Off-Label Drug Use: What You Need to Know

Prescription drugs are often prescribed for uses other than what the FDA has approved. Find out why.

From the WebMD Archives

The next time your doctor writes you a prescription, consider this: The medication may not be approved for your specific condition or age group.

But you probably shouldn't call the medical board. The practice, called "off-label" prescribing, is entirely legal and very common. More than one in five outpatient prescriptions written in the U.S. are for off-label therapies.

"Off-label" means the medication is being used in a manner not specified in the FDA's approved packaging label, or insert. Every prescription drug marketed in the U.S. carries an individual, FDA-approved label. This label is a written report that provides detailed instructions regarding the approved uses and doses, which are based on the results of clinical studies that the drug maker submitted to the FDA.

“Many people may be surprised to know that the FDA regulates drug approval, not drug prescribing, and ... doctors are free to prescribe a drug for any [reason they think is medically appropriate],” says G. Caleb Alexander, MD, MS, a medical ethics advocate and assistant professor of medicine at the University of Chicago Medical Center. "Off-label use is so common, that virtually every drug is used off-label in some circumstances."

Unaware of Off-Label Usage

Despite the prominence of off-label drug use, experts say few patients are aware that they are receiving a drug off-label. And doctors are not required to tell a patient that a drug is being used off-label.

Atlanta suburbanite Michelle Murphy was stunned to learn nadolol, the beta-blocker medicine she had been taking every day for several years to prevent migraines, was not actually approved for that use.

"It’s almost like we are test subjects, being reassured that everything will be fine because it worked to help people in studies that were taking it, but not exactly for what we are taking it for," Murphy says.

Benefits of Off-Label Drug Use

Off-label prescribing isn't necessarily bad. It can be beneficial, especially when patients have exhausted all other approved options, as may be the case with rare diseases or cancer.

According to the American Cancer Society, cancer treatment often involves using certain chemotherapy drugs off-label, because a chemotherapy drug approved for one type of cancer may actually target many different types of tumors. Off-label use of a drug or combination of drugs often represents the standard of care.

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Beta-blockers are another example of beneficial off-label prescribing. Such medications are FDA-approved for the treatment of high blood pressure, but are widely recognized by cardiologists as a standard of care for patients with heart failure. And in fact, some beta blockers are now formally approved to treat heart failure. It's not uncommon for off-label uses to eventually get approved by the FDA.

Other drugs commonly prescribed off-label include tricyclic antidepressants for chronic pain, and antipsychotics for attention deficit hyperactivity disorder (ADHD) "Name the drug, and one can come up with off-label uses," Alexander says.

A Risky Practice?

There is debate about off-label drug use. Doctors emphasize that off-label prescribing has its place in medical practice, but they also admit that using a drug off-label can raise the risk of lawsuits should a patient have unwanted or bad side effects.

"Off-label prescribing can expose patients to risky and ineffective treatments," medical ethics professor Rebecca Dresser and Joel Frader, MD, write in the fall 2009 issue of The Journal of Law, Medicine & Ethics.

Fen-Phen is one of the best examples of off-label use with a poor outcome. The FDA approved medications fenfluramine hydrochloride and phentermine hydrocholoride as individual, short-term treatments for obesity. But doctors eventually began prescribing the two drugs together after an article describing the cocktail's dramatic weight loss effects appeared in a medical journal and numerous mainstream publications.

That off-label drug combination had devastating results: Many patients ended up with severe, and potentially deadly, heart valve damage, an outcome that triggered a multi-billion dollar lawsuit. In 1997, the FDA ordered Fen-Phen off the market.

Although some off-label therapies can be beneficial and even lifesaving for some patients, in most cases, there is little or no scientific evidence to prove they work. In a recent commentary in the Archives of Internal Medicine, three scientists from the National Institutes of Health (NIH) Clinical Center's department of bioethics say that "off-label use has been identified as one aspect of problematic drug prescribing," in part because of inadequate data regarding drug safety and effectiveness for the off-label use.

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An Issue for Doctors

Some doctors may also be confused about a drug's approval status. A surprising number of doctors think a medicine is FDA-approved for something when it is not, Alexander and colleagues recently reported in Pharmacoepidemiology and Drug Safety.

