Patients, groups eye off-label use of prescription drugs

When Sanford "Sandy" Gerber awoke the morning after his first Botox shots in his arm he wept openly with joy. He could unclench his fist for the first time in seven years.

Gerber, 60, of Melville, hadn't seen the palm of his hand since 2003 when a near-fatal stroke damaged his right side and also limited the use of his right leg. After his first Botox injections in March, Gerber said, his leg felt better, too.

"When my doctor gave me the shots he said I should be able to feel something in five to seven days," said Gerber, the former manager of a Starbucks in Manhasset, now on permanent disability. "But the next morning I was able to turn my palm to my face, and I said to myself: 'Oh my God.' "

His treatment came the same month the U.S. Food and Drug Administration approved Botox and two similar drugs for treating stroke-affected arms and hands. But the approval arrived nearly 20 years after doctors worldwide began injecting stroke patients with the drug, which is best known as a wrinkle-eraser.

"I have been using botulinum toxin for over 10 years, and there are doctors who have been using it even longer," said Dr. John Kelemen, Gerber's Plainview neurologist.

The injections have not yet been approved for stroke-affected legs and feet. But doctors, including Gerber's, are continuing without approval in a practice known as "off-label" prescribing, when a medication is approved for one purpose but prescribed for another for which it has not been scientifically vetted. Doctors have engaged in the practice for decades based on anecdotal evidence and their own knowledge of diseases. Breast cancer and degenerative eye problems are among the dozens of medical maladies treated with drugs used off-label.

Powerful supporters

About 20 percent of all medications prescribed for adults are for off-label purposes, according to research from Stanford University and the Institute of Medicine, a federally chartered nonprofit organization that provides advice to government agencies, lawmakers and the public. But among certain drug classes, particularly heart medications, off-label prescribing may be as high as 46 percent. And for children, the institute estimates off-label prescribing may range between 50 percent and 75 percent because so few medications are tested for pediatric safety and correct dosages.

The practice is legal and strongly defended by the American Medical Association - and the FDA.

"The FDA does not regulate the practice of medicine," said agency spokeswoman Sandy Walsh. "Health care professionals are free to choose medicines for uses not approved by the FDA if they feel such use will benefit a patient's condition."

She said the agency's role is to make certain drugs are safe and effective. The hands-on practice of medicine is regulated by state boards of medicine and pharmacy.

Botox is just one of dozens of medications prescribed off-label. Another drug, Avastin, first approved in 2004 for metastatic colon cancer, has been used off-label for years in patients with macular degeneration and diabetic retinopathy, two leading causes of blindness. Both are characterized by excessive blood vessel development in the retina.

Even though Genentech, Avastin's maker, manufactures an eye-specific drug that also thwarts the growth of blood vessels, doctors have forged ahead with off-label Avastin, saying it saves patients money.

Trend draws concerns

Off-label prescribing is common across a wide range of medical conditions - cancer, HIV infection, psychiatric disorders and rare diseases. A study presented last year at the American Society of Clinical Oncology revealed that more than one-third of breast cancer patients receive chemotherapy medications that, while FDA-approved, have not been vetted for the disease.

"The history of off-label use - and I don't think anybody has done a 50-year or 100-year survey - the general impression is that it has benefitted patients," said Dr. Samuel Packard, chairman of the ethics committee of the North Shore-Long Island Jewish Health System in Manhasset.

Freedom to prescribe drugs off-label encourages innovation in clinical practice, said Dr. Randall Stafford of Stanford University, a leading medical policy expert on the practice of off-label drug use.

But concerns also persist about the trend. Stafford also found in a study a slew of drugs that are inappropriately prescribed off-label. Most are anti-psychotics and anti-depressants.

Drugs prescribed off-label have not been studied well enough to determine if their benefits outweigh the risks, said Dr. Sidney Wolfe, director of the Health Research Group at Public Citizen, a consumer watchdog in Washington, D.C. The group contends a lack of clinical research means no scientific consensus exists on proper dosages.

Pharmaceutical companies do operate under one key restriction with their drugs that may become popular off-label: They're prohibited from advertising their products for purposes other than their approved uses. Ortho-McNeil Pharmaceutical, a subsidiary of Johnson & Johnson, pleaded guilty last month to illegally promoting its epilepsy drug Topamax for uses other than approved by the FDA.

