GAITHERSBURG, Md., March 25-Prescription topical corticosteroids may have more potential to cause adrenal suppression than many physicians realize, according to data presented yesterday at an FDA advisory committee hearing.
The data reviewed at a joint meeting of the Nonprescription Drugs and Dermatologic and Ophthalmic Drugs advisory committees surprised many panelists, who said they were not aware the drugs had such a high incidence of hypothalamic-pituitary-adrenal (HPA) axis suppression.
Action Points
- Understand hypothalamic-pituitary-adrenal axis suppression and its potential effects on your patients.
- Explain to patients that prescription corticosteroids for topical use are usually stronger and for different indications than those currently sold over-the-counter, and require careful monitoring for side effects and appropriate use.
- Check in with your patients on whether they use over-the-counter hydrocortisone appropriately.
- Understand that the FDA panel's recommendations were aimed at manufacturers and the FDA, who will likely work together on applying them to future new drug applications.
The suppression can lead to debilitating and potentially fatal conditions such as Cushing's syndrome.
The committees were meeting to give advice on what data manufacturers would need to submit to convince the FDA that their products were safe to be sold over-the-counter. The panel did not discuss any specific application, though GlaxoSmithKline representatives presented data from studies of consumer use of hydrocortisone creams.
Denise Cook, M.D., a medical officer in FDA's Division of Dermatology and Dental Drug Products, presented data from studies in adults and children for 10 currently marketed topical corticosteroids.
The biggest problems seemed to be with betamethasone propionate, which was approved in 2001, and comes as a cream, ointment or lotion.
In one study of Diprolene AF Cream (0.05%) in 60 patients with atopic dermatitis, ages 1 to 12, 58% had adrenal suppression. For Diprosone Ointment (0.05%), the rate was 53%.
For Clobex lotion (clobetasol propionate), which was approved in 2003, 56% of adults in a small study of atopic dermatitis using the drug for two weeks had suppression. In another Clobex study, 8 of 10 adults treated for four weeks twice daily had adrenal suppression.
Though the effects seemed to be reversible after discontinuation, the high incidence gave panelists pause.
Michael Wilkerson, M.D., a panel member and dermatologist at Utica Park Clinic in Tulsa, Okla., said he was surprised, and that physicians should be more concerned about prescription use. "I think this is the biggest safety signal to come out of this entire meeting," he said.
He and other panelists said it would be difficult to approve these drugs for over-the-counter use. They sought better data on how to avoid adrenal suppression and who it disproportionately affects.
Currently, all the drugs in the class carry warnings that systemic absorption can cause HPA axis suppression, leading to Cushing's syndrome, hyperglycemia and glucosuria. Children are at greater risk, and are more vulnerable to growth retardation, delayed weight gain, and intracranial hypertension.
Since 1969, the FDA has received reports of severe adrenal suppression in 65 adults and 29 children, said Dr. Cook. Two adults died, and two children died. Most of the serious problems followed prolonged or excessive use of the drugs, use of a super-potent steroid, using multiple topical steroids, or using them at the same time as oral or inhaled steroids.
Manufacturers first applied to sell topical steroids over-the-counter in the mid-1950s. The FDA rejected the move in 1957. But in 1973, the FDA said that topicals of 0.25% to 0.5% were generally recognized as safe, opening the door to over-the-counter sales in those strengths. In 1990, the agency agreed that strengths up to 1% were safe for drugstore sales.
Topical corticosteroids that came on the market after 1975 are regulated under a different scheme. To be moved over the counter, manufacturers have to submit a new drug application. The expert panelists gave their input on what would be needed to convince them over the counter use was safe.
Most panelists agreed that the adrenal suppression and growth retardation were significant side effects that should block over-counter sales, although some said consumers should be given the benefit of the doubt.
The American Academy of Dermatology Association disagreed. A spokesman said the AADA was opposed to OTC sales. "Used improperly, these medications can cause great harm," said Sandra Read, M.D., a dermatologist in private practice in Washington, DC.
"If you remove the physician from this equation you'd be effectively removing a very important safeguard," she said.