Cushing's syndrome is a rare and debilitating endocrine disorder caused by prolonged exposure to elevated levels of endogenous or exogenous glucocorticoids (hypercortisolism).1
Adapted from the National Institute of Diabetes and Digestive and Kidney Diseases.
The potent metabolic effects of excess cortisol influence multiple tissues and body systems and cause high blood pressure, decreasing immune response, and a loss of connective tissue in the skin.2
Adapted from Tritos NA, et al. Nat Rev Endocrinol.5
Endogenous Cushing's syndrome is most commonly caused by an ACTH-secreting pituitary adenoma. Other causes of endogenous Cushing's syndrome include adrenal tumors, and ectopic ACTH syndrome.1
Pituitary adenomas, which are benign tumors that secrete extra ACTH, cause the adrenal glands to overproduce cortisol. Seventy percent of patients with endogenous Cushing's syndrome are affected by these adenomas.1,6 Most people with this disorder (called Cushing's disease) have a single adenoma.1
Ectopic ACTH syndrome occurs when cancerous tumors (or, less often, benign tumors) arise outside the pituitary and produce excess ACTH. This ACTH, in turn, causes the adrenal glands to produce more cortisol. The most common forms of ACTH-producing tumors are carcinoid tumors and small cell lung cancer, which accounts for about 13% of all lung cancer cases.7 Other less common types of ACTH-producing tumors are thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid.1
In rare cases, Cushing's syndrome is caused by an abnormality of the adrenal glands, most often an adrenal tumor. Most cases involve adrenal adenomas, which release excess cortisol into the blood.1 With adrenocortical carcinomas, cancer cells secrete excess levels of several adrenocortical hormones, including cortisol and adrenal androgens. Adrenocortical carcinomas usually cause very high hormone levels and rapid development of symptoms.1
The annual incidence of Cushing's syndrome in the U.S. is estimated to be 13 cases per 1 million individuals.8
Adapted from Patil CG, et al. Clin Endocrinol Metab.9
Data from a retrospective review of 215 subjects with Cushing's disease who underwent initial transsphenoidal surgery for resection of a presumed pituitary microadenoma from 1992-2006.9
Recurrence was defined as an elevated 24-hour urine-free cortisol level with clinical symptoms consistent with Cushing's disease.9
1. National Institute of Diabetes and Digestive and Kidney Diseases: National Endocrine and Metabolic Diseases Information Service. Cushing's syndrome. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx. Accessed April 10, 2014.
2. Nussey S, Whitehead S. Endocrinology: An Integrated Approach. Oxford, UK: BIOS Scientific Publishers; 2001. Available at: http://www.ncbi.nlm.nih.gov/books/NBK26?report=printable. Accessed January 27, 2012.
3. DeSimone EM II, Morales PC, Vetter JM. Management of Cushing's syndrome. http://www.uspharmacist.com/content/d/featured%20articles/c/21057/. Accessed January 27, 2012.
4. Bowen R. Glucocorticoids. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/adrenal/gluco.html. Accessed January 27, 2012.
5. Tritos NA, Biller BMK, Swearingen B. Management of Cushing disease. Nat Rev Endocrinol. 2011;7(5):279-289.
6. Nieman LK, Ilias I. Evaluation and treatment of Cushing's syndrome. J Amer Med. 2005;118(12):1340-1346.
7. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539-4544.
8. Adler GK. Cushing syndrome. http://emedicine.medscape.com/article/117365-overview. Accessed February 23, 2012.
9. Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing's disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93(2):358-362.
10. Mazziotti G, Gazzaruso C, Giustina A. Diabetes in Cushing syndrome: basic and clinical aspects. Trend Endocrinol Metabol. 2011;22(12):499-506.
Korlym (mifepristone) is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.
Korlym should not be used in the treatment of patients with type 2 diabetes unless it is secondary to Cushing's syndrome.
Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym and prevented during treatment and for one month after stopping treatment by the use of a non-hormonal medically acceptable method of contraception unless the patient has had a surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be excluded if treatment is interrupted for more than 14 days in females of reproductive potential.
Korlym is contraindicated in women who are pregnant. Pregnancy must be excluded before the initiation of treatment with Korlym or if treatment is interrupted for more than 14 days in females of reproductive potential. Nonhormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential.
Korlym is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events.
Korlym is contraindicated in patients who require concomitant treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because Korlym antagonizes the effect of glucocorticoids.
Korlym is contraindicated in women with a history of unexplained vaginal bleeding and women with endometrial hyperplasia with atypia or endometrial carcinoma.
Korlym is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of the product components.
Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels remain elevated and may even increase during treatment with Korlym, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving Korlym. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue treatment with Korlym immediately and administer glucocorticoids without delay. High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours). Treatment with Korlym at a lower dose can be resumed after resolution of adrenal insufficiency. Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).
In a study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects during treatment with Korlym. Hypokalemia should be corrected prior to initiating Korlym. During Korlym administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of Korlym and periodically thereafter. Hypokalemia can occur at any time during Korlym treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation, consider adding mineralocorticoid antagonists.
Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding. Korlym should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during Korlym treatment should be referred to a gynecologist for further evaluation.
Mifepristone and its metabolites block IKr. Korlym prolongs the QTc interval in a dose-related manner. There is little or no experience with high exposure, concomitant dosing with other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. To minimize risk, the lowest effective dose should always be used.
Use of Korlym in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as Korlym antagonizes the desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic corticosteroid therapy is life-saving (e.g., immunosuppression in organ transplantation), Korlym is contraindicated.
Korlym should be used with extreme caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Mifepristone should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 300 mg per day.
Patients with endogenous Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during Korlym treatment. Patients may present with respiratory distress shortly after initiation of Korlym. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.
Korlym does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying heart conditions including heart failure and coronary vascular disease.
The most frequently reported adverse reactions (reported in ≥20% of patients, regardless of relationship to Korlym) were nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, and endometrial hypertrophy. Drug-related adverse events resulted in dose interruption or reduction in study drug in 40% of patients.
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