Off-label drug use: The risk vs benefit analysis

By Samar Mahmoud, PhD | Fact-checked by Barbara Bekiesz
Published August 28, 2023

Key Takeaways

  • Off-label use of drugs is common, and the practice has the potential to provide benefit to patients—particularly for those for whom no other treatment option is available or for groups excluded from clinical trials. 

  • There are risks associated with off-label drug use, including a higher likelihood of adverse events. 

  • HCPs should exercise caution when prescribing off-label drugs, taking into account the benefits and potential risks. 

The FDA’s role is to regulate drug marketing and ensure the safety of drugs and devices in the United States. However, once a drug is approved, physicians can legally prescribe these medications for purposes other than their approved indications, as described in the product labeling. 

While off-label use can benefit patients, it is not without risks. 

What constitutes off-label drug use?

Off-label use may include the following situations, as discussed in a review published in JACC: Basic to Translational Science:[]

  • Prescribing a drug or a device for a purpose other than the one it was approved for by the FDA

  • Prescribing a drug in a dosage or route of administration that was not tested during the FDA’s drug approval process

  • Prescribing a drug or device to a different patient population than the one involved in the clinical phase trials

Off-label drug prescriptions are common, according to the review author, constituting approximately 21% to 32.3% of all prescriptions. The prevalence of off-label use is highest among cardiovascular drugs—with the exception of antihyperlipidemic and antihypertensive medications—and lowest among diabetes medications.[] 

Benefits of off-label use 

Off-label drug use has the potential to offer patients a treatment option or relief from symptoms in the event that no other treatment modalities exist.[] 

In other cases, off-label use allows patients who were excluded from clinical trials to receive treatment. 

Risks of off-label use 

The JACC: Basic to Translational Science review article lists some potential risks of off-label drug use, including: 

  • Discouraging drug manufacturers from conducting clinical studies to ensure that a drug is safe and effective when used off-label 

  • Exposing patients to unproven treatments that potentially have no benefit

  • Increasing patients’ risk of drug-related adverse events 

  • Undermining the mission of the FDA 

A 2016 study published in JAMA Internal Medicine found that off-label drug use was associated with a 44% greater likelihood of adverse events in adults.[] 

In children, studies have indicated greater risk of adverse events, with the relative risk for off-label use in comparison to on-label use being as high as 3.44.[] These results indicate that healthcare providers should exercise caution in prescribing drugs for off-label use. 

As the review article points out, off-label use also commonly occurs in vulnerable patient populations that have been historically under-represented in clinical studies, such as pregnant women, children, the elderly, and patients with mental health conditions. 

Recent work found that up to 97% of pediatric inpatients were exposed to at least one off-label drug prescription. 

Tips for HCPs

For HCPs who are considering prescribing a drug for an off-label use, the JACC: Basic to Translational Science article advises them to ask themselves the following questions: 

  • Does the off-label use constitute a medical necessity? 

  • Are there peer-reviewed studies on the off-label use of the drug or device?

  • Is the off-label use of the medication or device non-experimental? 

In addition to these questions, there are benefit and risk assessment frameworks that have been developed, such as BRAvO, which is a tool to aid HCPs in evaluating the use of off-label drugs in children. 

The BRAvO framework takes into consideration the problem, objectives, alternatives, consequences, trade-offs, uncertainty, risk attitudes, and linked decisions.  

What this means for you 

Off-label drug use can provide treatment options and symptom relief to patients who may not have an alternative treatment available. However, HCPs should be wary of prescribing drugs for off-label use and should weigh the risks and benefits for each patient case by case. HCPs should ask themselves if there is sufficient peer-reviewed data to justify the off-label use of a drug or device and if the off-label use is medically necessary. 

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