Teriflunomide

Uses

Teriflunomide is a pyrimidine synthesis inhibitor with anti-inflammatory and immunomodulatory properties used to treat patients with the relapsing-remitting form of multiple sclerosis.

Used in the treatment of relapsing forms of multiple sclerosis (MS).

Teriflunomide is also used to associated treatment for these conditions: Disseminated Sclerosis

How Teriflunomide works

The exact mechanism by which teriflunomide acts in MS is not known. What is known is that teriflunomide prevents pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, and this may be involved in its immunomodulatory effect in MS.

Toxicity

Teriflunomide is contraindicated in pregnant women or women of childbearing age due to the risk of teratogenicity. Teriflunomide is also contraindicated in severe hepatic impairment due to reports of hepatotoxicity, hepatic failure, and death.

Food Interaction

• Take with or without food.

Teriflunomide Alcohol interaction

[Major] MONITOR CLOSELY:

The recent, concomitant, or subsequent use (without the recommended leflunomide washout period or procedure) of other agents known to induce hepatotoxicity may potentiate the risk of liver injury associated with leflunomide.

The risk is thought to extend to teriflunomide, its principal active metabolite, because recommended dosages of both result in a similar range of plasma concentrations of teriflunomide.

Elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis have been reported with the use of leflunomide.

Liver enzyme elevations were generally mild (2 times the upper limit of normal or less) and resolved while continuing treatment.

Marked elevations (greater than 3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment in most cases.

However, fatalities associated with severe liver injury have also been reported rarely.

A 2009 review of leflunomide adverse event reports by the FDA identified 49 cases of severe liver injury, including 14 cases of fatal liver failure, between August 2002 and May 2009.

An additional five patients required a liver transplant and nine patients experienced a life-threatening event.

In this review, concomitant use of other hepatotoxic drugs and preexisting liver disease were associated with the greatest risk for liver injury during leflunomide treatment.

Specifically, 46 of the 49 patients were also taking other medications that have been associated with liver injury including methotrexate, TNF-alfa blockers, hydroxychloroquine, acetaminophen, nonsteroidal anti-inflammatory drugs and statins, and 14 patients had preexisting liver disease such as active or chronic hepatitis and/or a history of alcohol abuse.

The estimated duration of leflunomide exposure before onset of severe liver injury ranged from 9 days to 6 years, with the majority occurring within the first 6 to 12 months of treatment.

Caution is advised if leflunomide or teriflunomide must be used in patients who are currently receiving or have recently received treatment with other hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice), and vice versa.

Liver enzymes and bilirubin should be measured prior to initiation of leflunomide/teriflunomide therapy and at least monthly for the first six months of treatment and every 6 to 8 weeks thereafter.

Patients with preexisting liver disease or elevated baseline liver enzymes (i.e., ALT greater than two times ULN) should not receive leflunomide or teriflunomide.

Patients who develop elevated serum ALT greater than three times ULN while receiving these medications should discontinue treatment and be given washout procedures with cholestyramine or activated charcoal to accelerate elimination of leflunomide's active metabolite from plasma, which otherwise may take up to two years.

Follow-up monitoring should be conducted at least weekly until the ALT value is within normal range, and washout procedures repeated as necessary.

All patients treated with leflunomide or teriflunomide should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

Teriflunomide Hypertension interaction

[Moderate] Teriflunomide may increase the blood pressure.

Caution should be taken when using this agent in hypertensive patients.

It is recommended to check blood pressure before the start of teriflunomide treatment and periodically thereafter and elevated blood pressure should be appropriately managed during treatment with teriflunomide.

Teriflunomide Drug Interaction

Major: aspirin, ibuprofen, contained in alcoholic beverages , ethanol, acetaminophen / hydrocodone, budesonide / formoterol, acetaminophenModerate: cyclobenzaprineUnknown: amphetamine / dextroamphetamine, fluticasone / salmeterol, loratadine, fluticasone nasal, eszopiclone, pregabalin, levothyroxine, tramadol, cyanocobalamin, cholecalciferol, alprazolam, cetirizine

Teriflunomide Disease Interaction

Major: infections, PML, hepatotoxicityModerate: hypertension, immunosuppression, peripheral neuropathy, respiratory complications, tuberculosis, vaccination

Volume of Distribution

After a single intravenous dose, the volume of distribution is 11 L.

Elimination Route

After oral administration of teriflunomide, maximum plasma concentrations are reached, on average, in 1-4 hours.

Half Life

The median half-life is 18 to 19 days.

Clearance

After a single IV dose, teriflunomide has a total body clearance of 30.5 mL/h.

Elimination Route

Teriflunomide is eliminated unchanged and mainly through bile. Specifically 37.5% is eliminated in the feces and 22.6% in urine.

Innovators Monograph

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