Exercise Caution with “Off Label” Drug Prescriptions

In order to put a drug on the market in the United States, it must first pass three rounds of testing in human subjects to show not only its effectiveness, but its safety in treating a specific condition or disease. However, once that drug is approved and on the market, a doctor may prescribe it for any condition, a practice known as “off-label” prescribing. Previous studies have shown this to be a very common occurrence. A study in 1985 found that 31 of the 100 most common uses of marketed drugs did not have approval from the FDA. And a study in 2006 showed that of the estimated 21 percent of off-label drug uses in 2001, 73 percent did not have significant scientific support. But despite its scope, prescribing drugs for conditions they aren’t specifically approved for carries unknown risks since often the drug has not been rigorously tested on patients with that condition, and a new report concludes that, in many cases, there is not enough evidence to justify the practice.

To determine which drugs were most in need of additional research to see how effective and safe they are for off-label use, Randall Stafford, M.D., Ph.D., associate professor of medicine at the Stanford Prevention Research Center, convened a panel of nine experts from the FDA, the health-insurance industry, the pharmaceutical industry and academia. “Although previous research has highlighted the substantial frequency of off-label drug use without good evidence, we have identified and prioritized specific drugs warranting attention,” the authors of the new study write in the journal Pharmacotherapy.

The researchers identified 14 widely prescribed medications, many of which are antidepressants and antipsychotics. Topping the list was quetiapine, marketed by AstraZeneca under the brand name Seroquel, an antipsychotic drug approved by the FDA in 1997 for the treatment of schizophrenia. The researchers found that not only did the drug have the highest rate of off-label use with limited evidence (76 percent); it also carries a high price tag, at a cost of $207 per prescription, is heavily marketed and has a “black-box” warning about increased risks of hyperglycemia, high blood pressure and diabetes associated with use of the drug. Also, according to the FDA, older patients with dementia-related psychosis treated with the drug are at an increased risk of death.

Rounding out the top five are the blood thinner warfarin, prescribed off-label to treat hypertensive heart disease; the antidepressant escitalopram (Lexapro), used off-label to treat bipolar disorder; the antipsychotic drug risperidone (Risperdal), used off-label to treat bipolar disorder; and the asthma drug montelukast (Singulair), used off-label for the treatment of chronic obstructive pulmonary disease. The other drugs on the list are:

• Antidepressant bupropion (Wellbutrin) used off-label for bipolar disorder
• Antidepressant sertraline (Zoloft) used off-label for bipolar disorder
• Antidepressant venlafaxine (Effexor) used off-label for bipolar disorder
• Celecoxib (Celebrex) approved for joint sprain/strain, used off-label for fibromatosis—soft tissue tumors
• High blood pressure drug lisinopril (Prinivil, Zestril) used off-label for coronary artery disease
• Antidepressant duloxetine (Cymbalta) used off-label for anxiety
• Antidepressant trazodone (Desyrel) used off-label for sleep disturbance
• Antipsychotic olanzapine (Zyprexa) used off-label for depression
• Epoetin alfa (Procrit, Epogen) approved for the treatment of chronic renal failure, used off-label for anemia from chronic disease

“Off-label prescribing is not based on the same level of evidence as on-label prescribing,” said study lead researcher Surrey Walton, an assistant professor of pharmacy administration at the University of Illinois at Chicago. “Typically, drugs have to pass a number of safety tests, but once they are put on the market, because they have received approval for an on-label indication, they can be used off-label.” Walton went on to explain that most patients aren’t aware that doctors can prescribe a drug for a use other than the one it was approved for.

“It’s not that these off-label uses are necessarily harmful or that these drugs don’t work,” Stafford says. The problem is that no one can be certain, because needed studies haven’t been done. “Clearly, for many of these off-label uses, the manufacturers are benefiting enormously, and in some cases I think one could argue that off-label use has allowed them to circumvent the regulatory process.” Although the regulatory process is not infallible, he says, “it does provide a level of scrutiny” beyond what the off-label uses have received. “When the volume of off-label use of any drug reaches the magnitude that we’re documenting, it suggests a role of the pharmaceutical industry in facilitating these types of uses,” he added.

Although it is illegal for drug companies to actively market their drugs for off-label use, sales representatives are allowed to share studies that support off-label uses. A spokeswoman for the drug industry lobbying group, PhRMA, said her organization could not comment on off-label drug use, and its members do not promote such use. “That’s nothing being driven by our companies,” she said. “This is an activity that our companies aren’t allowed to do under FDA regulations.”

Stafford said he hopes that, in addition to prompting the FDA and other government agencies to study the priority drugs on the list, his research will spur patients to ask their doctors why they are prescribing a particular drug. “A dialogue needs to occur more frequently between physicians and patients regarding the level of evidence that supports a particular use of a drug.”