Dissolving Hydrocortisone Tablets for CAH May Lead to Higher Dosing, Cushing’s

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Dissolving hydrocortisone tablets in water for multiple daily dosing to treat congenital adrenal hyperplasia (CAH) in children may result in higher-than-intended dosing and exogenous Cushing’s syndrome — a form of the disease that occurs in those taking steroid hormones — a case report shows.

The case highlights the health risks of manipulating and dividing currently available hydrocortisone tablets to allow the delivery of smaller doses to young children, the researchers noted.

It also underscores the need for suitable commercially available pediatric formulations, they said.

Titled “Manipulation of Hydrocortisone Tablets Leads to Iatrogenic Cushing Syndrome in a 6-Year-Old Girl With CAH,” the case study was published in the Journal of the Endocrine Society.

Exogenous, or drug-related, Cushing’s syndrome is caused by abnormally high levels of the hormone cortisol in the body following prolonged exposure to cortisol-like steroid medications, such as hydrocortisone.

Hydrocortisone tablets are commonly prescribed for people with adrenal glands deficiency. Located above the kidneys, the adrenal glands are responsible for producing several hormones, including cortisol.

CAH is a rare inherited disorder caused by an enzymatic deficiency that impairs the production of one or more of the adrenal hormones early in life. One of the most common forms of the disease, called salt-wasting CAH, is characterized by a deficient production of not only cortisol, but also aldosterone — a hormone that controls salt and water retention.

Currently available hydrocortisone formulations, with the lowest doses being 5 mg and 10 mg, are not well-suited for the dosing needs of infants and young children with CAH. For such patients, treatment usually involves three to four doses of less than 2.5 mg over a day.

“This lack of availability has led physicians to recommend dividing hydrocortisone 5-mg tablets into 4 to 6 pieces, compounding capsules or hydrocortisone suspension, or crushing 5- or 10-mg tablets in 5 or 10 mL of water,” the researchers wrote.

However, several studies have shown that both splitting scored hydrocortisone tablets or dissolving them in water, followed by withdrawal of the required volume, are associated with dose variability, which can result in lower- or higher-than-intended dosing.

On the other hand, a previous study has shown that alcohol-free compounded liquid formulations of either 1 and 2 mg/mL were stable and effective in treating children with CAH. These formulations, however, are not commercially available.

Such types of formulations currently are only available through compounding pharmacies, which can make prescribed medications meet the needs of specific patients. However, “it is important that the prescribing physician is familiar with the reliability of their local compounding pharmacy,” the researchers wrote.

Now, researchers at the University of Minnesota reported the case of a 6-year-old girl with salt-wasting CAH who developed Cushing’s syndrome following the administration of higher-than-indented doses of hydrocortisone by dissolving tablets in water.

Diagnosed with salt-wasting CAH shortly after birth, she had begun recommended treatment for cortisol and aldosterone deficiencies on her sixth day of life. Until 5 months of age, hydrocortisone treatment (1.2 to 1.3 mg three times daily) was given through a compounded 2 mg/mL suspension.

Due to a suspicion of inaccurate dosing, the hydrocortisone formulation was changed to tablets. The girl’s parents were instructed to make a water solution with crushed tablets and then draw the prescribed amount for each dose.

From age 3.5 years onward, the child’s physicians noted that she presented Cushing-like features, including slightly rounded cheeks and an increase in fine, soft hair on her face, upper arms, and back.

At age 4, her hydrocortisone total daily dose started to exceed 5 mg and was split into four doses a day. That forced her parents to dissolve two 5 mg tablets in 10 mL of water and use that solution over 24 hours.

At 6 years and 11 months of age, she was admitted to the researchers’ CAH clinic for a consultation regarding her hormonal management.

She was gaining weight abnormally fast and had poor growth, accumulation of fat in the face (moon face) and between the shoulders (buffalo hump), and excessive body hair. Her hydrocortisone dose was 8.1 mg/m2 a day, divided into four doses.

Based on blood work and the confirmation of the presence of higher-than-normal cortisol levels, she was switched to a pharmacy-compounded, alcohol-free, hydrocortisone suspension with total daily doses ranging from 6.5 to 8.2 mg/m2/day.

This resulted in the resolution of her Cushing-like features, a decrease in body hair and body-mass index, and growth normalization.

“Our case highlights that manipulation of hydrocortisone tablets by parents can result in great variability in dosing and the need for commercially available pediatric formulations allowing for smaller dosing required in young children,” the researchers wrote.

The team noted that Alkindi, a pediatric formulation of hydrocortisone granules (minimum dose of 0.5 mg each) marketed by Diurnal, was approved in Europe in 2018, but is not yet available in the U.S.