Manufacturer withdraws Accutane

Teenagers and young adults who have severe, scarring acne may lose the most effective treatment for the condition.

Roche quietly pulled its blockbuster drug Accutane off the market over the summer amid early signs that the drug may be linked to inflammatory bowel disease. A new study quantified those risks, finding that users of the medication have almost twice the odds of developing a serious bowel disorder as nonusers.

Generic versions are available, but the latest troubles could lead to the withdrawal of the medication considered the treatment-of-last-resort for acne so damaging it can lead to pitting of the face and a lifetime of anguish.

Roche officials said the decision to withdraw Accutane reflected market pressures and the cost of lawsuits, not safety concerns. Accutane costs about $1,200 a month, and many consumers choose the generics, which cost 25 percent to 50 percent less. Meanwhile, plaintiffs have won an estimated $33 million in judgments against Roche for bowel disorders, according to an industry publication, Dermatology Times.

In its tumultuous 25-year history, the drug (also known as isotretinoin), has been found to cause serious birth defects and possibly to increase the risk of depression and suicidal behavior. Women who take it must register with the government, sign a consent form saying they understand the medication's risks, use two forms of birth control and submit to monthly pregnancy tests.

That it's still on the market puzzles some former users and consumer advocates, and reflects the profound lengths to which doctors, pharmacists, pharmaceutical companies, regulatory agencies and patients have gone to ensure its survival.

"It would be a true disaster if this medication would become unavailable," said Dr. Steven Stone, chairman of an American Academy of Dermatology committee that has reviewed the drug's safety. "People don't die of acne, so it's easy to say, 'This is a drug that causes inflammatory bowel disease; let's take if off the market.' But that ignores the psychological harm of severe acne."

A form of vitamin A, isotretinoin usually is taken daily for three to six months, resulting in lasting improvements in 99 percent of patients and a cure in about 70 percent. It also is used occasionally for psoriasis, lupus and cancer. Accutane has been used by more than 13 million people worldwide and was one of Roche's best-selling drugs, with about $200 million a year in sales before its patent expired in 2002.

When approved in 1982, the drug was known to cause birth defects if taken during pregnancy and was labeled with warnings to that effect. In 2005, the Food and Drug Administration (FDA) implemented the stringent iPledge program, requiring patients, doctors and pharmacists to join a risk-management registry to try to ensure that women didn't become pregnant while on the drug.

Cumbersome system

The program has kept isotretinoin on the market, although the system is so cumbersome that some doctors and patients have given up trying to obtain the medication, said Dr. Amy Forman Taub, a dermatologist and assistant professor at Northwestern University in Chicago. "This drug has had so many fears associated with it over the years," she said. "There are no other medications, other than thalidomide, where there is a registry. But we've mastered it, and it works."

Isotretinoin, however, can cause a range of other side effects, including increased sensitivity to the sun; joint and muscle pain; headaches; thinning hair; elevated cholesterol levels; and liver toxicity.

The drug also has been publicly and emotionally linked to an increased risk of depression, including suicides, and some families of those who killed themselves have pressed the FDA for its removal. U.S. Rep. Bark Stupak, D-Mich., whose teenage son committed suicide after taking Accutane, has been among them.

A study published in January in the Annals of General Psychiatry, however, found that the relationship between isotretinoin and psychiatric problems has not been proved.

Now research has found a possible link to inflammatory bowel disease. At the recent annual meeting of the American College of Gastroenterology in San Diego, researchers from the University of North Carolina, Chapel Hill, presented evidence showing a higher rate of bowel disorders in isotretinoin users. Before the study, the connection was largely anecdotal. In inflammatory bowel disease, the intestines become chronically red and swollen, producing pain, cramping, diarrhea, weight loss and bleeding. Surgery to remove all or part of the colon sometimes is required.

Dr. Seth Crockett and his colleagues compared 8,189 cases of inflammatory bowel disease with 21,832 healthy individuals and found the odds of developing such diseases were 1.68 times higher among isotretinoin users. People who had filled four or more prescriptions had increased odds of 2.67.

The odds of having ulcerative colitis, a type of bowel disease that causes open sores in the lining of the rectum and colon, were 4.36 times higher among isotretinoin users. The risk of having Crohn's disease, perhaps the most severe of the diseases, was not increased.

But only five to 10 people among 100,000 a year are diagnosed with inflammatory bowel disease, Crockett said.

"The absolute risk of getting inflammatory bowel disease is very low," he said. "So if someone has disfiguring acne that was affecting their quality of life, it might be a risk they are willing to take."

Because the data have not been published in a peer-reviewed journal, Crockett noted, they must be considered preliminary. A similar study, published in July in the American Journal of Gastroenterology by University of Manitoba researchers, found no such association. That study examined a large database in Canada and found that 1.2 percent of people diagnosed with inflammatory bowel disease had used the drug before diagnosis compared with 1.1 percent of people who had not used isotretinoin.

Intent of lawsuits

There is no biological explanation for why isotretinoin might increase the risk of bowel disease, Crockett said. "There are a lot of things that are not understood."

The new data are certain to spark renewed opposition to the drug, said Michael Brown, a lawyer who specializes in personal-injury claims.

The intent of the lawsuits is to drive the medication off the market, he said. "That has been our goal for several years or, in the alternative, to make full disclosure in a way in which the public is properly informed," he said.