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About Cushing's Syndrome

Cushing's syndrome is a rare and debilitating endocrine disorder caused by prolonged exposure to elevated levels of endogenous or exogenous glucocorticoids (hypercortisolism).1

Normal production of cortisol1

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

  • Cortisol production begins with the release of corticotropin-releasing hormone (CRH) from the hypothalamus1
  • CRH stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland1
  • ACTH is carried by the blood down to the adrenal cortex, where it triggers the release of cortisol1,3
  • Cortisol is produced by the adrenal gland in the zona fasciculata, the second of 3 layers comprising the outer adrenal cortex3,4
  • Once produced, cortisol binds to the glucocorticoid receptor in the cytoplasm. This binding is responsible for most of cortisol's effects because only a small fraction of free cortisol is thought to be biologically active4
Chart Image

Adapted from Tritos NA, et al. Nat Rev Endocrinol.5

Causes of Cushing's syndrome

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 (Cushing's disease)

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

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

Adrenal tumors

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

Prevalence

The annual incidence of Cushing's syndrome in the U.S. is estimated to be 13 cases per 1 million individuals.8

  • Peak incidence occurs between the ages of 20 and 50 years1

In Cushing's disease, persistence/recurrence after transsphenoidal surgery is common

  • Pituitary surgery fails to achieve remission in up to 30% of patients with Cushing's disease5
  • Of those who do achieve remission through surgery, 26% experience recurrence within 5 years9
Chart Image

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

Excess cortisol affects multiple tissues and body systems, causing1,2,8,10:

  • Glucose intolerance or type 2 diabetes mellitus
  • Central obesity
  • Depression
  • Cognitive dysfunction
  • Cushingoid appearance
  • Skin changes (acne, hirsutism, striae)
  • Severe fatigue
  • Weak muscles

Glucose intolerance or type 2 diabetes mellitus occurs in the majority of patients with Cushing's syndrome.10

  • Males and females are equally affected by abnormal glucose metabolism in Cushing's syndrome10
    • In patients with Cushing's syndrome, hyperglycemia occurs independent of obesity10

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.

INDICATIONS AND USAGE

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.

Important Limitations of Use

Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing's syndrome.

IMPORTANT SAFETY INFORMATION

WARNING: TERMINATION OF PREGNANCY

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 nonhormonal 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.

DOSAGE AND ADMINISTRATION

Administer once daily orally with a meal. The recommended starting dose is 300 mg once daily. Renal impairment: Do not exceed 600 mg once daily. Mild-to-moderate hepatic impairment: Do not exceed 600 mg once daily. Do not use in severe hepatic impairment. Based on clinical response and tolerability, the dose may be increased in 300-mg increments to a maximum of 1200 mg once daily. Do not exceed 20 mg/kg per day.

Concomitant use of Korlym with a strong CYP3A inhibitor resulted in a 38% increase in mean plasma concentration of mifepristone. For patients already being treated with a strong CYP3A inhibitor, start with a Korlym dose of 300 mg per day and titrate to a maximum of 600 mg per day if clinically indicated. When a strong CYP3A inhibitor is administered to patients already receiving Korlym, adjust the dose as follows: For patients receiving a daily dose of 600 mg, reduce the daily dose to 300 mg. Titrate to a maximum of 600 mg per day if clinically indicated. For patients receiving a daily dose of either 900 mg or 1200 mg, reduce the daily dose to 600 mg.

CONTRAINDICATIONS

Pregnancy; use of simvastatin or lovastatin and CYP3A substrates with narrow therapeutic range; concurrent long-term corticosteroid use; women with history of unexplained vaginal bleeding; women with endometrial hyperplasia with atypia or endometrial carcinoma.

WARNINGS AND PRECAUTIONS

Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.

Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment.

Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if the patient also has a hemorrhagic disorder or is on anticoagulant therapy.

QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.

Use of Strong CYP3A Inhibitors: Concomitant use increases mifepristone plasma levels. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary and do not exceed a Korlym dose of 600 mg.

ADVERSE REACTIONS

Most common adverse reactions in Cushing's syndrome (≥20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

DRUG INTERACTIONS

Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym.

CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Adjust Korlym dose as described in Dosage and Administration. Use only when necessary, and do not exceed a Korlym dose of 600 mg.

CYP3A inducers: Do not use Korlym with CYP3A inducers.

Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym.

Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz.

Hormonal contraceptives: Do not use with Korlym.

USE IN SPECIFIC POPULATIONS

Nursing mothers: Discontinue drug or discontinue nursing.

Please see accompanying full Prescribing Information and Medication Guide.