Aubagio

Hepatotoxicity

Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with Aubagio. 

Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2× the upper limit of normal (ULN) before initiating treatment, should not normally be treated with Aubagio. 

Obtain serum transaminase and bilirubin levels within 6 months before initiation of Aubagio therapy. Monitor ALT levels at least monthly for 6 months after initiation. Consider additional monitoring when Aubagio is given with other potentially hepatotoxic drugs.

Consider discontinuing Aubagio if serum transaminase increase (>3×ULN) is confirmed. Monitor serum transaminase and bilirubin on Aubagio therapy, especially in those who develop symptoms suggestive of hepatic dysfunction. If liver injury is suspected to be Aubagio-induced, discontinue Aubagio and start an accelerated elimination procedure; monitor liver tests weekly until normalized. If Aubagio-induced liver injury is unlikely because some other probable cause has been found, resumption of Aubagio therapy may be considered.

Embryofetal Toxicity

Aubagio may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryofetal lethality occurred in animal reproduction studies in multiple animal species at plasma teriflunomide exposures similar to or lower than that in humans at the maximum recommended human dose (MRHD) of 14 mg/day.

Aubagio is contraindicated for use in pregnant women and in females of reproductive potential not using effective contraception. Exclude pregnancy prior to initiation in females of reproductive potential. Advise females of reproductive potential to use effective contraception during Aubagio treatment and during an accelerated drug elimination procedure after Aubagio treatment. If a woman becomes pregnant while taking Aubagio, discontinue treatment, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve a plasma teriflunomide concentration of <0.02 mg/L. Based on animal data, human plasma concentrations of teriflunomide of <0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryofetal risk.

Procedure for Accelerated Elimination of Teriflunomide

Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations <0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of Aubagio. Elimination can be accelerated by either of the following procedures:

• Administer cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times daily is not well tolerated, cholestyramine 4 g three times daily can be used.
• Administer oral activated charcoal powder 50 g every 12 hours for 11 days.

If either elimination procedure is not tolerated well, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.

At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to >98% decrease in teriflunomide plasma concentrations.

Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to Aubagio treatment.

Bone Marrow Effects/Immunosuppression Potential/Infections

Bone Marrow Effects

Compared to baseline in WBC count, a  mean decrease of ~15% (mainly neutrophils and lymphocytes) and in platelet count of ~10% were observed in placebo-controlled trials in adult patients with Aubagio 7 mg and 14 mg. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. Neutrophil count <1.5×10⁹/L and lymphocyte count <0.8×10⁹/L were also observed in the placebo-controlled studies. Cases of thrombocytopenia with Aubagio, including rare cases with platelet counts <50,000/mm³, have been reported in the postmarketing setting. 

Obtain CBCs within 6 months before the initiation of Aubagio treatment. Further monitoring should be based on signs/symptoms suggestive of bone marrow suppression.

Risk of Infection/Tuberculosis Screening

In patients with active acute or chronic infections, do not start Aubagio treatment until the infection(s) is resolved. If a serious infection occurs, consider interrupting treatment and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy.

Aubagio is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Aubagio has immunosuppression potential and may cause patients to be more susceptible to infections, including opportunistic infections.

Cases of tuberculosis have been seen in clinical studies with Aubagio in adult patients. Prior to initiation, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to Aubagio therapy.

Vaccination

No clinical data are available on the efficacy and safety of live vaccinations in patients taking Aubagio. Vaccination with live vaccines is not recommended. Consider the long half-life of Aubagio when contemplating use of a live vaccine after stopping Aubagio.

Malignancy

The risk of malignancy (esp. lymphoproliferative disorders), is increased with the use of certain immunosuppressive medications. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the Aubagio clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with Aubagio.

Hypersensitivity Reactions

Aubagio can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue.

Serious Skin Reactions

Cases of serious skin reactions (sometimes fatal), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with Aubagio. Fatal outcomes were reported in one case of TEN.

Drug Reaction and Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with Aubagio. One fatal case of DRESS that occurred in close temporal association (34 days) has been reported in the postmarketing setting. 

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. 

Discontinue Aubagio, unless an alternative etiology for the signs/symptoms is established, and begin an accelerated elimination procedure immediately. In such cases, patients should not be re-exposed to teriflunomide.

Peripheral Neuropathy

Patients >60 years of age, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If peripheral neuropathy symptoms develops, consider discontinuing Aubagio and performing an accelerated elimination procedure.

Increased Blood Pressure

Check blood pressure before the start of Aubagio treatment and periodically thereafter. Manage appropriately if elevated blood pressure develops.

Respiratory Effects

Interstitial lung disease, including acute interstitial pneumonitis, has been reported with Aubagio in the postmarketing setting.

Interstitial lung disease may be fatal and may occur acutely at any time during therapy with a variable clinical presentation. If new onset or worsening pulmonary symptoms develop, evaluate promptly. Consider initiation of an accelerated elimination procedure if discontinuation of Aubagio is necessary.

Concomitant Use with Immunosuppressive or Immunomodulating Therapies

Coadministration with antineoplastic or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which Aubagio was concomitantly administered with other immune modulating therapies for up to 1 year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.