Drug Interaction Report

MONITOR: Human growth hormone may reduce the pharmacologic effects of corticosteroids. Growth hormone is thought to enhance the activity of CYP450 3A4, an enzyme involved in the catabolism of corticosteroids. In addition, growth hormone (GH) inhibits microsomal enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11BHSD-1), which is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Consequently, individuals with untreated GH deficiency have relative increases in 11BHSD-1 and serum cortisol, and initiation of GH therapy may result in inhibition of 11BHSD-1 and reduced serum cortisol levels. Previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. In patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism, an increase in their maintenance or stress doses may be required following initiation of GH treatment. Cortisone acetate and prednisone may be affected more than others because conversion to their biologically active metabolites, cortisol and prednisolone, respectively, is dependent on the activity of 11BHSD-1.

MONITOR: Treatment with pharmacologic and supraphysiologic glucocorticoid dosages may attenuate the growth promoting effects of human growth hormone in children due to inhibition of the hypothalamic-pituitary-adrenal axis.

MANAGEMENT: Higher dosages of corticosteroids may be required during concomitant use of human growth hormone. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of GH treatment. In addition, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant GH treatment to avoid both hypoadrenalism and an inhibitory effect on growth.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of 21-desdeflazacort, the active metabolite of deflazacort that is formed by esterases after oral administration and further metabolized by CYP450 3A4 to several inactive metabolites. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism in the gut wall by certain compounds present in grapefruit. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased systemic exposure to 21-desdeflazacort may increase the risk of corticosteroid adverse effects such as hypercorticism, hyperglycemia, adrenal suppression, immunosuppression, hypertension, salt and water retention, electrolyte abnormalities, behavioral and mood disturbances, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents.

MANAGEMENT: Deflazacort should not be administered with grapefruit juice.