Studying the Issue of Off-label Prescribing in Primary Care

Abstract & Commentary

By Rahul Gupta, MD, MPH, FACP

Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV

Dr. Gupta reports no financial relationships relevant to this field of study.

Synopsis: Off-label prescribing is common in primary care and most of the time lacks the scientific evidence to support it.

Source: Eguale T, et al. Drug, patient, and physician characteristics associated with off-label prescribing in primary care. Arch Intern Med 2012;172:781-788.

SIMPLY PUT, OFF-LABEL PRESCRIBING CAN BE DEFINED AS THE prescribing of a drug or medical device outside its licensed indication to treat a condition or disease for which it has not specifically received regulatory approval. For prescription drugs, the Food and Drug Administration (FDA) approval process is a complex one that requires submission of substantial evidence of efficacy and safety for specific clinical conditions. In the United States, based on the principle that the physician should partner with the patient to make the best treatment decision possible, it is legal for physicians to prescribe off-label drugs. Omission from the approved label does not mean that the FDA disapproves of an off-label use, it simply indicates that the agency has not reviewed that specific use.

Unlike the use of drugs prescribed for FDA-approved indications, off-label uses may lack rigorous scientific scrutiny. In 2001, a study demonstrated that off-label prescribing accounted for 21% of overall use for 160 commonly prescribed drugs in the United States.1 Off-label use was most common among cardiac and anticonvulsant medications and most off-label drug use had little or no scientific support. When an off-label use lacks such scientific basis, the potential for harm is the greatest. However, the risks and benefits of off-label prescribing have not been meticulously studied. As more and more physicians begin to use electronic health records (EHR), meeting the meaningful use requirement, including e-prescribing, and before having to provide an indication for each drug prescribed will become the norm, rather than the exception. Therefore, it is important that we understand the particular drug, patient, and physician characteristics associated with off-label prescribing in primary care.

In their study, Eguale et al used an EHR system to obtain prescription data from 113 primary care physicians in Quebec, Canada, from January 2005 to December 2009. A total of 253,347 electronic prescriptions for 50,823 patients were written during this period and treatment indication entry for prescriptions was mandatory. Any indication that could not be matched to the labeled therapeutic indication reported in the drug’s package insert was considered off-label. Additionally, for each off-label use, methodology was used to determine whether there is strong scientific evidence for the off-label use of a drug for a particular treatment indication.

The researchers found that 11% of all prescriptions were prescribed for off-label indications and the results showed that 79% of off-label use lacked strong scientific evidence. Further, they discovered that the highest percentage of off-label prescriptions were for central nervous system medications (26.3%), with 17.1% for anti-infective agents followed by 15.2% for ear, nose, and throat medications. Among central nervous system medications, the highest proportions of off-label use were for anticonvulsants (66.6%), antipsychotics (43.8%), and antidepressants (33.4%). Additionally, among specific drugs with the highest off-label use were quinine sulfate (99.5% of total prescriptions), followed by gabapentin (99.2%), clonazepam (96.2%), amitriptyline (93.7%), trazodone (92.6%), and betahistine (91.5%). Medications with three or four approved indications were associated with lower off-label use compared to those with one or two approved indications. Sicker patients had lower off-label use than their counterparts. Medications approved after 1995 were also associated with lower off-label use than those approved before 1981. Physicians with high scores on evidence-based practice were less likely to prescribe off-label.


Like many things in life, there is no simple answer to the issue of off-label prescribing. In an ideal world, all uses of a prescription drug would be well analyzed and found to be safe and effective. However, in reality, when a physician writes a prescription, patients often assume that the drug has been tested and approved for the specific use by the FDA. While reasonable, that assumption does not hold true in one in every five prescriptions written in the United States. Such off-label use is both legal and often beneficial. Examples include the common use of some of the beta-blockers for performance anxiety and anticonvulsants for migraine prophylaxis. However, sometimes this type of use in the absence of rigorous scientific data can cause significant harm, as exemplified by drugs such as Fen-Phen, which led to cardiac valve damage in patients. So, the idea is neither to reject nor to encourage the use of off-label prescribing but rather to understand the process better in order for physicians to effectively use it.

It is important to note that there is a significant gap between what approved/indicated drugs are available and the needs of the primary care physician in a busy practice. While there is no doubt that with the implementation of health reform and EHR the scrutiny will increase over the proper utilization of health resources, including off-label prescribing, it would be a mistake to attempt to eliminate it. Patients do benefit from off-label prescribing that is supported by sound scientific and medical evidence. Physicians’ autonomy to prescribe drugs off-label carries important advantages. It recognizes that clinical practice has many more challenges than can be classified into drug categories, and innovation at the clinical level allows discovery as well. However, gaps in clinical innovations and data scrutiny must be filled by an aggressive clinical effectiveness research agenda that focuses on the scientific support for drug indications that may not necessarily be FDA approved. The current study by Eguale et al attempts to initiate this process by better understanding the various characteristics associated with off-label prescribing. As EHRs are implemented, it may be wise for the Centers for Medicare & Medicaid Services to consider systematically collecting post-marketing data to quantify harms and benefits of common off-label drug uses to develop evidence for their use on a case-by-case basis as may be appropriate. This will help to better guide physicians’ clinical decisions as to where it is most appropriate to use off-label drugs vs scenarios that compromise patient safety and/or represent wasteful use.


1. Radley DC, et al. Off-label prescribing among office-based physicians. Arch Intern Med 2006;166:1021-1026.