Taking aim at Botox

The phenomenon called Botox, which has moved rapidly from obscure eye-disorder treatment to mass-market wrinkle cure used by 500,000 Americans, has achieved such broad success that doctors at the prestigious Johns Hopkins School of Medicine have thrown Botox parties and lexicographers at the venerable Oxford English Dictionary included an entry in their latest edition.

Doctors and patients swear by Botox’s ability to bring a youthful glow to aging faces with few side effects. Now the drug’s maker, Allergan Inc., is aggressively pursuing new medical uses for its biggest product, which already is generating several hundred million dollars in sales annually. At the top of Allergan’s list: treatment of two problems that plague millions of Americans -- migraine headaches and excessive sweating.

Indeed, Allergan executives sound almost breathless when they talk about the future of Botox. Says company Vice President Mitchell Brin: “Botox will transform the world the way penicillin has transformed infectious diseases.”

The drug already has transformed Irvine-based Allergan from a low-profile eye-drop and acne-treatment company into one of corporate America’s glitziest success stories. But controversy often follows in the shadow of success. Even as Botox sales continue to soar, the pharmaceutical firm is beset by complaints from federal regulators over its marketing tactics and growing consumer wariness about the safety of the drug.

The Food and Drug Administration repeatedly has chastised Allergan for advertisements that it says suggest the drug is effective for unapproved uses and has criticized the company for minimizing the drug’s side effects. In December, the FDA expects to release a report on consumer and doctor complaints about Botox side effects. Allergan also faces a lawsuit, set for trial early next year, in which a prominent Hollywood socialite claims that her Botox treatments caused a raft of maladies that left her bedridden.

Botox is also facing competition from other products that threaten to topple the drug from its perch as king of the wrinkle remedies. Santa Barbara-based Inamed Corp. is developing the European botulinum toxin Type A, Dysport, for cosmetic use in the U.S., Canada and Japan. And a new class of synthetic wrinkle fillers that, for some people, have longer-lasting results than Botox are gaining popularity.

There is also concern that some doctors, in their enthusiasm for Botox, may not always be acting in their patients’ best interests. Interviews with Botox patients and an informal review of consent forms that physicians have patients read and sign suggest that some doctors are failing to disclose important information about some serious potential side effects of Botox.

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Allergan takes action

Allergan, meanwhile, has aggressively defended its product in the face of increased public scrutiny. In June, “NBC Dateline” aired a segment on the suit filed by Irena Medavoy, whose husband is movie producer Mike Medavoy, against Allergan and a prominent Beverly Hills dermatologist, Arnold Klein. The TV report featured interviews with doctors and former Botox patients who claim the drug caused months-long illness, even permanent fatigue and facial paralysis.

By the next morning, Allergan had bought full-page ads that carried the headline: “The Truth About Botox” in newspapers across the nation and company sales reps were scurrying to physicians’ offices with a “talking points” letter aimed at easing doctors’ anxiety about the product.

“You may be aware,” the Allergan letter read, “that there has been some recent negative attention in part caused by claims from a high-profile Hollywood producer’s wife, that may have created misconceptions among current and prospective patients. This campaign serves to reinforce the positive and long-standing safety profile of Botox.”

After weeks of widespread media attention on the Medavoy suit, Allergan dispatched physicians to shopping malls in 24 U.S. cities to assuage the fears of potential patients. The promotional tour, explains Allergan spokeswoman Christine Cassiano, “was a way to correct some of the general misunderstanding that we believe existed in the marketplace.”

Botulinum toxin (Botox is a trade name) is the most deadly substance known. It was identified in the 1820s as the bacterium found in contaminated food that causes botulism poisoning, which can be fatal. During World War II, U.S. scientists studied the neurotoxin’s effectiveness as a weapon. And during the 1980s and early 1990s, it was a key part of Iraq’s arsenal of biological weapons. The danger associated with botulinum toxin perhaps has fueled the public’s fascination with Botox -- the biological beast turned into a thing of beauty. But the substance’s ugly past, says Allergan’s Brin, “is not something that we tend to expand on very much.”

In fact, Allergan’s promotional materials for patients sound as though the product might be found in the local health store. Botox is a “natural, purified protein derived from a bacterium in much the same way penicillin is derived from mold,” some company advertisements and brochures state. In June, the FDA warned Allergan that its magazine ads for Botox “falsely identify your product as a cosmetic treatment, fail to reveal material facts about the product’s use and minimize the risk information presented.”

