By: Alexandra Alleva, Pharm.D. Candidate c/o 2013
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On February 17, 2012, the US Food and Drug Administration (FDA) approved the first medication indicated specifically for patients with endogenous Cushing’s syndrome, a hormone disorder characterized by elevated blood levels of cortisol. Mifepristone (Korlym®) is for the treatment of glucose intolerance and Type 2 Diabetes Mellitus resulting from hypercortisolism. Such patients experience hyperglycemia through the glucocorticoid-mediated activation of gluconeogenesis. Prior to this, only a few drugs (e.g. ketoconazole) were used off-label to combat increased cortisol production. Korlym® is only for Cushing’s patients who have developed glucose intolerance secondary to elevated cortisol. They must also either be non-candidates for surgery or have failed surgery in the past, as well as have recurring symptoms.
Cushing’s syndrome, primarily caused by adrenal or pituitary tumors, can bring about serious consequences with long-term exposure to increased plasma cortisol. The FDA classified Korlym® as an orphan drug, which means the medication is targeted toward treating rarer diseases for which there is not much incentive to develop new therapies. As a result, the manufacturer, Corcept, retains marketing exclusivity until February 2019.
Pharmacologically, mifepristone acts as a cortisol receptor blocker at glucocorticoid type II (GR-II) receptors. This limits the gluconeogenic effects that would otherwise be troublesome for those with Cushing’s syndrome. At low doses, mifepristone is a progesterone antagonist, and at increased doses, it blocks the GR-II receptors with high affinity. It displays little or no affinity for estrogen, muscarinic, or GR-I mineralocorticoid receptors.
Mifepristone is also an abortifacient, particularly due to its known progesterone antagonism. Accordingly, the drug carries a black box warning for termination of pregnancy and is designated category X. Physicians should only prescribe non-hormonal contraceptives during treatment because Korlym® will likely interfere with hormonal contraceptives.
Mifepristone, an inhibitor of CYP3A isoenzymes, may also significantly affect levels of other drugs. There are also documented interactions with CYP2C8, 2C9, and 2B6 substrates. Patients should not take mifepristone in combination with lovastatin, simvastatin, CYP3A substrates with narrow therapeutic indexes, or corticosteroids due to this antagonism. Women with a prior history of endometrial hyperplasia are also of great concern, since the drug encourages unopposed proliferation of the endometrium (through its hormonal effects).
Common side effects include nausea, fatigue, headache, edema, and dizziness. Adverse effects include QT interval prolongation, hypokalemia, and bleeding. Due to the endocrinologic nature of Cushing’s syndrome, patients need close monitoring for any signs of adrenal insufficiency or other aforementioned complications.
The clinical trial supporting the drug’s approval was an uncontrolled, open-label, multi-center, and 24-week phase III study involving 50 patients. A significant number of patients experienced relief and reduction in glucose tolerance tests from baseline, as well as HbA1C levels. Another noted effect was a reduction in anti-diabetic medications needed to maintain glycemic control.
Korlym® will be available as a 300 mg tablet, taken once daily. It may be titrated in 300 mg increments, depending on symptom improvements, to a maximum of 1200 mg per day. Dosing adjustments are necessary for those with renal and hepatic impairment. Since there is no clear understanding of safety in several patient populations, physicians should exercise caution when prescribing the medication.
By May 1, 2012, specialty pharmacies will be able to process prescriptions for Korlym®. SPARK (Support Program for Access and Reimbursement for Korlym®) will be utilized by patients and their providers to coordinate the distribution. Korlym® is now a substantiated drug that patients suffering from Cushing’s can resort to when prior treatments fail or surgery is not viable.
SOURCES:
- FDA Approves Korlym for Patients with Endogenous Cushing’s Syndrome. FDA, 17 Feb. 2012. Web. Mar. 2012. <http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm292462.htm>.
- Korlym. Corcept Therapeutics Incorporated, Feb. 2012. Web. Mar. 2012. <https://www.korlym.com>.
- Loli P, Berselli ME, Tagliaferri M. Use of ketoconazole in the treatment of Cushing’s syndrome. J Clin Endocrinol Metab. 1986 Dec;63(6):1365-71.
