Live
  • Poliovirus Vaccine, Live
  • Repaglinide
  • Rosuvastatin
  • Rotavirus Vaccine, Live
  • Rubella Virus Vaccine, Live
  • Smallpox Vaccine
  • Typhoid Vaccine
  • Varicella Virus Vaccine
  • Warfarin
  • Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Bone marrow problems or
  • Carpal tunnel syndrome or
  • Hyperkalemia (high potassium in the blood) or
  • Hypertension (high blood pressure) or
  • Liver disease or
  • Lung disease (eg, acute interstitial pneumonitis, interstitial lung disease) or
  • Peripheral neuropathy (nerve problem) or
  • Tuberculosis, history of or
  • Weak immune system—Use with caution. May make these conditions worse.
  • Diabetes—May increase risk of having nerve problems.
  • Infection, active—Should be treated first before starting this medicine.
  • Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
  • Liver disease, severe—Should not be used in patients with this condition.

Proper Use of Aubagio

Take this medicine exactly as directed by your doctor. Do not suddenly stop using it, do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

This medicine should come with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

You may take this with or without food.

Teriflunomide may stay in your blood for up to 2 years after your treatment. Your doctor may want you to use activated charcoal or cholestyramine (Questran®) to help remove this medicine from the body much faster if necessary. Talk to your doctor if you have questions about this.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For multiple sclerosis:
      • Adults—7 or 14 milligrams (mg) once a day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

What do I need to tell my doctor BEFORE I take Aubagio?

  • If you have an allergy to teriflunomide or any other part of Aubagio.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have a weak immune system.
  • If you have any of these health problems: Bone marrow disease (like low white blood cell count, low platelet count, or anemia).
  • If you have an infection.
  • If you have liver disease.
  • If you are taking leflunomide.
  • If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Aubagio with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Aubagio Dosage and Administration

The recommended dose of Aubagio is 7 mg or 14 mg orally once daily. Aubagio can be taken with or without food.

Monitoring to assess safety

  • Obtain transaminase and bilirubin levels within 6 months before initiation of Aubagio therapy. Monitor ALT levels at least monthly for six months after starting Aubagio [see Warnings and Precautions (5.1)].
  • Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with Aubagio. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].
  • Prior to initiating Aubagio, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection [see Warnings and Precautions (5.4)].
  • Exclude pregnancy prior to initiation of treatment with Aubagio in females of reproductive potential [see Warnings and Precautions (5.2)].
  • Check blood pressure before start of Aubagio treatment and periodically thereafter [see Warnings and Precautions (5.7)].

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.

Contraindications

Aubagio is contraindicated in/with:

  • Patients with severe hepatic impairment [see Warnings and Precautions (5.1)].
  • Pregnant women and females of reproductive potential not using effective contraception. Aubagio may cause fetal harm [see Warnings and Precautions (5.2 and 5.3) and Use in Specific Populations (8.1)].
  • Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in Aubagio. Reactions have included anaphylaxis, angioedema, and serious skin reactions [see Warnings and Precautions (5.5)].
  • Coadministration with leflunomide [see Clinical Pharmacology (12.3)].

Drug Interactions

Effect of Aubagio on CYP2C8 substrates

Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking Aubagio, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3)].

Effect of Aubagio on warfarin

Coadministration of Aubagio with warfarin requires close monitoring of the international normalized ratio (INR) because Aubagio may decrease peak INR by approximately 25%.

Effect of Aubagio on oral contraceptives

Aubagio may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with Aubagio [see Clinical Pharmacology (12.3)].

Effect of Aubagio on CYP1A2 substrates

Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking Aubagio, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3)].

Effect of Aubagio on organic anion transporter 3 (OAT3) substrates

Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking Aubagio, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3)].

Effect of Aubagio on BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) substrates

Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking Aubagio, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking Aubagio [see Clinical Pharmacology (12.3)].

Use in specific populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aubagio during pregnancy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2

Risk Summary

Aubagio is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of the potential for fetal harm based on animal data. Human data are not available at this time to inform the presence or absence of drug-associated risk with the use of Aubagio during pregnancy.

In animal reproduction studies in rat and rabbits, oral administration of teriflunomide during organogenesis caused teratogenicity and embryolethality at plasma exposures (AUC) lower than that at the maximum human recommended dose (MHRD) of 14 mg/day [see Data].

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown.

Clinical Considerations

Women who wish to become pregnant 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). Effective contraception should be used until is it verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)]. Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryofetal risk [see Contraindications (4) and Warnings and Precautions (5.3)].

If the patient becomes pregnant while taking this drug, stop treatment with Aubagio, inform the patient of the potential risk to the fetus, and perform the accelerated drug elimination procedure to achieve plasma concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Refer the patient to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling [see Warnings and Precautions (5.2, 5.3)].

Data

Animal Data

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.

