FDA Puts Strict Limits on Oral Ketoconazole Use

By John Gever, Deputy Managing Editor, MedPage Today

SILVER SPRING, Md. -- Oral ketoconazole (Nizoral) should never be used as first-line therapy for any type of fungal infection because of the risk of liver toxicity and interactions with other drugs, the FDA said Friday.

The agency ordered a series of label changes and a new medication guide for patients that emphasize the risks, which also include adrenal insufficiency. It noted that the restrictions apply only to the oral formulation, not topical versions.

Late Thursday, the chief advisory body for the FDA's European counterpart went further. The EU's Committee on Medicinal Products for Human Use (CHMP) recommended that member nations pull oral ketoconazole from their markets entirely.

Both the FDA and the CHMP cited studies indicating high risks of severe, acute liver injury in patients taking the drug. Studies using the FDA's adverse event reporting system and a similar database in the U.K. indicated that liver toxicity was more common with oral ketoconazole than with other anti-fungals in the azole class.

The FDA also said that oral ketoconazole "is one of the most potent inhibitors" of the CYP3A4 enzyme. This effect can lead to sometimes life-threatening interactions with other drugs metabolized by CYP3A4, and also to adrenal insufficiency, since the enzyme also catalyzes release of adrenal steroid hormones.

"This accounts for clinically important endocrinologic abnormalities observed in some patients (particularly when the drug is administered at high dosages), including gynecomastia in men and menstrual irregularities in women," the FDA said.

The only indication for oral ketoconazole still supported by the FDA is for use in life-threatening mycoses in patients who cannot tolerate other anti-fungal medications or when such medications are unavailable.

In such instances, the FDA said, physicians should assess liver function before starting the drug. It is contraindicated in patients with pre-existing liver disease, and patients should be instructed not to drink alcohol or use other potentially hepatotoxic drugs.

Adrenal function should also be monitored in patients using the drug.

The CHMP also indicated the topical formulations of ketoconazole should stay on the market, but it found no basis for keeping the oral form available for any purpose.

"Taking into account the increased rate of liver injury and the availability of alternative anti-fungal treatments, the CHMP concluded that the benefits did not outweigh the risks," the panel indicated in a statement.

It recommended that physicians stop prescribing oral ketoconazole and that they should review alternatives in patients currently receiving the drug. The committee also said that patients now taking oral ketoconazole "make a non-urgent appointment" with their physicians to discuss their treatment.

From MedPage Today

Use of ketoconazole in the treatment of Cushing's syndrome

An older, but still useful, abstract:

J Clin Endocrinol Metab. 1986 Dec;63(6):1365-71.

 

Loli P, Berselli ME, Tagliaferri M.

Abstract

The therapeutic value of ketoconazole for long term treatment of patients with Cushing's syndrome was studied. Seven patients with Cushing's disease and one with an adrenal adenoma received 600-800 mg/day ketoconazole for 3-13 months. Plasma ACTH, cortisol, and dehydroepiandrosterone sulfate levels and urinary cortisol, 17-ketosteroid, and tetrahydro-11-deoxycortisol excretion were determined periodically during the treatment period.

Plasma ACTH and cortisol responses to CRH stimulation were determined before and during treatment. Rapid and subsequently persistent clinical improvement occurred in each patient; plasma dehydroepiandrosterone sulfate and urinary 17-ketosteroid and cortisol excretion decreased soon after the initiation of treatment, subsequently remaining normal or nearly so throughout the treatment period. Urinary tetrahydro-11-deoxycortisol excretion increased significantly. Plasma cortisol levels decreased. Plasma ACTH levels did not change, and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another.

The seven patients tested recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment. Ketoconazole is effective for long term control of hypercortisolism of either pituitary or adrenal origin. Its effect appears to be mediated by inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion in patients with Cushing's disease.

From http://www.ncbi.nlm.nih.gov/pubmed/3023421

 

Surgical Versus Medical Treatment for Cushing Disease, the New and the Old

Surgical Versus Medical Treatment for Cushing Disease the New and the Old

Cortendo Receives Positive Orphan Drug Opinion from EMA for NormoCort for Cushing’s Disease

Cortendo AB with support from their preclinical development partner, PharmaDirections, Inc. received a positive opinion from the European Medicines Agency for NormoCort.

Radnor, PA (PRWEB) June 26, 2012

Cortendo AB [ticker: CORT on the Norwegian NOTC-A], a biopharmaceutical Corporation focused on the development of new therapies in the field of Metabolic Diseases, obtained a positive opinion by the European Medicines Agency's Committee for Orphan Medicinal Products, on its application for orphan drug designation for NormoCort (COR-003) for the treatment of hypercortisolism (Cushing’s Syndrome). The positive opinion of the COMP for NormoCort has now been forwarded to the EU commission for final approval and publication in the EU community register. With orphan drug designation granted in the US by the FDA in March and now with this positive opinion from the EU’s COMP, Cortendo is well positioned to move NormoCort into pivotal global clinical trials in Cushing’s Syndrome.

Cortendo is a biopharmaceutical company that relies in part on quality consultants and CRO’s to support the research and development of its pipeline. For the past year, Cortendo has contracted with PharmaDirections for a number of key services ranging from CMC to US and European Regulatory support. PharmaDirections’ regulatory services have ranged from the successful preparation and support to orphan drug designation applications in both the US and Europe to support with both IND and CTA preparation. “Cortendo has appreciated the high quality of support particularly in the areas of regulatory, CMC, and project management services offered by PharmaDirections”, said Dr. Ted Koziol, COO of Cortendo.

