The government's most-aggressive effort yet to curb drug side effects is having an impact on a popular and highly effective acne drug -- with some doctors and pharmacists saying they have stopped dispensing it and some patients turning to illegal Internet sales.
In March, the Food and Drug Administration launched a program known as iPledge, which aims to keep pregnant women from taking Accutane or its generic, isotretinoin. The drug is linked to a very high incidence of birth defects, including misshapen heads, missing ears and heart defects. But patients clamor for it despite the frightening risks, because it is the only effective treatment for the most disfiguring form of acne.
There had been a number of previous efforts to educate patients and require women to sign statements that they understand the dangers, but still up to about 200 women a year were becoming pregnant while using the drug, according to FDA estimates. So, under pressure from the FDA, the four manufacturers of isotretinoin got together and designed the current program. Isotretinoin is sold as Accutane, from Roche Holding AG, and in three generic versions: Amnesteem from Mylan Laboratories Inc., Claravis from Barr Pharmaceuticals Inc. and Sotret from Ranbaxy Laboratories Ltd.
Now, to obtain the drug, patients must register online for the iPledge program with the FDA, see their dermatologist monthly to get a fresh prescription, answer monthly online questionnaires and fill their prescription within a seven-day window after it is written. Women must also visit a certified lab for a blood pregnancy test each month and be on two forms of birth control. The testing and office visits are usually covered by insurance. But if the steps aren't completed properly, the patient will be denied that month's prescription at the pharmacy.
There were many initial glitches with the iPledge system that kept doctors and patients on the phone for hours, and prevented many patients from getting the drug at first. These have largely been worked out, the FDA says. But doctors and patients remain frustrated with the program, saying that people are frequently denied access to the drug for even minor missteps, resulting in interruption of treatment. Men, too, must participate in parts of the program, to monitor other potential serious side effects such as liver damage and suicidal thoughts.
Some patients like Tiffany Smith, a college student from Havre de Grace, Md., say that even though they complied with the requirements, they still couldn't get isotretinoin. Both Ms. Smith and her dermatologist, David Jaffe, say she was listed as "inactive" in the iPledge computer for two months before she got her first prescription in July. Ms. Smith also says she had to call three pharmacies before finding one that participated in iPledge. "It's been horrible trying to get the prescription," says Ms. Smith, who must now drive home from school in Pennsylvania for the next few months to complete her treatment.
"It's just a continuous nightmare," says Lawrence Parish, a Philadelphia dermatologist who practices with his daughter, Jennifer Parish. He says all five of the patients he has had on the drug have had trouble registering or getting their prescriptions each month. Dr. Parish says he recently had a 40-year-old male patient denied his monthly supply because he went to the pharmacy eight days after the prescription was written, rather than the required seven.
Sandra Kweder, the FDA's office of new drugs deputy director, concedes that isotretinoin is "a pain in the neck to get," but says the restrictions need to be tough to be meaningful. "This is a pretty toxic drug," she says. "It's not Tylenol."
Indeed, some doctors say that while focusing on preventing pregnancies is important, patients on the drug -- including men -- need to be monitored for other serious side effects like liver damage, possible links to suicidal thoughts in adolescents, brain pressure, vision problems, bone and muscle damage, along with blood lipid and cholesterol problems.
Prescriptions and sales of isotretinoin and Accutane are down dramatically. The number of Accutane prescriptions fell by 46% and prescriptions for the leading generic brand dropped by 16%, during the first half of 2006 compared with the same time in 2005, according to IMS Health, which tracks prescription sales. Roughly one million prescriptions for isotretinoin were written annually before this, with about a combined $300 million in sales.
"The intention is good," says David Pariser, who runs a five-clinic dermatology practice in the Norfolk, Va., area. "But it's really become a barrier to care." Although he still has several patients on the drug, Dr. Pariser says he will now use isotretinoin as only a last resort for the most severe cases. He says some smaller practices in the area have stopped prescribing it altogether.
It is too soon to say if iPledge has lowered the pregnancy rate. So far, no pregnancies have been reported, according to the FDA. But the program may turn into something of a referendum on the agency's ability to manage the risk and benefits of powerful drugs. Paul Seligman, the FDA's new director for drug-safety policy and communication, says the agency has started a planned review of all of its restricted-distribution programs to see "what is working and what is not."
The FDA has been under increasing pressure since Merck & Co.'s Vioxx was taken off the market two years ago to do more to protect consumers from being hurt by prescription drugs. A recent drug-safety bill introduced last month by Sen. Michael Enzi (R., Wyo.) and Sen. Edward Kennedy (D., Mass.) would require drug makers to submit post-marketing risk-management plans as part of the drug-approval process. The bill is unlikely to pass this year, but legislators need to approve a funding bill for the FDA next year, which could provide a vehicle for drug-safety provisions.
Isotretinoin is one of roughly two dozen drugs subject to some type of restricted-access plan intended to curb misuse or unnecessary side effects. Most of the FDA's risk-management programs are reserved for drugs that are administered in hospitals or doctors' offices, such as the multiple sclerosis drug Tysabri, or certain cancer drugs. But some -- like Accutane, or the antipsychotic clozapine, which can lead to a condition that harms the immune system -- are filled at pharmacies. Because these drugs are self-administered, regulators are especially concerned about ensuring proper use. FDA officials say that Accutane faces more hurdles for patients and doctors than any of the other restricted drugs.
While a treatment interruption is inconvenient, many dermatologists say it doesn't derail acne treatment because isotretinoin appears to work cumulatively even with breaks in treatment. The drug is approved to treat severe nodular acne that can lead to disfiguring scars and doesn't respond well to other existing treatments, such as Retin-A or antibiotics. However, many dermatologists also use isotretinoin to treat milder cases of acne that have failed to respond to treatment. Most cases of all types clear up permanently with a one-time four- or five-month treatment course with isotretinoin.
Ms. Smith, the college student in Pennsylvania, says she is aware of the dangers of isotretinoin. But after living since her early teens with severe acne that she struggled to hide, and spending "thousands and thousands of dollars" on treatments, this is the first thing that is starting to work. "I can look in the mirror and I'm totally satisfied," she says. "There are a lot of risks but it's worth it."
A few dermatologists try to give patients additional medicine so there is no break in the treatment, says Dr. Parish. The iPledge program is designed to dispense only a 30-day supply of medicine at one time. But Dr. Parish explains that because it is dosed by weight, a prescription can be written based on a heavier weight, giving patients additional medicine.
Sandra Read, a Washington, D.C., dermatologist, says she sees a few patients who have turned to the Internet to buy isotretinoin illegally. But when she tells them she won't treat them under those terms and urges them to go through iPledge, "they don't come back," she says.
FDA officials don't want patients to turn to the Internet and say they will discuss with the four drug manufacturers during the next six months ways to make some changes to iPledge -- including more flexibility in the monthly scheduling of office visits. They may also ease the seven-day rule for picking up a prescription, or allow pharmacists and doctors to override denials in some cases.
The agency is also working on a consumer-education Web site designed to pop up whenever someone might type in "buy isotretinoin" into a search engine to help them think twice about buying over the Internet by warning them about the risks associated with the drug.
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