"This is not a trivial issue," Alexander says. "Our findings suggest that some off-label prescribing might be driven by mistaken beliefs about FDA approval and the level of evidence supporting off-label drug use."

Alexander says better strategies and tools are urgently needed to inform doctors about common, off-label uses that pose the greatest harm. Misunderstandings about a drug's approved use or side effects can increase the patient's risk of medication errors and dangerous outcomes.

For example, Alexander's research showed that nearly one in five doctors questioned who prescribed the drug quetiapine (Seroquel) for dementia with agitation mistakenly believed it was approved for such use. But the medicine carries a "black box" warning -- the FDA's sternest warning -- stating that the use of antipsychotic drugs was associated with an increased death risk in elderly patients with dementia.

Psychiatric medicines are among the most common drugs to be prescribed off-label, and their use in children is of special concern. Many drugs prescribed to children are used off-label because medications are less commonly tested in this age group. In March 2009, researchers reported in Academic Pediatrics that 62% of outpatient pediatric visits resulted in an off-label prescription. Children under age 6 were most likely to be prescribed a drug off-label.

Who Is in Control?

Off-label drug use can sometimes evoke negative connotations and may diminish public expectations that drugs will go through the rigorous testing required by the FDA, experts say. Murphy says she'd be more comfortable knowing the medicine she takes was specifically tested for her particular condition.

The big question, Alexander says, is how to best regulate off-label drug use without unduly stifling clinical innovation. Some have called for a greater emphasis on evidence-based prescribing, with stricter rules governing off-label drug use. But others worry that tightening the reins could hinder patients' early access to novel therapies.

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Off-Label, Higher Costs?

Greater promotion of off-label drug uses could have patients reaching deeper into their pockets to cover prescription costs. Health insurance companies closely scrutinize drugs that are used off-label. Although Medicare recently changed its rules to allow for wider coverage of off-label uses of cancer drugs, insurers do not always pay for an unapproved, or unproven, product.

"This trend is likely to continue as coverage decisions target wasteful spending," Emily Largent, BSN, Frank Miller, PhD, and Steven Pearson, MSc, tell WebMD by email. Largent, Miller, and Pearson work for the department of bioethics at the NIH Clinical Center.

Questions to Ask Your Doctor

Doctors aren't required to disclose off-label drug use to patients, and doctors, including Alexander, say doing so would be impractical. So it's important for patients to understand the difference between on- and off-label prescribing. Largent, Miller, and Pearson recommend asking your doctor the following questions whenever you are given a prescription:

  • Is the medication used on- or off-label?
  • What is the evidence behind your decision to prescribe this to me?
  • How certain are you that I am likely to benefit from this medication?

If the drug is being used off-label, you may want to check with your insurance company to make sure it's covered. You might also consider asking your doctor if there are any clinical trials studying the off-label use in which you could enroll. A number of clinical trials are being done to test the safety and effectiveness of off-label drug uses.

WebMD Feature

Sources

SOURCES: 

G. Caleb Alexander, MD, MS, assistant professor of medicine and affiliate faculty, MacLean Center for Medical Ethics, University of Chicago.

Radley, D. Archives of Internal Medicine. 2006; vol 166: pp 1021-1026.

Largent, E. Archives of Internal Medicine. 2009; vol 169: pp 1745-1747.

Walton, S.M. Pharmacotherapy, 2008; vol 28: pp 1443-1452.

News release, University of Chicago.

Stafford, R. New EnglandJournal of Medicine, April 3, 2009; vol 358: pp 1427-1429.

Email from Emily Largent, BSN; Frank Miller, PhD; and Steven Pearson, MSc, department of bioethics, NIH Clinical Center.  

Consumer Reports: "Off-Label Drug Use: The Pros and Cons."

News release, Children's Hospital of Philadelphia.

American Cancer Society: "Off-Label Drug Use."

Bazzano, A. AcademicPediatrics, March 2009; vol 9: pp 81-88.

American Medical Association: "Report 10 of the Council on Scientific Affairs (A-05): Safety and Efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) in Children and Adolescents, November 21, 2009."

Chen, D. Pharmacoepidemiology and Drug Safety, November 2009; vol. 18: pp 1094-100.

Dresser, R. The Journal of Law, Medicine & Ethics, Fall 2009; vol. 37: pp 476-86, 396.

U.S. Department of Justice: "Settlement Agreement."

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