Aubagio

A Comprehensive Overview of Aubagio (Teriflunomide)

Introduction

Aubagio, known generically as teriflunomide, is an oral medication primarily used in the treatment of relapsing forms of multiple sclerosis (MS). Multiple sclerosis is a chronic autoimmune disease that affects the central nervous system (CNS), leading to a wide range of symptoms, including fatigue, muscle weakness, vision problems, and cognitive impairment. Aubagio is one of several disease-modifying therapies (DMTs) available to help manage MS by reducing the frequency of relapses and slowing the progression of disability.

Mechanism of Action

Teriflunomide, the active ingredient in Aubagio, is an immunomodulatory agent that exerts its effects by selectively and reversibly inhibiting dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in the de novo synthesis of pyrimidine nucleotides. Pyrimidine nucleotides are essential building blocks for DNA and RNA synthesis, particularly in rapidly dividing cells such as activated lymphocytes.

By inhibiting DHODH, teriflunomide reduces the proliferation of activated T and B lymphocytes, which are key players in the autoimmune attack on the myelin sheath in MS. This leads to a reduction in the inflammatory response and a decrease in the number of immune cells infiltrating the CNS, thereby mitigating the damage to nerve fibers and slowing the progression of the disease.

Indications and Usage

Aubagio is indicated for the treatment of relapsing forms of multiple sclerosis, including:

• Clinically isolated syndrome (CIS): A first episode of neurological symptoms suggestive of MS.

• Relapsing-remitting MS (RRMS): The most common form of MS, characterized by periods of relapse (worsening of symptoms) followed by periods of remission (partial or complete recovery).

• Secondary progressive MS (SPMS): A form of MS that follows RRMS, where the disease progresses more steadily, with or without relapses.

Aubagio is not indicated for primary progressive MS (PPMS), a form of the disease characterized by a steady progression of symptoms from the onset without distinct relapses.

Dosage and Administration

Aubagio is available in two dosage strengths: 7 mg and 14 mg tablets. The recommended dose is 7 mg or 14 mg once daily, taken orally with or without food. The 14 mg dose is generally preferred due to its greater efficacy in reducing relapses and MRI lesions.

Before starting treatment with Aubagio, healthcare providers should assess liver function and perform a complete blood count (CBC) to rule out pre-existing liver disease or blood disorders. Additionally, a pregnancy test should be conducted in women of childbearing potential, as teriflunomide is contraindicated during pregnancy due to its potential to cause fetal harm.

Pharmacokinetics

Teriflunomide is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1 to 4 hours. The drug is extensively bound to plasma proteins (>99%) and has a long half-life of approximately 18-19 days, allowing for once-daily dosing. Teriflunomide is metabolized in the liver and excreted primarily through the bile, with a small portion eliminated in the urine.

The long half-life of teriflunomide means that it can remain in the body for an extended period after discontinuation. In cases where rapid elimination is desired (e.g., in the event of pregnancy or severe adverse effects), an accelerated elimination procedure using cholestyramine or activated charcoal can be employed to reduce the plasma concentration of teriflunomide.

Efficacy

The efficacy of Aubagio has been demonstrated in several clinical trials, including the TEMSO, TOWER, and TENERE studies.

• TEMSO Trial: This Phase III study involved 1,088 patients with relapsing forms of MS. Patients were randomized to receive either 7 mg or 14 mg of teriflunomide or placebo once daily for 108 weeks. The results showed that both doses of teriflunomide significantly reduced the annualized relapse rate (ARR) by approximately 31% compared to placebo. Additionally, the 14 mg dose significantly reduced the risk of disability progression compared to placebo.

• TOWER Trial: This Phase III study included 1,169 patients with relapsing MS. Similar to the TEMSO trial, patients were randomized to receive 7 mg or 14 mg of teriflunomide or placebo. The 14 mg dose significantly reduced the ARR by 36.3% and the risk of disability progression by 31.5% compared to placebo.

• TENERE Trial: This study compared the efficacy and safety of teriflunomide (7 mg and 14 mg) with interferon beta-1a (Rebif) in 324 patients with relapsing MS. The results showed that teriflunomide 14 mg was comparable to interferon beta-1a in terms of reducing the ARR, with a more favorable tolerability profile.

Safety and Tolerability

Aubagio is generally well-tolerated, but like all medications, it can cause side effects. The most common adverse reactions reported in clinical trials include:

• Gastrointestinal Disorders: Nausea, diarrhea, and abdominal pain are among the most frequently reported gastrointestinal side effects. These symptoms are usually mild to moderate and tend to resolve over time.

• Hair Thinning or Loss: Hair thinning or alopecia is a common side effect of teriflunomide, occurring in approximately 10-15% of patients. This effect is usually reversible upon discontinuation of the drug.

• Elevated Liver Enzymes: Teriflunomide can cause an increase in liver enzymes (ALT and AST), which may indicate liver injury. Regular monitoring of liver function is required during treatment, and the drug should be discontinued if significant liver enzyme elevations occur.