“Our Cortendo relationship is a great example of a virtual company using outsourced resources to their maximum advantage” said Dr. Richard Soltero, President of PharmaDirections.

About Cortendo:

Cortendo is a pioneer in the field of cortisol inhibition. The development of the lead drug candidate NormoCort (COR-003), the 2S,4R-enantiomer of ketoconazole, has been directed to Cushing’s Syndrome. The company’s strategy is to focus its resources to opportunities where the path to commercialization or partnership is clear and relatively near-term. Strategically, Cortendo’s business model is to commercialize relevant opportunities in the United States while partnering its assets ex-US. Backed by a highly experienced leadership team Cortendo has plans to continue to implement its pipeline expansion efforts in osteoarthritis and diabetes, as well as other near term revenue opportunities.

About PharmaDirections:

PharmaDirections, Inc. provides pharmaceutical consulting and project management services with a focus on preclinical development, formulation development and CMC, and regulatory affairs. The company was founded in 2003 and is based in Cary, North Carolina.

From PRWeb

Dr. Theodore Friedman Returns to Answer Our Questions

Have questions about the new Korlym? How about Korlym vs ketoconazole? About medical vs surgical treatment for Cushing's.

Ask Dr. Theodore Friedman.

Theodore C. Friedman, M.D., Ph.D. has opened a private practice, specializing in treating patients with adrenal, pituitary, thyroid and fatigue disorders. Dr. Friedman has privileges at Cedars-Sinai Medical Center and Martin Luther King Medical Center. His practice includes detecting and treating hormone imbalances, including hormone replacement therapy. Dr. Friedman is also an expert in diagnosing and treating pituitary disorders, including Cushings disease and syndrome.

Dr. Friedman's career reflects his ongoing quest to better understand and treat endocrine problems. With both medical and research doctoral degrees, he has conducted studies and cared for patients at some of the country's most prestigious institutions, including the University of Michigan, the National Institutes of Health, Cedars-Sinai Medical Center, and UCLA's Charles Drew University of Medicine and Science.

Read Dr. Friedman's First Guest Chat, November 11, 2003. 
Read Dr. Friedman's Second Guest Chat, March 2, 2004. 

Listen to Dr. Friedman First Live Voice Interview, January 29, 2009. 
Listen to Dr. Friedman Second Live Voice Interview, March 12, 2009. 
Listen to Dr. Friedman Third Live Voice Interview, February 13, 2011.

 

Listen live at http://www.blogtalkradio.com/cushingshelp/2012/03/13/questions-about-medical-therapies-for-cushings

Call in to ask your question at 

(646) 200-0162

This interview will be archived afterwards at the same link and on iTunes Cushie Podcasts 

Cushing's Disease Treatment

A 19-year-old woman was referred to Dr. Adriana Ioachimescu for evaluation following an abnormal 1-mg dexamethasone suppression test. She started to experience weight gain, hirsutism and oligomenorrhea at age 16. At that time, she was diagnosed with type 2 diabetes, which was not controlled, despite oral medications and 200 units of insulin daily. A few months before her initial visit to the Emory Pituitary Center, the patient experienced a hip fracture and required surgery. On examination, it was discovered that she had typical Cushing’s stigmata, severe proximal myopathy and depression. She was unable to walk without assistance.

Laboratory testing results were remarkable for hypokalemia, elevated serum cortisol and adrenocorticotropic hormone (ACTH) levels, and elevated bedtime salivary cortisol (15 times above normal). A high-dose dexamethasone suppression test was equivocal. Magnetic resonance imaging (MRI) of the pituitary gland showed no abnormalities. The patient was scheduled for a corticotropin-releasing hormone (CRH) test; however, she was unable to keep the appointment due to MRSA sepsis/perineal cellulitis.

Dr. Ioachimescu started the patient on ketoconazole, which she took for three months, along with multiple courses of antibiotics, during which her diabetes and hypokalemia improved. Once the MRSA infection cleared, she underwent inferior petrosal sinus sampling at Emory University Hospital, which showed a 5:1 central-to-periphery gradient on the right side. A computed tomography (CT) scan of the neck, chest, abdomen and pelvis and an octreoscan did not identify a tumor.

Dr. Oyesiku performed 3-D transsphenoidal endoscopic surgery to remove the tumor causing Cushing’s disease, and her postoperative cortisol on postoperative day three was low at 1.4 mcg/dL. The patient did not experience postoperative endocrine or neurosurgical complications. She required hydrocortisone postoperatively and lost 19 kg in the first three months following the procedure. Her appearance, mood and muscle strength improved significantly.

This case illustrates challenges related to diagnosis of Cushing’s disease in the setting of multiple complications. An accurate diagnosis was made only after inferior petrosal sinus sampling. Treatment with transsphenoidal surgery was successful, despite a lack of tumor identification by preoperative imaging. At the Emory Pituitary Center, Cushing’s disease has a 92% rate of remission at three months following surgery. These statistics are based on the electronic database review of almost 70 patients with Cushing’s disease operated on by Dr. Oyesiku over a period of 15 years. Based on Dr. Ioachimescu’s research, cortisol levels lower than 5 mcg/dL in the first two postoperative days are predictive of surgical success, but do not correlate with recurrence rate.

From http://emoryheartfailure.com/neurosciences/case-studies/cushings-treatment.html