The FDA argues that although the drug’s brand name is Botox Cosmetic, it is approved only for “severe glabellar lines,” which are the wrinkles between the brows, and not “frown lines,” as stated in Allergan’s ads. In response, Allergan pulled the ads. New ads, without the disputed text, started appearing in magazines this month.

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The record so far

Allergan officials stress Botox’s safety record, dating to the late ‘70s, when clinical trials of the drug began.

Indeed, reported difficulties with the drug are rare with just seven people in the 1990s suffering serious side effects, according to Allergan. In California, the state medical board reports just six complaints against Botox in the last two years; none of the complaints resulted in disciplinary action against any doctors.

The only known Botox-related death, according to Allergan, was that of an elderly woman with a preexisting neurological condition who suffered from head and neck spasms and had difficulty swallowing. After Botox treatment, her symptoms were exacerbated.

According to documents filed with the FDA, the agency has received dozens of reports of severe side effects, including some deaths and prolonged hospitalizations, possibly associated with Botox use from 1989 to 2001. The FDA said it has not studied the events sufficiently to determine if Botox was the cause or a contributing factor in those incidents. FDA officials say an ongoing analysis of these and other reports has turned up nothing alarming..

“We haven’t seen unusual kinds of events that would worry us about the safety of this product,” said Susan Ellenberg, the FDA’s director of the Office of Biostatistics and Epidemiology.

Allergan consultant Alastair Carruthers, the Canadian dermatologist who, with his ophthalmologist wife, Jean Carruthers, popularized the use of Botox as a wrinkle cure in the ‘80s, said he’s confident of its safety.

First, he said, the recommended 20-unit doses are far too minuscule to damage the body. Second, the muscle soaks up the drug before it ever enters the bloodstream. “What we presume is, when it’s injected, tiny, tiny amounts get into the circulation ... [and] bind to the nerve muscle junction elsewhere in the body,” Alastair Carruthers said. However, he added, that “doesn’t translate into any clinical effect. It’s just in laboratory tests.”

But James Adams, an associate professor at USC’s School of Pharmacy who has studied Botox for more than 15 years, said the risks increase when improperly administered. “If it’s injected too deeply, it can go into blood, not muscle,” said Adams. “Then you could get all the classical signs of botulism. People can die from having too much botulinum in their blood.”

Most doctors interviewed for this story don’t believe the drug can lead to symptoms of botulism. They share Carruthers’ view that years of clinical experience prove the drug’s safety.

Other physicians, though, caution that the drug’s side effects deserve more study.

Botox “works by causing damage to the nervous system,” British biochemist Nicholas Abrishamian said in an article in the Lancet, a prestigious British medical journal, in September 2002. “How do I know that it’s not going to slowly cause even more nervous system damage?”

UCLA neurologist Andrew Charles, who treats Medavoy and blames Botox for her months-long illness, believes that the risk of the drug damaging the body is higher than most physicians realize. “Some toxin may travel up the nerve into the brain or spinal cord,” he said. “The potential consequences of this kind of spread are not known.”

Each warning label lists many unknowns associated with Botox, including how the drug affects pregnant women, whether it’s excreted in human milk, and its relationship to rare cases of “significant disability,” pneumonia and death. The label also cautions that in patients with preexisting neuromuscular disorders Botox may cause “clinically significant systemic effects,” including the inability to swallow or breathe.

The effect of doses higher than 20 units is unknown, but physicians typically treat head and neck spasms, migraines and excessive sweating with doses from 50 to more than 300 units.

Although a 10-year Italian study published last year on the drug’s effectiveness on facial spasm concluded that side effects to Botox were minimal and transient, longer-term effects are unknown.

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Patients not aware

Most patients interviewed for this story were unfamiliar with the serious side effects associated with Botox. While Allergan provides a lengthy warning label to physicians, the doctor must decide what information to pass on to the patient. Some doctors give Allergan’s warnings verbatim to patients, but others discuss only the drug’s minor complications, such as the possibility of a droopy eyelid or nausea. Some patients said in interviews that they recall few cautions from doctors, except perhaps not to lie down for several hours after treatment and not to exercise for 24 hours.

