Before Starting Therapy :
- CBC, liver enzymes, bilirubin, phosphate,
- HIV, HBsAg, anti-HBc, anti-HBs, hepatits C serology, VZV serology
- Chest Xray and/or quantiferon to eliminate latent TB
- Negative pregnancy test and counsel with regards to contraception for both male and female patients
- Check blood pressure
- Bring vaccinations up to date
- Give Hib and Pneumococcus vaccines
- Teriflunamide takes 3 months to reach serum steady state
- Avoid overlap with other immunosuppressive agents or combination with other potentially hepatotoxic drugs
Monitoring During Therapy :
- Monthly liver enzymes X6 then Q6months
- CBC Q6months and in case of infection
- Periodic blood pressure monitoring
- Avoid all live vaccines
- Give annual influenza vaccine
- Adjust contraception as Teriflunamide increases the serum concentrations by 1.5X
- Adjust warfarin dose as Teriflunamide decreases INR by 25% when co administered
- Avoid potentially hepatotoxic medication and other immunosuppressive agent
Stopping Therapy :
- It takes a mean of 8 months but in some up to 2 years to clear Teriflunomide.
- Rapid elimination procedure using cholestyramine 8 gms Q8H PO X 11 days is recommended.
- May need to repeat if serum levels remain above 0.02mg/L.
- Teriflunamide absorption is not affected by food intake.
- It is extensively (>99%) bound to plasma protein.
- It takes 3 months to reach serum concentration steady state and may require without the accelerated elimination procedure, on average, 8 months to 2 years to eliminate completely. Severe renal impairment does not affect its metabolism but it has not been tested in dialysis patients.
Severe liver injury including fatal liver failure occurred rarely in the post marketing setting. Concomitant use of Aubagio with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Liver enzyme elevations tend to occur, but are limited to the first year of treatment. 90% of cases were reversible with normalization within 40 days of wash out.
Monitor the following :
- Obtain transaminase and bilirubin levels within 6 months before initiation of Aubagio therapy.
- Monitor ALT levels at least monthly for six months after starting Aubagio. The latter is contraindicated in patients with severe hepatic impairment. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking Aubagio.
Risk of Teratogenicity :
Based on animal data, Aubagio may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting Aubagio. Aubagio is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during Aubagio treatment or prior to the completion of an accelerated elimination procedure after Aubagio treatment.
Teriflunomide has been found in the following :
- Teriflunomide is detected in human semen. Animal studies to specifically evaluate the 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 reliable contraception.
- Animal studies have shown excretion of teriflunomide in breast milk.
- It is not known whether this drug is excreted in human milk.
Peripheral Neuropathy :
In the pivotal, placebo-controlled studies, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 2.2% (15 patients out of 685) on 14 mg of teriflunomide, compared with 0.6% (4 patients out of 708) on placebo.
Most Common Adverse Reactions :
The following most common adverse reactions were reported with a frequency ≥10% in the 14 mg teriflunomide group and a difference of ≥1% as compared to placebo: alopecia, diarrhea, ALT increased, and nausea.
Teriflunomide is the main metabolite of leflunomide. The safety profile of leflunomide in patients suffering from rheumatoid arthritis may be pertinent when prescribing teriflunomide in MS patients.
Long Term Studies :
The 9 year follow-up of the TEMSO study showed showed a 63% retention from extension study onset(7yrs) or a 43% retention from randomization in TEMSO(9yrs). The most common reason for discontinuation was withdrawal of consent. 11% discontinued because of adverse events mostly ALT elevations. There was no apparent increased risk for malignancies and no unexpected adverse event. De novo hypertension was noted in 6-10% and neutropenia in 2-5%.
Mean increases in EDSS scores varied between 0.22 to 0.46 over 348 weeks of follow-up from core study baseline
Post-Market Adverse Events :
In post-marketing experience with AUBAGIO, the following adverse reactions have been identified:
- Hypersensitivity reactions • Immediate or delayed, some of which were severe, such as anaphylaxis and angioedema
- Severe skin reactions including toxic epidermal necrolysis and Stevens Johnson syndrome
- Stomatitis (such as aphthous or ulcerative)
- Pancreatitis, Hepatitis