48 Tablets of Teriflunomide? Nothing Should Be Overdone! − Case Study

Eliminating Teriflunomide

Teriflunomide is an immunomodulatory substance with anti-inflammatory effects, which inhibits the mitochondrial enzyme dihydroorotate dehydrogenase functionally related to the respiratory chain. The consequence of the inhibition is the suppression of the proliferation of rapidly dividing cells, which depends on pyrimidine synthesis de novo. The therapeutic effect of teriflunomide in multiple sclerosis (MS) lies in reducing the number of lymphocytes. For adults, the recommended dose is 14 mg once daily.

Teriflunomide is eliminated from plasma slowly, with an elimination half-life of 19 days with repeated administration. It is excreted mainly via bile into feces, with a smaller portion excreted renally. Without acceleration of elimination, achieving plasma concentrations < 0.02 mg/l takes an average of 8 months. Due to individual differences in the clearance of the substance, this process can take up to 2 years. In case of teriflunomide overdose, accelerated elimination can be used at any time by administering cholestyramine or activated charcoal. The recommended procedure involves administering cholestyramine at a dose of 8 g 3× daily for 11 days. If the patient cannot tolerate this dosage, 4 g of cholestyramine can be administered 3× daily for 11 days. If cholestyramine is not available, 50 g of activated charcoal can be administered 2× daily for 11 days.

A Terrifying Cocktail

A 37-year-old MS patient arrived at the emergency department at 11 PM, reporting the ingestion of 48 tablets containing 14 mg of teriflunomide, 14 tablets containing 12.5 mg of hydrochlorothiazide prescribed to his mother, 2 beers, 4 joints of marijuana, and 0.5 g of cocaine in the past 2 hours. Upon arrival, he had only a mild headache, and other signs of intoxication (such as chest pain, visual disturbances, etc.) were not present.

Renal function was assessed (due to the risk of interstitial nephritis), liver tests were performed, and the QTc interval was also checked as part of the diagnosis. Due to the risk of myelosuppression, a complete blood count was evaluated, and given the risk of arterial hypertension, blood pressure — which was slightly elevated (165/117 mmHg) — was measured. Among the other aforementioned examinations, only the QTc interval was outside the physiological range (453 ms; normal < 420 ms). As expected, increased diuresis was also observed due to the overdose of hydrochlorothiazide.

Given the relatively favorable course, the man was admitted only for observation, and the administration of 50 g of activated charcoal 2× daily and cholestyramine at a dose of 8 g 3× daily was initiated. Observation, including regular repetition of the performed examinations, was indicated for 2 weeks due to teriflunomide's half-life. However, the patient left the hospital after 12 hours against the doctors' recommendations. He was advised to resume taking teriflunomide at the dose of 14 mg once daily the following day.

Exception? Hopefully

Documented cases of teriflunomide overdose are rare. The safety of higher doses was assessed in a study evaluating the use of 70 mg daily by healthy volunteers for a maximum of 14 days. Adverse effects were consistent with the safety profile at the standard dosage. Additionally, a case was reported of a 28-year-old woman who ingested 10 tablets of teriflunomide in combination with wine and beer. No symptoms were observed 1 hour after the intoxication, but information about further follow-up is lacking.

Conclusion

Although the literature does not provide much data on the safety of extreme doses of teriflunomide, the available data suggest that careful monitoring and accelerated elimination represent adequate strategies for managing these situations.

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Sources:
1. Mian P., van Haaften W. T., Assink M., van Drie-Pierik R. J. H. M. Acute teriflunomide overdose with relatively mild symptoms: a case report. J Clin Pharm Ther 2021; 46 (6): 1784−1786, doi: 10.1111/jcpt.13360.
2. SPC Aubagio. Available at: www.ema.europa.eu/en/documents/product-information/aubagio-epar-product-information_cs.pdf