teriflunomide (Rx)

Brand and Other Names:Aubagio
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Dosing & Uses

AdultPediatric

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

Monitoring to assess safety

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

Safety and efficacy not established

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Interactions

Interaction Checker

and teriflunomide

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Headache (19-22%)

            Diarrhea (15-18%)

            Increased ALT (12-14%)

            Alopecia (10-13%)

            Influenza (9-12%)

            Nausea (9-14%)

            Paresthesia (9-10%)

            Phosphatemia (5-18%)

            1-10%

            URTI (9%)

            Bronchitis (5-8%)

            Upper abdominal pain (5-6%)

            Sinusitis (4-6%)

            Musculoskeletal pain (4-5%)

            Hypertension (4%)

            Toothache (4%)

            Increased GGT (3-5%)

            Anxiety (3-4%)

            Myalgia (3-4%)

            Pruritus (3-4%)

            Blurred vision (3%)

            Cystitis (2-4%)

            Viral gastroenteritis (2-4%)

            Oral herpes (2-4%)

            Neutropenia (2-4%)

            Increased AST (2-3%)

            Seasonal allergy (2-3%)

            Burning sensation (2-3%)

            Palpitations (2-3%)

            Decreased weight (2-3%)

            Decreased neutrophil count (2-3%)

            Sciatica (1-3%)

            Conjunctivitis (1-3%)

            Increased WBC (1-3%)

            Acne (1-3%)

            Carpal tunnel syndrome (1-3%)

            Leukopenia (1-2%)

            Abdominal distention (1-2%)

            <1%

            Cardiovascular death (0.25%)

            Postmarketing Reports

            Hypersensitivity reactions

            Severe skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome)

            Thrombocytopenia

            Interstitial lung disease

            Pancreatitis

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            Warnings

            Black Box Warnings

            Hepatotoxicity

            • Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis
            • Similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide
            • Concomitant use of teriflunomide with other potentially hepatotoxic drugs may increase the risk of severe liver injury
            • Obtain transaminase and bilirubin levels within 6 months before initiating therapy; monitor ALT levels at least monthly for 6 months after starting therapy
            • If drug-induced liver injury is suspected, discontinue treatment and start an accelerated elimination procedure with cholestyramine or charcoal
            • Contraindicated in patients with severe hepatic impairment; patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases during treatment

            Embryofetal toxicity

            • Use is contraindicated in pregnant women and in females of reproductive potential who are not using effective contraception because of the potential for fetal harm
            • Teratogenicity and embryo lethality occurred in animals at plasma teriflunomide exposures lower than that in humans
            • Exclude pregnancy before initiating treatment in females of reproductive potential
            • Females of reproductive potential should use effective contraception during treatment and during an accelerated drug elimination procedure after treatment
            • Stop teriflunomide and use an accelerated drug elimination procedure if patient becomes pregnant

            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; 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

            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 increase 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

            Bone Marrow Effects / Immunosuppression Potential

            • Fatal case of klebsiella pneumonia sepsis reported with therapy
            • Fatal infections, especially Pneumocystis jirovecii pneumonia and aspergillosis reported in patients receiving therapy
            • Most reports confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection
            • Cytomegalovirus hepatitis reactivation observed with therapy

            Drug interaction overview

            • Teriflunomide is CYP2C8 inhibitor, weak CYP1A2 inducer, organic anion transporter 3 (OAT3) inhibitor; BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) inhibitor
            • Coadministration with CYP2C8 substrates (eg, paclitaxel, pioglitazone, repaglinide, rosiglitazone) may increase exposure to the CYP2C8 substrates
            • Coadministration with warfarin requires close monitoring of INR because teriflunomide may decrease peak INR by ~25%
            • Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel; consider the type or dose of contraceptives used in combination with teriflunomide
            • Coadministration with OAT3 substrates may increase exposure of the OAT3 substrates
            • Concomitant use with CYP1A2 substrates and teriflunomide may reduce expose of the CYP1A2 substrates
            • Immunosuppressive or immunomodulating therapies
              • Coadministration with antineoplastic or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated
              • When switching from teriflunomide to another agent with a known potential for hematologic suppression, monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds
              • Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to treatment

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            Pregnancy & Lactation

            Pregnancy

            Contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of potential for fetal harm based on animal data

            Exclude pregnancy before initiating treatment in females of reproductive potential; advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment

            Discontinue treatment in female who wish to become pregnantand undergo accelerated elimination procedure to decrease plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL); use effective contraception until is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL), which are expected to have minimal embryofetal risk

            If patient becomes pregnant during therapy, stop treatment, inform patient of potential risk to fetus, and perform accelerated drug elimination procedure to achieve plasma concentrations of less than 0.02 mg/L (0.02 mcg/mL); refer patient to obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling

            Pregnancy exposure registry

            • Registry monitors pregnancy outcomes in women exposed to therapy during pregnancy; healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2

            Males

            • Drug is detected in human semen; animal studies to specifically evaluate 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
            • Discontinue therapy in men wishing to father a child 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)
            • To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception

            Lactation

            Not known whether drug is excreted in human milk; detected in rat milk following a single oral dose; because of potential for adverse reactions in a breastfed infant from therapy, women should not breastfeed during treatment

            Consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Immunomodulatory agent that inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis

            Exact mechanism of action on multiple sclerosis is unknown; may involve reducing the number of lymphocytes in the CNS

            Absorption

            Peak plasma time: 1-4 hr

            Distribution

            Protein Bound: >99%

            Vd: 11 L (single IV-dose)

            Metabolism

            Primary biotransformation to minor (inactive) metabolites by hydrolysis

            Secondary pathways: Oxidation, N-acetylation, sulfate conjugation

            CYP2C8 inhibitor; CYP1A2 inducer

            Elimination

            Total body clearance: 30.5 mL/hr

            Excretion (after 21 days): Feces (60.1%); urine (22.6%)

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            Administration

            Oral Administration

            Take with or without food

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.