“I went in and said, ‘I have these frown lines between my eyebrows,’ and the doctor said, ‘Yeah, we’ll take that away,’ ” said a 27-year-old Los Angeles attorney who has received Botox from a plastic surgeon three times. “He never warned me about anything.”

Charles Inlander, president of the People’s Medical Society, an Allentown, Pa.,-based patient advocacy group, said Botox is a “very lucrative” business for doctors, and that money may influence doctors’ decisions on which warnings to pass on. “Once you start talking about the negatives, it starts to create a scare in people,” he said. “And once people start hearing that, the almighty mystic powers of the doctors seem lessened.”

Despite the risks, doctors continue to report encouraging results with Botox for treatment of juvenile cerebral palsy and migraines. In treating cerebral palsy in children, Botox paralyzes large spastic muscles, such as those in the leg and calf, enabling the child to strengthen and ultimately control them. For migraine treatment, some doctors believe Botox relaxes the pinched nerves in the forehead, temple and back of the neck that trigger the headache.

“A common remark is, ‘You’ve changed my life,’ ” said Dr. Bahman Guyuron, a plastic surgeon in Cleveland who has studied Botox and migraines for more than three years.

Still, the Medavoy lawsuit has tainted the image of the popular wrinkle treatment. Medavoy has accused dermatologist Klein of injecting too high a dose of Botox and failing to properly warn her of its risks.

Klein, a paid consultant to Allergan who has published articles on the drug, declined through his attorney to comment for this story. An Allergan statement issued shortly after the suit was filed called the allegations “frivolous.”

The suit accuses Allergan and Klein of negligence, fraud, product liability and improper promotion of Botox, among other charges. Medavoy’s suit claims that after she was treated in March 2002 with 86 units in her temples, at the base of her scalp and between her brows, she suffered numerous ailments, including “severe and unrelenting migraine headaches,” breathing problems and weakness.

“I was tested for cancer,” Medavoy said. “I was tested for MS [multiple sclerosis]. I had an MRI. I had an endoscopy because I couldn’t swallow. I had a full-body CAT scan. You’re doing blood work. You want to make sure you’re not missing anything.”

While media coverage of the case has sparked more conversation about the drug between doctors and patients, many satisfied with their treatment will continue to receive Botox despite the risks.

“I still worry sometimes, what’s going to happen in 10, 20 years,” said Los Angeles hairstylist Rachel Lindy, who has been getting Botox for four years. “But once you start, it’s kind of hard to stop because you go from wrinkles to no wrinkles.”

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(BEGIN TEXT OF INFOBOX)

From toxin to beauty treatment

The numbers

Who’s using it: 500,000 Americans have used Botox as a wrinkle cure.

How it works: Injected into muscle to smooth wrinkles.

Cost: A doctor typically pays about $400 for a 100-unit vial, then charges the patient about $400 per 20-unit injection.

Recommended dosage: 20 units.

The possible risks

Proponents, including the manufacturer, Allergan, say such a small amount is taken up by the injected muscle and is highly unlikely to get into the bloodstream. Others disagree and warn that it is possible for a significant amount of toxin to enter the blood.

The history

1820s: First identified by German doctor Justinus Kerner as the bacterium found in contaminated food that causes botulism. Classic symptoms of botulism are muscle paralysis that leads to blurred vision, drooping eyelids, slurred speech, difficulty swallowing and muscle weakness. If untreated, these symptoms may cause paralysis of the arms, legs, trunk and respiratory muscles.

1944: The U.S. government, in response to an erroneous report of the German military’s possible use of weapons containing botulinum toxin, produces enough botulinum toxoid to immunize the entire D-day assault force.

1970s: San Francisco eye specialists Alan Scott and Edward Shantz introduce the first successful therapeutic treatments using botulinum toxin. They developed a process to remove the bacteria, while salvaging the muscle-weakening toxin now known as Botox, or botulinum toxin Type A.

1989-2000: FDA approves Botox for treatment of crossed eyes, uncontrollable blinking and head and neck spasms.

April 2002: FDA approves Botox for treatment of vertical lines between the brows.

July 2002: A plastic surgeon at Johns Hopkins School of Medicine holds a Botox party and is roundly criticized by medical professionals and patient advocates.

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Sources: “The Medical Department; Medical Service in the European Theater of Operations (United States Army in World War II, The Technical Services).” Allergan Inc., Associated Press, Swiss Institute for Bioinformatics, National Library of Medicine, Centers for Disease Control and Prevention