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

Laparoscopic Bilateral Transperitoneal Adrenalectomy For Cushing Syndrome

Surgical Laparoscopy, Endoscopy & Percutaneous Techniques, 07/16/2013  Clinical Article

Aggarwal S et al. –

Laparoscopic adrenalectomy is well established for treatment of adrenal lesions. However, bilateral adrenalectomy for Cushing syndrome is a challenging and time–consuming operation.

The authors report their experience of laparoscopic bilateral adrenalectomy for this disease in 19 patients. Laparoscopic bilateral adrenalectomy for Cushing syndrome is feasible and safe. It confers all the advantages of minimally invasive approach such as less postoperative pain, shorter hospitalization, lesser wound complications, and faster recovery.

The advantages of the laparoscopic approach have led to an earlier referral for bilateral adrenalectomy by endocrinologist in patients with failed pituitary surgery.

This article is available on PubMed

Cushing’s Syndrome is Hazardous to Your Health

People with Cushing’s syndrome, even when treated, have higher morbidity and mortality rates that comparable controls. That is the conclusion of a new study published in the June issue of the Journal of Clinical Endocrinology Metabolism. The study by Olaf Dekkers et al, examined data records from the Danish National Registry of Patients and the Danish Civil Registration System of 343 patients with benign Cushing’s syndrome of adrenal or pituitary origin (i.e., Cushing’s disease) and a matched population comparison cohort (n=34,300).  Due to the lengthy delay of many patients being diagnosed with Cushing’s syndrome, morbidity was investigated in the 3 years before diagnosis while  morbidity and mortality were assessed during complete follow-up after diagnosis and treatment.

The study found that mortality was twice as high in Cushing’s syndrome patients (HR 2.3, 95% CI 1.8-2.9) compared with controls over a mean follow-up period of 12.1 years. Furthermore, patients with Cushing’s syndrome were at increased risk for:

• venous thromboembolism (HR 2.6, 95% CI 1.5-4.7)
• myocardial infarction (HR 3.7, 95% CI 2.4-5.5)
• stroke (HR 2.0, 95% CI 1.3-3.2)
• peptic ulcers (HR 2.0, 95% CI 1.1-3.6)
• fractures (HR 1.4, 95% CI 1.0-1.9)
• infections (HR 4.9, 95% CI 3.7-6.4).

The study also found that this increased multimorbidity risk was present before diagnosis indicating that it was due to cortisol overproduction rather than treatment.

Many of the Cushing’s syndrome patients underwent surgery to remove the benign tumor. For this group, the investigators performed a sensitivity analysis of the  long-term mortality and cardiovascular risk in this  subgroup (n=186)  considered to be cured after operation (adrenal surgery and patients with pituitary surgery in combination with a diagnosis of hypopituitarism in the first 6 months after operation).  The risk estimates for mortality (HR 2.31, 95% CI 1.62-3.28), venous thromboembolism (HR 2.03, 95% CI 0.75-5.48), stroke (HR 1.91, 95% CI 0.90-4.05), and acute myocardial infarction (HR 4.38, 95% CI 2.31-8.28) were also increased in this subgroup one year after the operation.

The standard treatment for endogenous Cushing’s syndrome is surgery. This past year, Signifor (pasireotide) was approved for treatment of adults patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.  Cushing’s disease, which accounts for the majority of Cushing’s syndrome patients, is defined as the presence of an ACTH producing tumor on the pituitary grand. In the study by Dekker’s et al, the percentage of patients with Cushing’s disease is not known. We look forward to reexamination of this dataset in a few years following the introduction of more treatment options for Cushing’s disease as well as an analysis that explores the differences in mortality/morbidity rates in the different subsets of patients that make of Cushing’s syndrome (Cushing’s disease, ectopic Cushing’s syndrome, Exogenous Cyshing’s syndrome).

References

Dekkers OM, Horvath-Pujo, Jorgensen JOL, et al, Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 2013 98(6): 2277–2284. doi: 10.1210/jc.2012-3582

- See more at: http://www.raredr.com/medicine/articles/cushing%E2%80%99s-syndrome-hazardous-your-health-0

An Adrenal Crisis Survey

This Survey is to gather information for the Adrenal Insufficiency Awareness Organization's grant project to create educational materials for ER personnel. 

The survey is for those of you who have been to the ER during an impending or full blown Adrenal Crisis. (you may fill it out for a child or yourself) 

Your help is appreciated! 

At the end of the survey you will have the chance to enter for a chance to win an Adrenal Insufficiency Awareness Pin.

https://www.surveymonkey.com/s/ERcare

Adrenal Glands

Anatomy of the adrenal glands:

Adrenal glands, which are also called suprarenal glands, are small, triangular glands located on top of both kidneys. An adrenal gland is made of two parts: the outer region is called the adrenal cortex and the inner region is called the adrenal medulla.

