Agents used for the medical treatment of Cushing syndrome

Agent and route	Dosing range^*	Onset of action^¶	Use during pregnancy	Adverse effects^Δ	Drug interaction potential (metabolism and transport effects)^◊	Notes
Adrenal steroidogenesis inhibitors
Ketoconazole (oral)	400 to 1600 mg/day in 2 to 4 divided doses	Rapid (days)	Yes; however, not treatment of choice due to potential for feminization of a male fetus	Adrenal insufficiency^§, nausea, diarrhea, increased LFTs (reversible hepatotoxicity) Less common: Prolonged QTc interval, hypogonadism, severe hepatotoxicity	Inhibits CYP3A4 and P-gp Substrate of CYP3A4	Requires an acidic environment for maximal bioavailability; concurrent administration with a proton pump inhibitor may reduce absorption. Commonly used where available, but not available in some countries.
Levoketoconazole (oral)	150 to 600 mg twice daily	Rapid (days)	Insufficient data	Adrenal insufficiency^§, nausea, diarrhea, headache, hypertension, hypokalemia, increased LFTs (reversible hepatotoxicity), prolonged QTc interval Less common: Hypogonadism, severe hepatotoxicity	Inhibits CYP3A4 and P-gp Substate of CYP3A4	Requires an acidic environment for maximal bioavailability; concurrent administration with a proton pump inhibitor may reduce absorption. Availability is limited outside the United States. Patient assistance programs may be available if cost is a barrier to use.
Metyrapone (oral)	750 to 4500 mg/day in 3 to 4 divided doses	Rapid (days)	Yes	Adrenal insufficiency^§, nausea, diarrhea Less common: Hirsutism, hypertension, hypokalemia, leukopenia (rare)	None	Access to metyrapone for treatment of Cushing syndrome may be limited. Refer to local product availability. Most patients show near-maximal response at a dose of 2000 mg/day.
Mitotane (oral)	500 to 3000 mg/day in 2 to 3 divided doses^¥	Slow (months); long half-life	No (teratogenic)	Adrenal insufficiency^§, nausea, diarrhea, central nervous system (eg, ataxia, confusion, speech or visual problems), hypothyroidism, increased LFTs, gynecomastia Less common: Hematologic (eg, leukopenia, thrombocytopenia, anemia)	Inhibits CYP3A4	Generally reserved for treating adrenocortical carcinoma. Increases CBG levels; serum cortisol levels cannot be used to monitor efficacy. Hypocortisolism may persist after discontinuation.
Osilodrostat (oral)	2 to 30 mg twice daily	Intermediate (days to weeks)	Insufficient data	Adrenal insufficiency^§, nausea, diarrhea, headache, hypokalemia, hyperandrogenism (females) Less common: Hypertension, prolonged QTc interval	None	Hypocortisolism may persist after discontinuation. Patient assistance programs may be available if cost is a barrier to use.
Etomidate (IV)	Loading dose of 3 to 5 mg (optional) followed by 0.02 to 0.05 mg/kg/hour titrated based on serum cortisol (eg, up to 0.1 to 0.3 mg/kg/hour)	Rapid (hours)	Insufficient data	Adrenal insufficiency^§	None	Requires monitoring in intensive care unit; however, sedation has not been reported at doses used for Cushing syndrome.
Corticotroph-directed agents
Cabergoline (oral)	0.5 to 7 mg/week, either once weekly or divided in 2 weekly doses	Slow (weeks)	Yes	Adrenal insufficiency^§, nausea, diarrhea, dizziness, headache Less common: Asthenia, decreased impulse control/increased compulsive behaviors, hypotension	None	Used to treat hypercortisolism due to a corticotroph tumor (Cushing disease). Works best if UFC <2-fold normal.
Pasireotide (SUBQ)	0.6 to 1.2 mg twice daily	Slow (weeks)	Unknown	Cholelithiasis, hyperglycemia, diarrhea, nausea Less common: Adrenal insufficiency^§, transient increase in LFTs, prolonged QTc interval	None	Used to treat hypercortisolism due to a corticotroph tumor (Cushing disease). Works best if UFC <2-fold normal. Patient assistance programs may be available if cost is a barrier to use.
Pasireotide ER (IM)	10 to 40 mg once every 4 weeks	Slow (months)	Unknown		None
Glucocorticoid receptor antagonist
Mifepristone (oral)	300 to 1200 mg once daily	Slow (weeks)	No (abortifacient)	Adrenal insufficiency^§, fatigue, nausea, diarrhea, hypokalemia, peripheral edema, arthralgias, headache, dizziness, endometrial thickening Less common: Hypertension, prolonged QTc interval	Inhibits CYP3A4, CYP2C9, and P-gp Substrate of CYP3A4	Used to control hyperglycemia from endogenous Cushing syndrome and has also been shown to effectively reduce cortisol-driven psychosis. Difficult to titrate due to lack of biomarker; goal is normalization of clinical and biochemical hypercortisolism. Hypocortisolism may persist after discontinuation. Patient assistance programs may be available if cost is a barrier to use.

Agents shown may be used as monotherapy or in combined regimens to treat Cushing syndrome. Key factors for selecting treatment regimens include availability, ability to achieve rapid control of hypercortisolism, safety of use during pregnancy, compatibility with other agents, adverse effect profile, and cost. Some agents may not have regulatory approval for treatment of Cushing syndrome; refer to local prescribing information. This table is intended for use with other UpToDate content on the diagnosis and treatment of Cushing syndrome.

ACTH: corticotropin; CBG: corticosteroid-binding globulin; CYP: cytochrome P450; ER: extended release; IM: intramuscular; IV: intravenous; LFTs: liver biochemical and function tests; P-gp: P-glycoprotein; SUBQ: subcutaneous; UFC: urinary free cortisol.

* Doses in this table represent the range of doses that may be used for the treatment of Cushing syndrome in adults. For additional information, including titration and dose adjustments (eg, for kidney or liver impairment or drug interactions), refer to UpToDate content on treatment of Cushing syndrome and individual drug monographs included with UpToDate.

¶ The rapidity of effect for each agent is based on published efficacy data for various titration strategies.

Δ This is not a complete list of adverse effects. For additional information, refer to UpToDate content on treatment of Cushing syndrome and individual drug monographs included with UpToDate.

◊ Drug interactions should be carefully considered prior to beginning any treatment regimen and can be assessed using the drug interactions program included with UpToDate.

§ Refer to UpToDate content on medical therapy of hypercortisolism for discussion of management including replacement glucocorticoid therapy.

¥ Mitotane dosing in this table is for hypercortisolemia in Cushing syndrome (eg, Cushing disease or ectopic ACTH secretion); higher doses may be used for adrenocortical carcinoma.

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Agents used for the medical treatment of Cushing syndrome