Practice Drug Point

Topiramate can induce hypoadrenalism in patients taking oral corticosteroid replacement

BMJ 2009; 338 doi: http://dx.doi.org/10.1136/bmj.39588.561840.BD (Published 08 January 2009) Cite this as: BMJ 2009;338:a1788
  1. K Jacob, specialist registrar1,
  2. P J Trainer, professor of endocrinology1
  1. 1Department of Endocrinology, Christie Hospital NHS Trust, Manchester M20 4BX
  1. drkoshyjacob{at}gmail.com

    Case history

    A 35 year old woman was taking life long glucocorticoid (dexamethasone) and mineralocorticoid (fludrocortisone, Florinef, Squibb) replacement for congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. She started taking topiramate (Topamax, Janssen-Cilag) in March 2005, and the dose was titrated to 100 mg daily for atypical seizures secondary to mesial temporal sclerosis.

    Before starting topiramate she had been taking stable doses of dexamethasone (0.25 mg a day) and fludrocortisone (100 μg a day), with biochemical evidence of good control of her congenital adrenal hyperplasia (figure). Within a few weeks of starting topiramate she complained of tiredness, nausea, weight loss, and muscle aches.

    A diagnosis of hypoadrenalism was supported by raised plasma 17- hydroxyprogesterone, adrenocorticotrophin, and plasma renin activity. The rises in 17-hydroxyprogesterone and adrenocorticotrophin indicate an inadequate replacement dose of glucocorticoid (dexamethasone), and the rise in plasma renin activity indicates an inadequate replacement dose of mineralocorticoid (fludrocortisone).

    Figure1

    Plasma concentrations of the cortisol precursor 17-hydroxyprogesterone, adrenocorticotrophin, and plasma renin activity, indicative of undertreatment of congenital adrenal hyperplasia. Increase in the daily doses to 0.75 mg dexamethasone and 150 μg fludrocortisone resulted in biochemical improvement

    Discussion

    Topiramate, an antiepileptic, is a dose dependent, weak inducer of the hepatic cytochrome CYP3A4, which is involved in steroid metabolism.1 2 Evidence of accelerated clearance of oestradiol induced by topiramate has resulted in a “packet insert” caution about reduced effectiveness of the oral contraceptive pill.

    In our patient a modest dose of topiramate accelerated the metabolic clearance of dexamethasone and fludrocortisone, manifest by a greater than fivefold increase in the concentrations of the cortisol precursor 17-hydroxyprogesterone, adrenocorticotrophin, and plasma renin activity, combined with symptoms of hypoadrenalism. The Medicines and Healthcare Products Regulatory Agency responded to our report by stating that no other glucocorticoid interactions had been reported to the agency or the Commission for Human Medicines.

    The manufacturer acknowledged the theoretical possibility of a pharmacokinetic interaction between topiramate and corticosteroids but has no other reports. The ability of topiramate to accelerate glucocorticoid and mineralocorticoid clearance to induce hypoadrenalism is not confined to patients with congenital adrenal hyperplasia but is applicable to any patient who is taking a fixed dose of glucocorticoid replacement. Such patients should be warned of the risk of hypoadrenalism.

    Notes

    Cite this as: BMJ 2009;338:a1788

    Footnotes

    • Competing interests: None declared.

    • Funding: None.

    • Patient consent: Obtained.

    • Provenance and peer review: Not commissioned; externally peer reviewed.

    References