Function of the adrenal glands:

The adrenal glands work interactively with the hypothalamus and pituitary gland in the following process:

• the hypothalamus produces corticotropin-releasing hormones, which stimulate the pituitary gland.
• the pituitary gland, in turn, produces corticotropin hormones, which stimulate the adrenal glands to produce corticosteroid hormones.

Both parts of the adrenal glands -- the adrenal cortex and the adrenal medulla -- perform very separate functions.

What is the adrenal cortex?

The adrenal cortex, the outer portion of the adrenal gland, secretes hormones that have an effect on the body's metabolism, on chemicals in the blood, and on certain body characteristics. The adrenal cortex secretes corticosteroids and other hormones directly into the bloodstream. The hormones produced by the adrenal cortex include:

• corticosteroid hormones
  • hydrocortisone hormone - this hormone, also known as cortisol, controls the body's use of fats, proteins, and carbohydrates.
  • corticosterone - this hormone, together with hydrocortisone hormones, suppresses inflammatory reactions in the body and also affects the immune system.
• aldosterone hormone - this hormone inhibits the level of sodium excreted into the urine, maintaining blood volume and blood pressure.
• androgenic steroids (androgen hormones) - these hormones have minimal effect on the development of male characteristics.

What is the adrenal medulla?

The adrenal medulla, the inner part of the adrenal gland, is not essential to life, but helps a person in coping with physical and emotional stress. The adrenal medulla secretes the following hormones:

• epinephrine (also called adrenaline) - this hormone increases the heart rate and force of heart contractions, facilitates blood flow to the muscles and brain, causes relaxation of smooth muscles, helps with conversion of glycogen to glucose in the liver, and other activities.
• norepinephrine (also called noradrenaline) - this hormone has little effect on smooth muscle, metabolic processes, and cardiac output, but has strong vasoconstrictive effects, thus increasing blood pressure.

From: University of Maryland Center for Diabetes and Endocrinology

Ask your Member of Congress to join the Rare Disease Congressional Caucus

Help us strengthen the rare disease community's voice on Capitol Hill!  Please take 3 minutes to ask your Member of Congress to join the Rare Disease Caucus at http://bit.ly/RareAlert.

It's easy - the Action Center has a draft letter that will automatically be sent to your Member of Congress - just put in your name and address & click send.  We also encourage you to personalize the letter to share information about your specific disease.  If your Congress Member is already on the Caucus, the letter will automatically populate as a thank you letter instead - these are just as important to send!

It can take up to 10 letters from constituents for a Member to respond so please share this Action Alert with your friends, family & colleagues.  Join our Facebook event & invite your friends:   http://on.fb.me/17Mlpjg 

The Rare Disease Congressional Caucus will help bring public and Congressional awareness to the unique needs of the rare disease community – patients, physicians, scientists, and industry, and create opportunities to address roadblocks in access to and development of crucial treatments.  The Caucus will give a permanent voice to the rare disease community on Capitol Hill.  Working together, we can find solutions that turn hope into treatments.

Multisystem Morbidity and Mortality in Cushings Syndrome: a Cohort Study

Journal of Clinical Endocrinology and Metabolism, 03/28/2013  Clinical Article

Dekkers O.M. et al.– To examine the risks for mortality, cardiovascular disease, fractures, peptic ulcers, and infections in CS patients before and after treatment.Cushing’s syndrome (CS) is associated with hypercoagulability, insulin resistance, hypertension, bone loss, and immunosuppression. To date, no adequately large cohort study has been performed to assess the multisystem effects of CS. It was concluded that despite the apparently benign character of the disease, CS is associated with clearly increased mortality and multisystem morbidity, even before diagnosis and treatment.

Methods

• The study used Cox–regression, and computed hazard ratios (HR) with 95% confidence intervals (95% CI).
• Morbidity was investigated in the three years before diagnosis; morbidity and mortality was assessed during complete follow–up after diagnosis and treatment.

Results

• 343 CS patients and 34,300 controls were included. Mortality was twice as high in CS patients (HR 2.3, 95%CI 1.8–2.9) compared with controls.
• Patients with CS were at increased risk for venous thromboembolism (HR 2.6, 95%CI 1.5–4.7), myocardial infarction (HR 3.7, 95%CI 2.4–5.5), stroke (HR 2.0, 95%CI 1.3–3.2), peptic ulcers (HR 2.0, 95%CI 1.1–3.6), fractures (HR 1.4, 95%CI 1.0–1.9), and infections (HR 4.9, 95%CI 3.7–6.4).
• This increased multi–morbidity risk was present before diagnosis. Mortality and risk of myocardial infarction remained elevated during long–term follow–up.
• Mortality and risks for AMI, VTE, stroke and infections were similarly increased in adrenal and pituitary CS.

