1-in-5 Prescriptions Are Off-Label: What You Don’t Know Could Hurt You

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The headline may be hard to believe, but it’s true: One-in-five U.S. prescriptions are written “off-label,” meaning in a manner that has not been approved by the U.S. Food and Drug Administration.

Examples of off-label uses include antidepressants for chronic pain, high blood pressure beta-blockers for migraines, antipsychotics for insomnia and dementia, and seizure medicine for fibromyalgia.

“Many consumers aren’t aware that doctors are free to prescribe as they wish in accordance with good medical practice, they’re not constrained to using products only for FDA-approved indications,” Dr. Caleb Alexander, professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health, told MedTruth. “And that will come as a surprise.”

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Not only are doctors not required to disclose off-label use, doctors themselves often don’t know the status of a drug, according to a 2009 national survey of about 1,200 primary care physicians and psychiatrists co-authored by Alexander.

Nearly half the time, surveyed physicians incorrectly identified the FDA status of drugs paired with particular conditions.

“There’s very clear statutory limits on the FDA in terms of its interference with medical practice, and that goes back to the initial legislation that created the FDA,” Dr. Randall Stafford, professor of medicine at Stanford School of Medicine and director of the Program on Prevention Outcomes and Practices, told MedTruth.

Changing this framework, Stafford said, would take away some of the autonomy and decision-making power that the current policy gives doctors.

The FDA does, however, prohibit drug companies from promoting off-label uses. However, that doesn’t mean drug companies always comply.

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“On-Label:” The Arduous FDA Drug Approval Process

The FDA’s Center for Drug Evaluation and Research evaluates brand name and generic drugs before they can be sold — a costly multi-stage discovery and development process followed by multiple phases of randomized control trials in humans. On average it costs $2.6 billion and can take 6–8 years to bring a new drug to market. Currently, only 12% of drugs make it.

When the FDA approves a medication, it’s limited to specific condition(s), populations, age-ranges, usages and dosing for which the drug is deemed reasonably safe and effective. For instance, a drug may be approved in tablet form but not liquid. Note the granularity of the FDA’s medication guide for Seroquel, an atypical antipsychotic approved in 2007 also sold generically as quetiapine.

SEROQUEL is a prescription medicine used to treat:

  • schizophrenia in people 13 years of age or older
  • bipolar disorder in adults, including:
    depressive episodes associated with bipolar disorder
    manic episodes associated with bipolar I disorder alone or with lithium or divalproex
    long-term treatment of bipolar I disorder with lithium or divalproex
  • manic episodes associated with bipolar I disorder in children ages 10 to 17 years old

It is not known if SEROQUEL is safe and effective in children under 10 years of age.

What Does Off-Label Prescribing Look Like?

It’s important to recognize that there’s a wide spectrum of off-label uses — a whole continuum, Stafford said, with some uses being more logical and less extreme than others.

Stafford offered an example of “lightweight” off-label use: If an FDA-approved heart failure medication is dosed three times a day, Stafford said that for patient convenience, he might prescribe an off-label drug in the same class, with the same action, that’s dosed only once a day.

Which Groups Often Receive Off-Label Prescriptions?

Some populations, such as children, the elderly, pregnant women and psychiatric patients are often excluded from drug trials, making off-label prescribing more likely with these groups.

A 2015 study found that outpatient pediatric patients who were prescribed pharmaceuticals received at least one off-label prescription nearly 40% of the time. According to WebMD, psychiatric drugs are among the most commonly prescribed off-label, and their use in children is especially concerning.

Off-label prescribing also happens when there are limited or no FDA-approved treatments for a condition, or when approved treatments have been exhausted without success.

Cancer drugs are often approved for one type of cancer but then found effective for other types of tumors, according to the American Cancer Society. Cancer patients may have very limited options when it comes to FDA approved treatments, making oncologists and cancer patients perhaps more willing to go off-label than other specialties. In fact, off-label use is often the standard of care for certain cancer diagnoses or stages.

“Part of the conundrum of off-label prescribing is that sometimes it’s not only reasonable, but it’s best practice,” Alexander said. “What happens is that information comes in from many, many different sources regarding a product when it’s in development and especially once it’s on the market. Some of these may not be FDA approved but may have some evidence behind them — and word travels.”