• Hypertension: Some patients may experience an increase in blood pressure while taking Aubagio. Blood pressure should be monitored regularly, and appropriate management should be initiated if hypertension develops.

• Infections: Due to its immunomodulatory effects, teriflunomide may increase the risk of infections, including respiratory infections and urinary tract infections. Patients should be monitored for signs of infection, and appropriate treatment should be initiated if necessary.

• Peripheral Neuropathy: Rare cases of peripheral neuropathy have been reported in patients taking teriflunomide. Symptoms may include numbness, tingling, or weakness in the extremities. If peripheral neuropathy is suspected, the drug should be discontinued, and an accelerated elimination procedure should be considered.

Contraindications and Precautions

Aubagio is contraindicated in the following situations:

• Pregnancy: Teriflunomide is classified as Pregnancy Category X, meaning it is contraindicated in women who are pregnant or planning to become pregnant. The drug has been shown to cause fetal harm in animal studies, and there is a potential risk of teratogenicity in humans. Women of childbearing potential should use effective contraception during treatment and for up to two years after discontinuation, unless an accelerated elimination procedure is performed.

• Severe Liver Impairment: Aubagio should not be used in patients with severe hepatic impairment or those with pre-existing liver disease, as the drug is metabolized in the liver and may exacerbate liver dysfunction.

• Hypersensitivity: Patients with a known hypersensitivity to teriflunomide or any of the excipients in Aubagio should not use the medication.

Drug Interactions

Teriflunomide has the potential to interact with other medications, which may affect its efficacy or increase the risk of adverse effects. Some notable drug interactions include:

• Live Vaccines: Patients taking Aubagio should avoid live vaccines, as the immunomodulatory effects of teriflunomide may increase the risk of vaccine-related infections.

• CYP2C8 and CYP1A2 Substrates: Teriflunomide is an inhibitor of CYP2C8 and CYP1A2 enzymes. Co-administration with drugs that are metabolized by these enzymes (e.g., repaglinide, paclitaxel, theophylline) may increase their plasma concentrations, potentially leading to adverse effects.

• Warfarin: Teriflunomide may increase the anticoagulant effect of warfarin, necessitating close monitoring of INR (International Normalized Ratio) and adjustment of warfarin dosage as needed.

• Oral Contraceptives: Teriflunomide may increase the exposure to ethinyl estradiol and levonorgestrel, components of many oral contraceptives. However, this interaction is not considered clinically significant, and additional contraceptive measures are not required.

Special Populations

• Elderly Patients: The safety and efficacy of Aubagio in patients over 65 years of age have not been established. Elderly patients may be more susceptible to the side effects of teriflunomide, particularly infections and liver dysfunction.

• Pediatric Patients: The safety and efficacy of Aubagio in pediatric patients have not been established. The use of teriflunomide in children and adolescents is not recommended.

• Renal Impairment: No dosage adjustment is required in patients with mild to moderate renal impairment. However, the safety of teriflunomide in patients with severe renal impairment has not been established.

• Hepatic Impairment: Aubagio is contraindicated in patients with severe hepatic impairment. Caution should be exercised in patients with mild to moderate hepatic impairment, and liver function should be closely monitored.

Patient Counseling and Education

Patients prescribed Aubagio should receive comprehensive counseling on the following aspects:

• Adherence: Emphasize the importance of taking Aubagio exactly as prescribed, even if the patient feels well. Skipping doses or discontinuing the medication without medical advice can reduce its effectiveness.

• Monitoring: Inform patients about the need for regular blood tests to monitor liver function and blood cell counts. Encourage them to report any signs of liver problems (e.g., jaundice, dark urine, abdominal pain) or infections (e.g., fever, sore throat) promptly.

• Pregnancy and Contraception: Women of childbearing potential should be advised to use effective contraception during treatment and for up to two years after discontinuation, unless an accelerated elimination procedure is performed. Men should also use contraception during treatment and for at least six months after stopping Aubagio.

• Side Effects: Educate patients about the potential side effects of Aubagio, including hair thinning, gastrointestinal symptoms, and increased blood pressure. Reassure them that many side effects are manageable and may resolve over time.

• Drug Interactions: Advise patients to inform their healthcare provider about all medications, supplements, and herbal products they are taking to avoid potential drug interactions.

Conclusion

Aubagio (teriflunomide) is a valuable addition to the armamentarium of disease-modifying therapies for relapsing forms of multiple sclerosis. Its once-daily oral administration offers convenience and may improve adherence compared to injectable therapies. The drug's mechanism of action, which involves the selective inhibition of pyrimidine synthesis in activated lymphocytes, helps to reduce the inflammatory response and slow disease progression.

While Aubagio is generally well-tolerated, it is not without risks. Regular monitoring of liver function, blood pressure, and blood cell counts is essential to ensure patient safety. Additionally, the potential for teratogenicity necessitates careful counseling and contraception in women of childbearing potential.

Overall, Aubagio represents an important therapeutic option for patients with relapsing MS, offering a balance of efficacy, convenience, and tolerability. As with any medication, the decision to use Aubagio should be made on an individual basis, taking into account the patient's medical history, disease characteristics, and personal preferences.