I recently read a general news article in my local newspaper (Smith, 2012) that reported on the recent U.S. Food and Drug Administration (FDA) approval of two weight loss drugs: Belviq® (lorcaserin) and Qsymia™ (phentermine and topiramate extended release). The author, a local consumer health writer for the newspaper, stated that “Qsymia, approved on Tuesday, is a combination of two drugs approved long ago by the FDA: phentermine, an appetite suppressant, and topiramate extended release, which is used for seizures, migraines, and bipolar disorder but was discovered to also cause unintentional weight loss” (Smith, 2012, para. 3). After reading the article, I sent a brief e-mail to the author and told her that I thought it was unfortunate and misleading that she had described topiramate (Topamax®) as being used for the treatment of bipolar disorder. I explained that topiramate does not have an FDA-labeled indication for bipolar disorder and that none of the five randomized double-blind controlled studies found topiramate to be effective in the treatment of bipolar disorder. I included copies of the two published papers describing these negative findings (Chengappa, Schwarzman, Hulihan, Xiang, & Rosenthal, 2006; Kushner, Khan, Lane, & Olson, 2006). In her response to my e-mail, the author commented that, “While topiramate does not have an FDA-labeled indication for bipolar disorder, it is sometimes used off-label for that purpose” (P. Smith, personal communication, July 19, 2012).
Although I know that topiramate is used off label for the treatment of bipolar disorder, why would I believe the author’s comment was unfortunate and misleading? Prescribing medications for off-label uses is legal, but is it necessarily appropriate? How does a clinician decide whether off-label prescribing is appropriate? In this month’s article, I will discuss the issue of off-label medication use.
What is Off-label Prescribing?
Drugs that are approved for marketing by the FDA carry a product label, which includes information about the drug’s clinical pharmacology; what the drug is to be used for (its indication); the patient population for which the approval was granted; the recommended dosage range and duration of treatment; and contraindications, warnings, precautions, and adverse effects of the drug. Product label information is based on data derived from studies submitted to the FDA during the approval process. Product labels of approved drugs can be revised to include new information about other indications, additional patient populations, drug dosing, and so on, but these changes occur only after the submission of additional clinical studies.
The most common types of off-label prescribing are using medications for unapproved indications and use outside of the recommended dosage range (i.e., high doses) or duration of use (e.g., long-term use of hypnotic drugs). Less commonly, off-label prescribing may include use of a drug in certain unapproved patient populations, such as those defined by age (pediatric or geriatric age groups), sex (e.g., use of male hormone products in women), or particular clinical parameters (e.g., use of weight loss products in patients that do not meet body mass index criteria for obesity). In rare situations, off-label prescribing might even include the intentional use of a medication in a patient who has a known contraindication.
How Do Clinicians Decide Whether a Medication Can be Prescribed Off Label?
Typically, a drug would be considered appropriate for off-label use based on its known clinical pharmacology, evidence from clinical studies, and sometimes from the personal experience of the prescriber. Knowledge about the pharmacology of a drug and its putative mechanism of action can be used to justify its use for an unapproved indication. Similarly, the known pharmacokinetic properties of a drug (i.e., absorption, metabolism, clearance) can be helpful to support the use of unapproved higher doses in some patients. All drugs are approved based on randomized controlled studies for particular indications. Many drugs are further studied by independent investigators, such as for conditions outside of the product labeling, in other patient populations, in combination with or in comparison to other therapies. Such studies might be supported by funding from manufacturers, but not necessarily with the intent of pursuing a new indication or a product label change.
The best clinical evidence for considering the off-label use of a drug should be based on randomized clinical trials. Useful but less stringent evidence can be found in prospective open-label studies or retrospective chart review studies, especially if the number of participants in the study is large. Case reports or case series involving small numbers of patients are less helpful, although such reports might highlight certain aspects of a drug’s pharmacology or particular patient characteristics that are relevant to considering the off-label use of the drug. Published guidelines (e.g., expert opinion panels, consensus conferences, practice guidelines) can sometimes provide support for the off-label use of a drug, as these sources often comprehensively gather and rigorously evaluate the type and quality of evidence available.
Readers should be aware of potential conflicts of interest and publication bias when considering published studies that might pertain to the off-label use of a drug. Investigators, not just study sponsors, can have a vested interest (either financial or intellectual) in publishing their work or ideas, especially if the findings are interesting or positive. Negative studies or unfavorable findings are less likely to be published. Publicly accessible databases that contain unpublished information about clinical trials and their results are an important resource for obtaining unbiased information about drug effectiveness (Howland, 2011).
When Should Clinicians Use a Medication off Label?
The decision to use a drug off label should be based on a careful assessment of the patient’s treatment history, as well as the drug’s potential risks and anticipated benefits. Have other drugs approved for an indication been tried before considering using a medication off label? Are there valid clinical reasons to try a medication off label and avoid the use of an approved drug for a patient? Does the pharmacology of the proposed drug justify its off-label use? Is there clinical evidence from other studies to support its use? Does the chronicity, severity, or disability associated with the patient’s condition justify using a drug for an off-label indication, dosage, or duration of treatment?
When a decision is made to use a medication off label, patients should be given adequate informed consent. The way in which the drug is being used off label should be clearly stated, whether it is for an unapproved indication, at a dosage outside of the recommended range, for a duration longer than recommended, with an age or sex for which it is not approved, or in the presence of a contraindication. In addition, the reason(s) for the off-label use should be carefully explained. Finally, the known risks or side effects of the medication, based on the product’s label as well as other clinical studies or the prescriber’s experience with the drug, should be reviewed with the patient. Because insurance companies sometimes decline to pay for medications that are being used off label, all of this information can be used to justify the off-label use during an appeal for an insurance denial.
Different types of off-label prescribing can occur, and such use can be considered clinically appropriate if there is adequate justification and the relative risks and benefits are favorable. Using topiramate as an example, it is indeed used off label for the treatment of bipolar disorder, but such use cannot be easily justified because multiple controlled studies have demonstrated no benefit. Moreover, because bipolar disorder is a severe and chronic mental disorder, using such a medication off label might be considered inappropriate, especially if other approved drugs (for bipolar disorder) or unapproved drugs (having better supporting evidence in the treatment of bipolar disorder) are not used. Nurses in clinical practice, including those advanced practice nurses who have prescriptive privileges, should be knowledgeable about the reasons for using medications off label, the criteria for considering off-label medication use, and the importance of informed consent when medications are used off label.
- Chengappa, K.N.R., Schwarzman, L.K., Hulihan, J.F., Xiang, J. & Rosenthal, N.R. (2006). Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: A randomized placebo-controlled trial. Journal of Clinical Psychiatry, 67, 1698–1706. doi:10.4088/JCP.v67n1105 [CrossRef]
- Howland, R.H. (2011). What you see depends on where you’re looking and how you look at it: Publication bias and outcome reporting bias. Journal of Psychosocial Nursing and Mental Health Services, 49(8), 13–15. doi:10.3928/02793695-20110705-06 [CrossRef]
- Kushner, S.F., Khan, A., Lane, R. & Olson, W.H. (2006). Topiramate monotherapy in the management of acute mania: Results of four double-blind placebo-controlled studies. Bipolar Disorders, 8, 15–27. doi:10.1111/j.1399-5618.2006.00276.x [CrossRef]
- Smith, P. (2012, July19). FDA approves two drugs to aid weight loss. Pittsburgh Post-Gazette. Retrieved from http://www.post-gazette.com/stories/news/health/fda-approves-two-drugs-to-aid-weight-loss-645210