Side Effects of Aubagio (teriflunomide)

Aubagio (teriflunomide) is a pyrimidine synthesis inhibitor used to treat relapsing forms of multiple sclerosis (MS). Aubagio can decrease the number of MS flare-ups (relapses). Aubagio does not cure MS, but it can help slow down the physical problems that MS causes. 

Common side effects of Aubagio include:

• liver problems,
• influenza,
• hair loss or thinning hair,
• nausea,
• diarrhea,
• burning or prickly feeling in the skin, and
• numbness or tingling in the hands or feet that is different from MS symptoms.

Serious side effects of Aubagio include:

• fever,
• chills,
• body aches,
• flu symptoms,
• sores in the mouth and throat,
• itching,
• tired feeling,
• loss of appetite,
• dark urine,
• clay-colored stools,
• yellowing of the skin or eyes,
• fast or racing heartbeats,
• confusion,
• little or no urinating,
• chest pain,
• dry cough,
• wheezing,
• feeling short of breath,
• skin redness or peeling,
• swelling,
• rapid weight gain, and
• severe skin reactions (fever, sore throat, swelling in the face or tongue)
• burning in the 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.

Drug interactions of Aubagio include drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone), which may increase the blood levels of these drugs. 

Coadministration of Aubagio with warfarin requires close monitoring of the international normalized ratio (INR). 

Aubagio may increase the systemic exposures of oral contraceptives. 

Taking Aubagio with drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may reduce the exposure of these drugs. 

Taking Aubagio with OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may increase the exposure of these drugs. 

When 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, patients should be monitored closely for signs and symptoms of increased exposures to those drugs. 

Aubagio is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because it may harm a fetus. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aubagio during pregnancy. 

It is unknown if Aubagio is excreted in human milk. 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.

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.

The following serious adverse reactions are described elsewhere in the prescribing information:

• Hepatotoxicity
• Bone Marrow Effects/Immunosuppression Potential/Infections
• Hypersensitivity and Serious Skin Reactions
• Peripheral Neuropathy
• Increased Blood Pressure
• Respiratory Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A total of 2047 patients receiving Aubagio (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years.

Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for Aubagio patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the Aubagio 7 mg, Aubagio 14 mg, and placebo treatment arms, respectively).

Table 1: Adverse Reactions in Pooled Placebo-Controlled Studies in Patients with Relapsing Forms of Multiple Sclerosis

Cardiovascular Deaths

Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to Aubagio in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between Aubagio and cardiovascular death has not been established.

Acute Renal Failure

In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg Aubagio group and 6/1002 (0.6%) patients in the 14 mg Aubagio group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. Aubagio may cause acute uric acid nephropathy with transient acute renal failure because Aubagio increases renal uric acid clearance.

Hypophosphatemia

In clinical trials, 18% of Aubagio-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of Aubagio-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Aubagio. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypersensitivity reactions, some of which were severe, such as anaphylaxis and angioedema
• Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome
• Thrombocytopenia
• Interstitial lung disease
• Pancreatitis

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.

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.

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.

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.

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.