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Risks of Off-Label Prescribing

However, off-label drug use can also pose serious, even life-threatening, risks.

For instance, the antipsychotic Seroquel is used off-label to treat “an expansive array of ills, including insomnia, post-traumatic stress disorder and agitation in patients with dementia,” according to a Washington Post report. Doctors prescribing Seroquel off-label, however, may lack understanding of psychiatry and of Seroquel’s risks, including but not limited to weight gain, constipation, high blood sugar, high cholesterol and triglycerides, drowsiness, seizures, cataracts, possibly irreversible tardive dyskinesia (uncontrolled body movements), low blood pressure, low white blood cell count, and suicidal thoughts and actions.

An Institute for Safe Medication Practices analysis found that more than half the off-label related FDA adverse event reports for Seroquel from 2004–2010 involved prescriptions for insomnia and other sleep disorders, as reported by the Post.

“The fact is that there’s not a lot of good evidence that Seroquel should be used as a sleeping drug alone. I would say that’s a more suspect case of that process of extending into off-label use,” Stafford said.

It gets worse.

Multiple studies have shown that Seroquel and other atypical antipsychotics may nearly double the risk of death in elderly patients with dementia, prompting the FDA in 2005 to request a “Black Box Warning,” the agency’s most serious product label warning, on Seroquel and related drugs.

A Washington Post analysis of FDA adverse event reports over a more than four-year period revealed that Seroquel was suspected as the primary cause of death in 1,754 cases, 93% of which involved off-label prescribing.

“Ultimately the value of a medicine depends crucially upon the balance of risks and benefits,” Alexander said. “All too often off-label indications are under-studied, that is, we have relatively little information about the risk-benefit balance of products in these settings.”

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Off-Label Profits, Maximized

Given the FDA drug approval process, it’s not hard to understand why drug companies might hesitate to re-submit drugs for approval for novel indications, and why they might welcome off-label drug sales.

“It’s in pharmaceutical companies’ interests to see product uses expanded because the more uses for a product, the more revenue, the greater the return on investment. Manufacturers are keenly interested in identifying and encouraging additional uses of their product as you would expect them to be as a profit-maximizing firm,” Alexander said.

Profit maximizing indeed.

State and federal lawsuits have alleged that global health giant AstraZeneca, one of the five largest pharmaceutical companies in the world with more than 64,000 employees, aggressively encouraged off-label prescribing of Seroquel. The federal lawsuit alleged that AstraZeneca illegally paid doctors to promote off-label use by conducting studies, writing articles and making presentations to other doctors. Denying any wrongdoing, AstraZeneca settled with the federal government in 2010 for $520 million, a small cost of doing business compared to the more than $36 billion in revenue Seroquel generated between 2006–2018.

Patient Resources and Information

Concerned about off-label prescribing? There are a few ways to figure out whether a medication is being prescribed off-label:

  • Look for approved indications on drug product labels or package inserts and on drug information sheets usually provided with prescriptions.
  • Ask your pharmacist.
  • Visit the U.S. National Library of Medicine’s Daily Med online drug resource page.
    Type a generic or brand name drug into the search bar at the top.
    When results appear, select the form of the drug and the manufacturer.
    Then scroll down and click on section 1, “Indications and Usage.”
  • Ask a reference librarian for assistance researching drugs online.

If you or a loved one are considering or already taking an off-label prescription, your prescriber should be able to provide the following information:

  • What evidence is there for the safety and effectiveness of this off-label use?
  • What are the possible side effects and risks?
  • How commonly is this drug used off-label? For how long?
  • What FDA approved treatments are available?
  • What makes the off-label treatment superior to approved treatments?
  • Does health insurance cover this off-label use? (You may need to contact your health insurer.)

By Carah Wertheimer

Carah Wertheimer is an editor and reporter based in Boulder, Colorado. Her areas of specialization include food, health, environment, social justice and community reporting. Her work has appeared in National Geographic, The Denver Post, The Daily Beast, the Boulder Daily Camera, Boulder Weekly and other publications.

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MedTruth is a digital magazine reporting on health, safety and justice. Join the revolution today at https://medtruth.com/.

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