The US Food and Drug Administration has tightened up its restrictions on the acne drug isotretinoin, after concluding last year that existing controls to prevent the drug causing birth defects were not strong enough.

The FDA now insists that drug wholesalers, patients, pharmacists and doctors register with the four manufacturers of isotretinoin in a programme – called iPLEDGE - that replaces a voluntary risk management system. The programme is designed to ensure that patients who could become pregnant have negative pregnancy testing and birth control counselling before receiving the drug.

In February 2004, an FDA advisory panel concluded that the existing voluntary registration programme – SMART - had failed, and the agency resolved last November to implement new controls [[24/11/04f]].

Roche, which first marketed isotretinoin (as Accutane) in the USA in 1982, instituted new prescribing restrictions in April 2002, which included voluntary registry participation. Three generics firms - Ranbaxy, Barr and Mylan/Bertek - followed suit with similar programmes as their products came on the market. All four, led by the US division of Roche, proposed a mandatory registry at last year’s advisory committee meeting.

Under the voluntary system, isotretinoin was dispensed to patients upon presentation of a written prescription with a yellow adhesive qualification sticker from the prescriber that signified to the pharmacist that the patient was not pregnant. However, the FDA said its review of this system revealed that sometimes stickers were placed on prescriptions without pregnancy testing being done. In iPLEDGE, a centralised database will require a negative pregnancy test to be confirmed in the system prior to dispensing.

From December 31 of this year, only doctors registered in iPLEDGE will be able to prescribed isotretinoin, according to the FDA.

Sales of isotretinoin have been declining over the last few years, according to the manufacturers of the drug. FDA figures suggest that there was a 23% reduction in prescriptions in 2003, the year after the voluntary registration programme came into effect, likely attributed to concerns about the drug’s safety.

Accutane was one of five drugs highlighted by Dr David Graham as posing a risk to human health at the US inquiry into drug safety, which was spurred on by the recent Vioxx (rofecoxib) withdrawal [[22/11/04a]], and there have been calls for its removal from the market in the USA [[12/10/04d]] [[01/03/04d]].

- Meanwhile, in addition to approving the iPLEDGE program, the FDA has also approved changes to the existing labelling on isotretinoin to update information on the risks of psychiatric symptoms and depression before and after prescribing. The drug has also been linked to suicidal ideation and suicide, with just under 200 cases of suicide reported in users since it was put on the market in 1982. While no causal link has been established, isotretinoin labelling warns doctors to monitor patients carefully for signs of psychiatric disturbance.