Off-Label Prescribing: What you don’t know could hurt you

pill bottle with pills over moneyMany Canadians would be surprised to learn that many of the drugs they (or their children) are prescribed have never been tested or approved for the use being considered. They might also be shocked to learn that in many cases the drugs are being prescribed “off-label” without any strong evidence that they are effective.

Off-label prescribing is the prescribing of a drug to treat a condition for which it has not been tested or approved. An elderly patient in a nursing home may be anxious or having trouble sleeping and then be prescribed a drug which has only been tested and approved for schizophrenia even though the patient does not have schizophrenia. In addition, the drug may be associated with serious and sometimes fatal side effects including confusion, cognitive problems, diabetes and falls.

A child who is having adjustment problems in school may be prescribed an SSRI antidepressant even though the drug has never been tested on the growing brains or bodies of children and is associated with suicidality.

Although off-label prescribing by physicians is legal in Canada, it is illegal for pharmaceutical companies to promote drugs directly for off-label use. Despite this, drug companies use a range of strategies to implicitly or explicitly promote off-label prescribing. All  the major drug companies have been found in contravention of the laws on off-label prescribing and have been ordered to pay millions or billions of dollars in fines. These fines have not been effective in ending the promotion of off-label prescribing.

Because off-label prescribing is neither regulated nor tracked an accurate measure of the prevalence of such prescribing is impossible to determine. Only one recent Canadian (Quebec) study has looked at the frequency, type and potential risks of off-label prescribing. This study determined that the overall prevalence of off-label prescribing was 11% of all prescriptions but was highest for psychiatric drugs. For example, 43% of all anti-psychotics were prescribed off-label, as were one-third of antidepressants. In cases of specific drugs such as quinine sulfate (Qualaquin), gabapentin (Neurontin) and clonazepam (Klonopin) over 95% of the prescriptions were off label.

U.S. studies have estimated that off-label prescribing occurs with 21% of prescribed drugs. The highest rates of off-label prescribing were for anticonvulsants (74%), antipsychotics (60%) and antibiotics (42%). It is sobering to realize that some of these drugs are being prescribed to hundreds of thousands of patients.

Drugs that have been approved for only a few indications and that are expensive are most commonly prescribed off-label. Off-label prescribing is also common in relation to what are called “orphan diseases.” These are diseases that have no clear diagnostic criteria or with no effective treatments. Some of these diseases are also promoted through disease mongering (e.g. fibromyalgia, nocturnal leg pain, anxiety, insomnia or benign postural vertigo). Many of these conditions are experienced by women. Patients who are prescribed drugs off-label are frequently exposed to adverse drug reactions even though most of the drugs have no proven evidence of efficacy for these conditions. For example, the use of quinine for nocturnal leg cramps, an off-label indication, results in serious adverse drug events including thrombocytopenia and gastrointestinal bleeding.

Kesselheim has described three main situations in which pharmaceutical companies illegally promote off-label prescription drug use.

  1. Expansion of drug use to other diseases for which the drug has not been tested or approved. Gabapentin was approved to treat a rare type of seizure disorder and a specific type of pain but was later promoted widely for patients for at least eleven unapproved  medical conditions such as bipolar disorder, other pain syndromes or restless leg syndrome. The company pleaded guilty to criminal and civil charges for the illegal promotion of the drug for uses that were not shown to be safe or effective.
    In Canada the drug Domperidone is being prescribed off-label to increase the milk supply of breast-feeding mothers although it has never been approved or tested for this use. The drug is banned in the United States because of its potential for serious side effects related to heart rhythm problems. Concerns have been raised about potential risks to babies who receive the drug through breast-feeding.
  2. Expansion of prescribing to include new patient groups such as children – e.g. most psychiatric drugs have never been tested or approved for children.
  3. The promotion of higher dose levels for which the drug has not been tested or deemed safe.

Although serious criminal fines have been levied against all the major drug companies for off-label promotion in the past ten years, the costs of these fines has not even approached the profits gained through off-label drug sales. According to David Evans,

As large as the penalties are for drug companies caught breaking the off-label law, the fines are tiny compared with the firms’ annual revenues. The 2.3 billion in fines and penalties Pfizer paid for marketing Bextra and three other drugs…amounts to just 14% of its 16.8 billion in revenue for selling those medicines from 2001 to 2008. The total of 2.75 billion Pfizer has paid in off-label penalties since 2004 is little more than 1% of the company’s revenue of $245 billion from 2004 to 2008.

Most of our information about promotion comes from US whistleblower evidence (whistleblowers in the US, at least theoretically, have some protection). Researchers have identified four main types of marketing practices that companies use to illegally promote off-label use. These are:

  1. Promotion directed to prescribing physicians – The presentation of favourable studies, journal publications, the exaggeration of positive results in direct conversations with physicians or at seminars, giving physicians free samples with the recommendation to use them for off-label use, encouraging off-label use through financial incentives or gifts and physicians being invited to participate in focus groups or as thought leaders.
  2. Internal company policies and practices
  3. Payor-related strategies – This involves drug companies advising insurers about reimbursements for off-label prescribing.
  4. Consumer-related practices – Includes companies identifying consumers who would likely consider off-label prescribing and bringing those patients to a physician’s attention or providing payments to non-profit consumer disease (astro-turf) organizations in exchange for their support for off-label drug use. Other tactics involve the provision of indigent patients with gifts in order to induce them to seek out prescriptions of off-label drugs.

In about 80% of the cases where drugs are commonly prescribed off-label there is no proven evidence of efficacy. For example, psychiatric drugs are routinely prescribed off-label and in at least 90% of these cases have no strong evidence base.

One of the most serious impacts of off-label prescribing is that it creates a loophole for drug manufacturers to bypass regulatory oversight which exists to protect public health. Having such significant loopholes “normalizes” non-regulation which establishes a dangerous precedent.

What should be done about off-label prescribing?

Canadians have the right to know whether the drug they are being prescribed has been tested and approved for their health problem, the reasons why an off-label drug is being recommended and the “evidence-base” upon which the off-label prescription is being made.

Wilkes and John recommend that an informed consent process be implemented with patients by their doctors whenever off-label prescribing is done and that the process address the following four questions:

  1. Is the drug approved for the condition it is being prescribed to treat, or is it being prescribed off-label in Canada?
  2. Is there an approved drug (including generic medication) that has been tested as an acceptable alternative?
  3. What are the advantages and potential benefits of the off-label drug use?
  4. What credible research/evidence supports off-label use for the medical problem being addressed?

Health Canada and monitoring agencies such as the Drug Safety and Effectiveness Network (DSEN) need to monitor off-label prescribing through the routine linking of patient diagnostic and prescribing records to determine its extent. Only one study of this type has been completed in Canada. Studies should also assess the costs of off-label prescribing to employer-sponsored health benefit plans.

Drug companies should be required to collect systematic scientific data on drugs that are prescribed off-label and to seek market authorization for these uses. As a regulator, Heath Canada should make this a legal requirement.

About the Contributor

Janet Currie is a consumer advocate for the safe and informed use of prescription drugs and medical products. She runs a website on the risks associated with psychiatric drugs and sleeping pills and the pathologizing of normal human phenomena ( She was a member of Health Canada’s Expert Advisory Committee on the Vigilance of Health Products between 2007-2011) and she co-edits the Pharmawatch blog with Colleen Fuller.