From MDLinx

For Cushing's Awareness Challenge Bloggers

Cushie bloggers - who would like to share your post on April 8 (Cushing's Awareness Day) with our friends at Adrenal Insufficiency United, on their blog?

Also, they are interested in sharing others of our posts from April.  Please let me know if I have your permission to share your blog post(s) with them.  I won't without your permission.

Thanks!

Cushing's Awareness Blogging Challenge 2013

Do you blog? Want to get started?

Since April 8 is Cushing's Awareness Day, several people got their heads together to create the Second Annual Cushing's Awareness Blogging Challenge.

All you have to do is blog about something Cushing's related for the 30 days of April.

Robin designed this year's version of our "official logo" to put on your blogs.

 

 If your blog wants you to upload an image from your desktop, right-click on the image above and choose "save-as". Remember where you saved it to! 

 To link to the image with the yellow border, use this URL: http://www.cushings-help.com/images/challenge-2013b.jpg 

 To link to the image without a border, use this URL: http://www.cushings-help.com/images/challenge-2013nb.jpg 

 In all cases, the URL for the site is http://www.cushings-help.com 

Please let me know the URL to your blog in the comments area of this post or and I will list it on CushieBloggers ( http://cushie-blogger.blogspot.com/ ) 

The more people who participate, the more the word will get out about Cushing's. 

  Suggested topics - or add your own!

In what ways have Cushing's made you a better person?
What have you learned about the medical community since you have become sick?
If you had one chance to speak to an endocrinologist association meeting, what would you tell them about Cushing's patients?
What would you tell the friends and family of another Cushing's patient in order to garner more emotional support for your friend?
Challenges with Cushing's? How have you overcome challenges? Stuff like that.
I have Cushing's Disease....(personal synopsis)
How I found out I have Cushing's
What is Cushing's Disease/Syndrome? (Personal variation, i.e. adrenal or pituitary or ectopic, etc.)
My challenges with Cushing's
Overcoming challenges with Cushing's (could include any challenges)
If I could speak to an endocrinologist organization, I would tell them...
. What would I tell others trying to be diagnosed? What would I tell families of those who are sick with Cushing's?
Treatments I've gone through to try to be cured/treatments I may have to go through to be cured.
What will happen if I'm not cured?
I write about my health because...
10 Things I Couldn’t Live Without.
My Dream Day.
What I learned the hard way
Miracle Cure. (Write a news-style article on a miracle cure. What’s the cure? How do you get the cure? Be sure to include a disclaimer)
Health Madlib Poem. Go to http://languageisavirus.com/cgi-bin/madlibs.pl and fill in the parts of speech and the site will generate a poem for you.
The Things We Forget. Visit http://thingsweforget.blogspot.com/ and make your own version of a short memo reminder. Where would you post it?
Give yourself, your condition, or your health focus a mascot. Is it a real person? Fictional? Mythical being? Describe them. Bonus points if you provide a visual!
5 Challenges and 5 Small Victories.
The First Time I...
Make a word cloud or tree with a list of words that come to mind when you think about your blog, health, or interests. Use a thesaurus to make it branch more.
How much money have you spent on Cushing's, or, How did Cushing's impact your life financially?
Why do you think Cushing's may not be as rare as doctors believe?
What is your theory about what causes Cushing's?
How has Cushing's altered the trajectory of your life? What would you have done? Who would you have been?
What three things has Cushing's stolen from you? What do you miss the most? What can you do in your Cushing's life to still achieve any of those goals? What new goals did Cushing's bring to you?
How do you cope?
What do you do to improve your quality of life as you fight Cushing's?
Your thoughts...?

RARE Video Project

Global Genes | RARE Project would like your voice to be heard!

Share your home videos!

We are currently looking for your home videos that illustrate what life is like for rare disease patients and caregivers on this complex and often emotional journey.  This could be an assortment of moments that you’ve captured on your phone, a camera, or a digital recording device.  We want the key moments, the most beautiful, personal moments that represent not only the diseases, but you and your child(ren) as well.

A few examples of what we are looking for in these clips:

Births	In Pain	Overcoming
Birthdays	Sadness	Happiness
Hospital Visits	Loss	Laughter
Medicines	Struggle	Important Events
At Play	Tears	Family

Be creative, think outside the box.   Look for clips that are shot well, with nice light.  Give us variety!  Old footage, new footage, maybe even something your child has shot.  We want personal, private moments.  That is what will send the strongest message.

What are we going to do with this?

We are working with an award-winning filmmaking team to select submissions that will be compiled together to create a visual storyline of the years of your ongoing journey.  This is your chance to share the moments that you see and experience with a global audience.

This is your moment to be heard.

More information at http://globalgenes.org/rare-video-submission-form/