FDA Puts Strict Limits on Oral Ketoconazole Use

Posted on August 3, 2013 by MaryO

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

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Long-term mifepristone associated with endometrial thickening, bleeding

Posted on August 2, 2013 by MaryO

SAN FRANCISCO – Long-term mifepristone therapy for Cushing’s syndrome was associated with endometrial thickening, with some women showing histologic changes consistent with progesterone receptor modulator–associated endometrial changes, in two studies of a total of 35 patients.

The women received 300-1,200 mg/day of mifepristone in the 24-week open-label Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) and in an extension of the study in 18 patients who continued for a median of 27 months (range, 14-43 months).

Mifeprex is used, with misoprostol, to end an early pregnancy (within 49 days of the start of a woman’s last menstrual period), according to the Food and Drug Administration’s website. The treatment of Cushing’s syndrome is an off-label use.

Transvaginal ultrasounds in 26 women at baseline and 27 women after the start of the study showed that mifepristone use was associated with endometrial thickening, especially in premenopausal women. The endometrium thickened by more than 5 mm in 8 of 26 premenopausal women (31%) and in two of nine postmenopausal women (22%), with thickening of more than 10 mm in 4 premenopausal women (15%) and one postmenopausal woman (11%), Dr. Ty Carroll reported.

Four (22%) of the 18 women in the extension study who’d been on mifepristone for 14 or more weeks and who had endometrial thickening greater than 20 mm developed clinically relevant endometrial bleeding and underwent hysterectomy (three patients) or dilation and curettage. The endometrial thickening ranged from 25 to 55 mm in these women, who remained on mifepristone therapy throughout the studies, Dr. Carroll and his associates reported in a featured poster presentation at the annual meeting of the Endocrine Society.

“Gynecologic consultation may be required in patients with persistent endometrial bleeding,” said Dr. Carroll of the Medical College of Wisconsin, Milwaukee.

Vaginal bleeding of any kind occurred in 10 premenopausal women (38.5%) and two postmenopausal patients (7%). Three premenopausal women reported minor bleeding upon starting mifepristone, and one premenopausal woman reported minor bleeding after stopping mifepristone. Two premenopausal and two postmenopausal women reported intermittent, self-limited spotting or bleeding during treatment.

Bleeding did not always occur following endometrial thickening. Three patients with endometrial thickening greater than 20 mm after 6 months reported no bleeding.

Mifepristone use was not associated with precancerous endometrial lesions. In 33 endometrial biopsies obtained from 15 patients (11 premenopausal and 4 postmenopausal women), 31 biopsies (94%) had benign histology with variable findings of inactive, atrophic, disordered, or mixed-pattern endometrium, and 18 biopsies (56%) showed findings of progesterone receptor modulator–associated endometrial changes. Simple hyperplasia in one patient could not be confirmed on a repeat biopsy, and complex atypical endometrial hyperplasia in a second patient was thought to have existed prior to the study, Dr. Carroll reported. No patients showed evidence of endometrial carcinoma.

Previous studies have reported progesterone receptor modulator–associated endometrial changes from the use of mifepristone, a competitive progesterone receptor antagonist, in doses of 5-200 mg/day that are not associated with glucocorticoid receptor antagonism.

In the current study, median endometrial thickness for the premenopausal women was 5 mm at baseline and 11 mm at 6 months, and for postmenopausal women, was 3 mm at baseline and 6.4 mm at 6 months. The gain was statistically significant for premenopausal but not postmenopausal women. Endometrial thickness continued to increase in the extension study.

The SEISMIC study included adult females with endogenous Cushing’s syndrome and type 2 diabetes or impaired glucose function and/or hypertension. It excluded premenopausal women with an endometrial thickness greater than 20 mm, postmenopausal women with an endometrial thickness greater than 5 mm, patients with ovarian cysts with diameters measuring greater than 5 cm (premenopausal) or 2 cm (postmenopausal), or women with free fluid pockets greater than 4 cm. Premenopausal participants had a mean age of 39 years, and postmenopausal participants had a mean age of 57 years.

Dr. Carroll has been a speaker and researcher for Corcept Therapeutics, which markets mifepristone. His coinvestigators were employees, contractors, or consultants for Corcept, which provided some funding for the study.

By: SHERRY BOSCHERT, Clinical Endocrinology News Digital Network

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

From Clinical Endocrinology News

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Cushing Disease: A Multidisciplinary Treatment Update

Posted on June 30, 2013 by MaryO

Share this info with your endo in case he/she missed it!

This activity is intended for endocrinologists, primary care physicians, nurses, nurse practitioners, and pharmacists.

The goal of this activity is to review the diagnosis and treatment of Cushing disease from a multidisciplinary perspective.

Upon completion of this activity, participants will be able to:

  1. Outline the rationale for a multidisciplinary approach to the diagnosis and treatment of patients with Cushing disease
  2. Review the safety and efficacy of current management strategies for patients with Cushing disease
  3. Describe the diagnostic workup for Cushing disease and the reasons why timely diagnosis and treatment are important

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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Laurence Katznelson, MD

Professor of Medicine and Neurosurgery, Stanford University; Medical Director, Pituitary Center, Stanford Hospital and Clinics, Stanford, California

Disclosure: Laurence Katznelson, MD, has disclosed the following relevant financial relationships:
Received grants for clinical research from: Corcept Therapeutics Inc.; Novartis Pharmaceuticals Corporation

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Brooke Swearingen, MD

Associate Professor of Neurosurgery, Harvard Medical School; Associate Visiting Neurosurgeon, Massachusetts General Hospital, Boston, Massachusetts

Disclosure: Brooke Swearingen, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Novartis Pharmaceuticals Corporation
Owns stock, stock options or bonds from: Novartis Pharmaceuticals Corporation; Pfizer Inc; Amgen Inc; Roche

Dr Swearingen does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Swearingen does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Nicholas Tritos, MD

Assistant Professor of Medicine, Harvard Medical School; Staff, Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts

Disclosure: Nicholas Tritos, MD, has disclosed the following relevant financial relationships:
Served as an advisor or consultant for: Corcept Therapeutics Inc; Pfizer Inc
Received grants for clinical research from: Pfizer Inc; Ipsen

Dr Tritos does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Tritos does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Susan Cornell, PharmD, CDE

Associate Professor, Pharmacy Practice, Midwestern University-Chicago, Downers Grove, Illinois; Clinical Pharmacist/Certified Diabetes Educator, DuPage Community Clinic, Wheaton, Illinois

Disclosure: Susan Cornell, PharmD, CDE, has disclosed the following relevant relationships:
Served as a speaker or member of a speakers bureau for: Johnson & Johnson Diabetes Institute

Dr Cornell does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Cornell does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Rita Pach, RN, MSN

Nurse, Johns Hopkins Pituitary Center, Baltimore, Maryland

Participation by Mrs Pach in the development of this product does not constitute or imply endorsement by the Johns Hopkins University or the Johns Hopkins Hospital and Health System.
Disclosure: Rita Pach, RN, has disclosed no relevant financial relationships.

Mrs Pach does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Mrs Pach does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Kristin M. Richardson

Group Scientific Director, Medscape, LLC

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David Modrak, PhD

Freelance editor, Montville, New Jersey

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Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Laurie E. Scudder, DNP, NP

Nurse Planner, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC

Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

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This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test.

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Continue to activity: http://www.medscape.org/viewarticle/806559

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