Benefits of toxin

Botox, which is derived from the bacterial toxin that causes botulism poisoning, became a post-stroke treatment years before its approval. The theory behind it grew out of the work of a pioneering San Francisco ophthalmologist who used purified samples of the toxin in the early 1980s to treat uncontrolled muscle spasms around the eyes.

In 2001, Canada approved Botox to treat people who had suffered strokes. The drug works by blocking overactive nerve impulses that trigger excessive muscle contractions - what's known as "spasticity."

"It's interesting there is so little known about it in the public at large and so few neurologists are using it," Kelemen said. "But we know it's appropriate and there have been peer-reviewed studies showing that botulinum toxin works in stroke."

Injections of the toxin in stroke patients preceded most of the major scientific studies that ultimately validated the shots. But it was the research - not the anecdotal evidence - that provided the data on which the FDA's March approval was based.

Meanwhile, most insurers and Medicare pay for the injections in both the arms and legs because the shots dramatically improve life quality for stroke patients.

It is uncertain when - or if - the FDA will approve the botulinum-based drugs - Botox, Dysport and Myobloc - for lower limb injections. Even if they do gain approval, the treatments should not be seen as a permanent cure: Gerber is scheduled to receive a series of injections in his right arm and leg every three months. Still, he is now able to begin relearning how to use he right hand to write with a pen and use a knife and fork.

As for Kelemen, he said he feels gratified that he can help people who once seemingly were beyond help. "With Sandy, you can hear it in his voice," he said. "He really feels he has gotten his life back."

Are off-label drugs right for you?

Drugs are approved by the U.S. Food and Drug Administration in a rigorous process involving laboratory testing that can take years. The labels eventually arrived at for pill bottles are in place in part to protect patients from harmful side effects. Even so, doctors are allowed to prescribe drugs off-label, for uses for which they have not been tested.

Experts suggest patients can ask the following questions if their doctor recommends an off-label drug prescription:

1. How do you know a medication prescribed off-label will work for me?

2. Have you treated other patients suffering similar symptoms with the same medication? What was the outcome?

3. May I talk to a few of your patients who have been treated off-label?

4. How many formal studies have been conducted showing that this off-label usage works for my condition?

Some drugs and their off-label uses

Dozens of drugs are prescribed off-label, meaning doctors use them to treat conditions for which they have not been tested. Some examples:

ACTOS: Diabetes drug (not FDA-approved for pediatric use)

Used off label for: Autism in children

Why: Some doctors theorize the drug may reduce inflammation and have other properties that help improve the quality of life for children with autism. Drug carries an FDA "black box" warning because researchers have linked it to heart failure in adults.

AVANDIA: Diabetes drug (not FDA-approved for children)

Used off-label for: Autism in children

Why: It is almost chemically identical to Actos, and so some doctors theorize the drug may reduce inflammation and have other properties that help improve the quality of life for children with autism. Drug carries a "black box" warning because of a link to heart failure in adults.

AVASTIN: Cancer drug

Used off-label for: Age-related macular degeneration/diabetic retinopathy

Why: Reduces development of destructive blood vessels in retina.

BOTOX: Blocks nerve activity in muscles

Used off-label for: Cerebral palsy in children; enlarged prostate gland; migraine headaches

Why: Cuts down on involuntary muscle contractions and improves movement in cerebral palsy; decreases size of prostate gland and helps improve urine flow; doctors theorize Botox may help migraine sufferers by reducing inflammation and decreasing activity of pain receptors. Botox carries a "black box" warning because of side effects in some patients.

LONG-TERM ANTIBIOTICS: Kills bacterial infections

Used off-label for: Lyme disease

Why: Some patients and their physicians contend Lyme infections are chronic, requiring long-term antibiotic therapy.

NEURONTIN (Gabapentin): Anticonvulsant

Used off-label for: Bipolar disorder; hot flashes and essential tremor

Why: Drug reduces depression and anxiety in some patients. Doctors theorize it helps quell hot flashes by regulating the flow of calcium in cells, a mechanism involved in body temperature. New York researchers proved the drug is as effective as estrogen in controlling hot flashes. Several clinical trials demonstrate the drug works to control essential tremor.