Lactation

Risk Summary

It is not known whether this drug is excreted in human milk. Teriflunomide was detected in rat milk following a single oral dose.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Aubagio and any potential adverse effects on the breastfed infant from Aubagio or from the underlying maternal condition.

Females and Males of Reproductive Potential

Pregnancy Testing

Exclude pregnancy prior to initiation of treatment with Aubagio in females of reproductive potential. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.1)].

Contraception

Females

Females of reproductive potential should use effective contraception while taking Aubagio. If Aubagio is discontinued, use of contraception should be continued until is it verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL).

Females of reproductive potential who wish to become pregnant should undergo an accelerated elimination procedure. Effective contraception should be used until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

Males

Aubagio is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception. Men wishing to father a child should discontinue use of Aubagio and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

Infertility

Administration of teriflunomide to male rats resulted in no adverse effects on fertility. However, reduced epididymal sperm count was observed [see Nonclinical Toxicology (13.1)]. Effects of Aubagio on fertility in humans have not been evaluated.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Aubagio did not include patients over 65 years old.

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 [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Renal Impairment

No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3)].

Aubagio - Clinical 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.

Pharmacodynamics

Potential to prolong the QT interval

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.

Absorption

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.

Distribution

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.

Metabolism

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.

Elimination

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.

Drug Interaction Studies

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 [see Drug Interactions (7)].
  • 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 [see Drug Interactions (7)].
  • 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 [see Drug Interactions (7)].
  • 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) [see Drug Interactions (7)].
  • Oral Contraceptives
    There was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide [see Drug Interactions (7)].
  • 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.

Specific populations

  • 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 [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.6)].
  • Renal Impairment
    Severe renal impairment had no impact on the pharmacokinetics of teriflunomide [see Use in Specific Populations (8.7)].
  • 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.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Aubagio?

Avoid being near people who have colds, the flu, or other contagious illnesses. Contact your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using Aubagio, and for at least 6 months after you stop taking it. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Aubagio side effects

Get emergency medical help if you have signs of an allergic reaction to Aubagio: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using Aubagio and call your doctor at once if you have:

  • fever, chills, swollen glands, easy bruising or bleeding, muscle weakness, nausea, vomiting, tired feeling;

  • skin redness or peeling;

  • numbness, tingling, or burning pain in your hands or feet;

  • chest pain, new or worsening cough with fever, trouble breathing;

  • high blood pressure - severe headache, blurred vision, pounding in your neck or ears, nosebleed, anxiety, irregular heartbeats;

  • liver problems - upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes); or

  • severe skin reaction - fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common Aubagio side effects may include:

  • nausea, diarrhea;

  • thinning hair; or

  • abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

For the Consumer

Applies to teriflunomide: oral tablet

Along with its needed effects, teriflunomide (the active ingredient contained in Aubagio) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking teriflunomide:

More common
  • Body aches or pain
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • chills
  • cough
  • cough producing mucus
  • diarrhea
  • difficulty breathing
  • ear congestion
  • fever
  • general feeling of discomfort or illness
  • headache
  • joint pain
  • loss of appetite
  • loss of voice
  • muscle aches and pains
  • nasal congestion
  • nausea
  • runny nose
  • shivering
  • sneezing
  • sore throat
  • sweating
  • tightness in the chest
  • trouble sleeping
  • unusual tiredness or weakness
  • vomiting
Less common
  • Abdominal or stomach pain or tenderness
  • agitation
  • black, tarry stools
  • bloody or cloudy urine
  • blurred vision
  • burning, numbness, pain, or tingling in all fingers except smallest finger
  • clay colored stools
  • coma
  • confusion
  • dark urine
  • decreased appetite
  • decreased urine output
  • depression
  • diarrhea
  • difficult, burning, or painful urination
  • dizziness
  • fast, irregular, pounding, or racing heartbeat or pulse
  • frequent urge to urinate
  • hostility
  • irritability
  • itching or skin rash
  • lethargy
  • loss of appetite
  • lower back or side pain
  • muscle twitching
  • pale skin
  • pounding in the ears
  • rapid weight gain
  • seizures
  • slow or fast heartbeat
  • stupor
  • swelling of the feet or lower legs
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • weakness or heaviness of the legs
  • yellow eyes or skin
Rare
  • Blistering, peeling, or loosening of the skin
  • joint pain
  • red skin lesions, often with a purple center
  • red, irritated eyes

Some side effects of teriflunomide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Hair loss or thinning of the hair
Less common
  • Blemishes on the skin
  • bone pain
  • burning, dry, or itching eyes
  • difficulty with moving
  • discharge or excessive tearing
  • full or bloated feeling
  • muscle cramping or stiffness
  • pain in the lower back, bottom, or hips
  • pain in the upper leg
  • pimples
  • pressure in the stomach
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • swelling of the abdominal or stomach area
  • swollen joints
  • toothache
  • weight loss

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