Do’s And Don’ts For Off-Label Prescribing


By Naveed Saleh, MD, MS

According to US Department of Health and Human Services, one in five prescriptions is written for an off-label use—that is, an indication not approved by the FDA. Now consider that only an estimated 30% of off-label prescriptions are evidence based. Makes you think twice about the practice, doesn’t it?

The issue of off-label drug use is a quagmire of ethical and legal issues. It brings to mind either great benefit or great harm to patients. Furthermore, off-label prescription has been tainted by the influence of pharmaceutical companies, which, in part, has resulted in major lawsuits and out-of-court settlements.

To understand the issue of off-label prescribing in a clinical sense, it’s probably best to look at it from the perspectives of the physician, the patient, regulatory agencies, and pharmaceutical companies.

Physicians and off-label prescription

Importantly, the FDA does not stop physicians from prescribing drugs off-label, and Congress has taken many steps to protect this practice in a general effort to keep the FDA from impinging on the practice of medicine by physicians.

Nevertheless, many lawsuits have been filed by patients who were prescribed medications for off-label use. In these lawsuits, patients have argued that they did not give informed consent because their physicians never informed them of the off-label use in the first place. In these cases, judges usually side with physicians, with the finding that physicians have no legal obligation to inform patients about a drug’s regulatory status.

Physicians tend to prescribe off-label under three primary circumstances: the urgent need for a new drug or indication, evidence of on-label inefficacy in certain demographics, and cost effectiveness for the patient.

First, advances in clinical practice often outpace the FDA’s capability to green-light new drugs or re-label previously approved drugs with new indications. Getting a new drug approved can take 6-8 years and cost a little under $2 billion. Furthermore, the financial incentive for a pharmaceutical company to seek additional indications once a drug has been approved is often scant, given the high cost associated with conducting the necessary clinical trials.

Second, physicians may prescribe off-label when there is little evidence of effective on-label use in certain populations, such as in the elderly, children, pregnant women, and patients with mental health disorders.

“In psychiatric patients, in particular, symptom similarity between disease states might contribute to use of one medication off-label for various conditions. Specifically, off-label use of antidepressants, anticonvulsants, and antipsychotics is high and such use increases in prevalence with patients’ advancing age,” noted the authors of a commentary.

Third, in an effort to save a patient out-of-pocket costs, a physician may prescribe an off-label dosage and then instruct the patient on how to dose the new prescription. For instance, the 5α-reductase inhibitor finasteride is approved to treat benign prostatic hypertrophy, and is marketed as Proscar at 5 mg/day, for a cost of only a few dollars per month. On the other hand, finasteride 1 mg/day is approved by the FDA to treat androgenic alopecia when sold as Propecia, for the cost of several hundred dollars per month. The ethical concept of beneficence would guide a physician to prescribe the far less expensive Proscar to a patient with male-pattern baldness and then teach the patient to cut the pills in quarters (ie, 1.25 mg) for daily administration.

The problem with this type of off-label prescription, however, arises when the physician purposefully documents the patient as having benign prostatic hypertrophy instead of alopecia to get the prescription covered by insurance. Some physicians are fine with this duplicity as long as it secures the necessary care for their patients, thereby obviating the need for a lengthy appeals process.

“Although misrepresenting a diagnosis to gain insurance coverage may positively impact that individual patient, the repercussions are pervasive and compromise both the implied and contractual code of trust between providers and insurers. Routine breach of this trust by physicians could create an environment of strict guidelines that disrupt the efficiency of delivering patient care. In addition, misrepresenting a diagnosis could negatively impact the patient’s future care because the medical record will be used by other providers to make decisions,” wrote University of Pennsylvania researchers Shridat A. Jadoo and Jules B. Lipoff, MD, in a case scenario.

Here are some additional examples of drugs that are often prescribed off-label:

  • Erythromycin for gastroparesis
  • Omeprazole for reflux-related laryngitis
  • Meperidine for postanesthetic shivering
  • Propofol for intracranial hypertension
  • Albuterol for hyperkalemia
  • Gabapentin for bipolar disorder, diabetes, fibromyalgia, neuropathic pain symptoms, headache, hiccups, hot flashes, and restless leg syndrome
  • Sildenafil for sexual dysfunction in women
  • Magnesium sulfate for premature labor
  • Trazodone for insomnia in the elderly
  • Spironolactone for acne, female-pattern hair loss, and hirsutism in women
  • The interests of pharmaceutical companies

    As can be expected, it’s in the best interest of drug companies to inform prescribing physicians of indications for off-label drug use. Doing so translates into more sales without the cost of seeking additional FDA approval.

    In the past, the FDA strictly regulated off-label promotion, and its position was that approved drugs that are advertised for an unapproved use are misbranded. But thanks to two developments, restrictions loosened.

    First, in the 1990s, Congress allowed a limited amount of off-label promotion in the form of “enduring materials,” such as peer-reviewed journals and reference books. In return, the FDA expected these pharamaceutical companies to pursue FDA approval for off-label indications or file an exemption—as in the case of a rare disease that would make the investment financially untenable.

    Second, in the late 1990s, a federal court ruled that FDA provisions on off-label prescription were too constraining in light of the First Amendment’s guarantee to protect free speech. An appellate court dismissed an appeal by the FDA, and reduced limitations by the FDA on off-label promotion to mere guidance. Consequently, the FDA’s jurisdiction over off-label promotion became uncertain and without constitutional boundaries. These legal decisions left the FDA unable to require pharmaceutical companies to pursue FDA approval in exchange for off-label promotion.

    Patients and off-label drug use

    Like everything else related to off-label prescription, the issue of whether to inform patients of this practice is also complex. Several legal experts back a general legal requirement to disclose whether drugs are approved by the FDA for the patient’s condition.

    The Committee on Drugs recommends that physicians use their best judgment to decide whether to discuss a drug’s off-label prescription status and its support in the medical community.

    The FDA advises patients to ask their physicians for more information when being prescribed off-label medicines. So, be prepared for these kinds of questions:

  • What is the drug approved for?
  • Are there other drugs or therapies that are approved to treat my disease or medical condition? What scientific studies are available to support the use of this drug to treat my disease or medical condition?
  • Is it likely that this drug will work better to treat my disease or medical condition than using an approved treatment?
  • What are the potential benefits and risks of treating my disease or medical condition with this drug?
  • Will my health insurance cover treatment of my disease or medical condition with this drug?
  • Are there any clinical trials studying the use of this drug for my disease or medical condition that I could enroll in?
  • Dr. Frader and Dresser suggest that, when off-label treatment either lacks support in the literature or involves a lot of risk or won’t be covered by insurance, physicians should discuss the topic with patients and address what patients would expect to know to make an informed decision.

    Bottom line

    Ultimately, patients need access to beneficial off-label treatments, and physicians can provide this access. However, patients need to be protected from high-risk or ineffective treatment. By keeping abreast with current research and policy regarding off-label drug use, physicians can hone their approach to off-label prescribing and advocate for their patients’ health.


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      • Masthead

      • Editor-in Chief:
      • Theodore Massey
      • Editor:
      • Robert Sokonow
      • Editorial Staff:
      • Musaba Dekau
        Lin Takahashi
        Thomas Levine
        Cynthia Casteneda Avina
        Ronald Harvinger
        Lisa Andonis

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